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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Mapping the Global Network of Extracellular Protease Regulation in <named-content content-type="genus-species">Staphylococcus aureus</named-content></title><author><name sortKey="Gimza, Brittney D" sort="Gimza, Brittney D" uniqKey="Gimza B" first="Brittney D." last="Gimza">Brittney D. Gimza</name><affiliation><nlm:aff id="aff1"><addr-line>Department of Cell Biology, Microbiology & Molecular Biology, University of South Florida, Tampa, Florida, USA</addr-line></nlm:aff></affiliation></author><author><name sortKey="Larias, Maria I" sort="Larias, Maria I" uniqKey="Larias M" first="Maria I." last="Larias">Maria I. Larias</name><affiliation><nlm:aff id="aff1"><addr-line>Department of Cell Biology, Microbiology & Molecular Biology, University of South Florida, Tampa, Florida, USA</addr-line></nlm:aff></affiliation></author><author><name sortKey="Budny, Bridget G" sort="Budny, Bridget G" uniqKey="Budny B" first="Bridget G." last="Budny">Bridget G. Budny</name><affiliation><nlm:aff id="aff1"><addr-line>Department of Cell Biology, Microbiology & Molecular Biology, University of South Florida, Tampa, Florida, USA</addr-line></nlm:aff></affiliation></author><author><name sortKey="Shaw, Lindsey N" sort="Shaw, Lindsey N" uniqKey="Shaw L" first="Lindsey N." last="Shaw">Lindsey N. Shaw</name><affiliation><nlm:aff id="aff1"><addr-line>Department of Cell Biology, Microbiology & Molecular Biology, University of South Florida, Tampa, Florida, USA</addr-line></nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">31645429</idno><idno type="pmc">6811363</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6811363</idno><idno type="RBID">PMC:6811363</idno><idno type="doi">10.1128/mSphere.00676-19</idno><date when="2019">2019</date><idno type="wicri:Area/Pmc/Corpus">001639</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">001639</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Mapping the Global Network of Extracellular Protease Regulation in <named-content content-type="genus-species">Staphylococcus aureus</named-content></title><author><name sortKey="Gimza, Brittney D" sort="Gimza, Brittney D" uniqKey="Gimza B" first="Brittney D." last="Gimza">Brittney D. Gimza</name><affiliation><nlm:aff id="aff1"><addr-line>Department of Cell Biology, Microbiology & Molecular Biology, University of South Florida, Tampa, Florida, USA</addr-line></nlm:aff></affiliation></author><author><name sortKey="Larias, Maria I" sort="Larias, Maria I" uniqKey="Larias M" first="Maria I." last="Larias">Maria I. Larias</name><affiliation><nlm:aff id="aff1"><addr-line>Department of Cell Biology, Microbiology & Molecular Biology, University of South Florida, Tampa, Florida, USA</addr-line></nlm:aff></affiliation></author><author><name sortKey="Budny, Bridget G" sort="Budny, Bridget G" uniqKey="Budny B" first="Bridget G." last="Budny">Bridget G. Budny</name><affiliation><nlm:aff id="aff1"><addr-line>Department of Cell Biology, Microbiology & Molecular Biology, University of South Florida, Tampa, Florida, USA</addr-line></nlm:aff></affiliation></author><author><name sortKey="Shaw, Lindsey N" sort="Shaw, Lindsey N" uniqKey="Shaw L" first="Lindsey N." last="Shaw">Lindsey N. Shaw</name><affiliation><nlm:aff id="aff1"><addr-line>Department of Cell Biology, Microbiology & Molecular Biology, University of South Florida, Tampa, Florida, USA</addr-line></nlm:aff></affiliation></author></analytic><series><title level="j">mSphere</title><idno type="eISSN">2379-5042</idno><imprint><date when="2019">2019</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>The complex regulatory role of the proteases necessitates very tight coordination and control of their expression. While this process has been well studied, a major oversight has been the consideration of proteases as a single entity rather than as 10 enzymes produced from four different promoters. As such, in this study, we comprehensively characterized the regulation of each protease promoter, discovering vast differences in the way each protease operon is controlled. Additionally, we broaden the picture of protease regulation using a global screen to identify novel loci controlling protease activity, uncovering a cadre of new effectors of protease expression. The impact of these elements on the activity of proteases and known regulators was characterized by producing a comprehensive regulatory circuit that emphasizes the complexity of protease regulation in <named-content content-type="genus-species">Staphylococcus aureus</named-content>.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Torres, Vj" uniqKey="Torres V">VJ Torres</name></author><author><name sortKey="Stauff, Dl" uniqKey="Stauff D">DL Stauff</name></author><author><name sortKey="Pishchany, G" uniqKey="Pishchany G">G Pishchany</name></author><author><name sortKey="Bezbradica, Js" uniqKey="Bezbradica J">JS Bezbradica</name></author><author><name sortKey="Gordy, Le" uniqKey="Gordy L">LE Gordy</name></author><author><name sortKey="Iturregui, J" uniqKey="Iturregui J">J Iturregui</name></author><author><name sortKey="Anderson, Kl" uniqKey="Anderson K">KL Anderson</name></author><author><name sortKey="Dunman, Pm" uniqKey="Dunman 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<front><journal-meta><journal-id journal-id-type="nlm-ta">mSphere</journal-id><journal-id journal-id-type="iso-abbrev">mSphere</journal-id><journal-id journal-id-type="hwp">msph</journal-id><journal-id journal-id-type="pmc">msph</journal-id><journal-id journal-id-type="publisher-id">mSphere</journal-id><journal-title-group><journal-title>mSphere</journal-title></journal-title-group><issn pub-type="epub">2379-5042</issn><publisher><publisher-name>American Society for Microbiology</publisher-name><publisher-loc>1752 N St., N.W., Washington, DC</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">31645429</article-id><article-id pub-id-type="pmc">6811363</article-id><article-id pub-id-type="publisher-id">mSphere00676-19</article-id><article-id pub-id-type="doi">10.1128/mSphere.00676-19</article-id><article-categories><subj-group subj-group-type="heading"><subject>Research Article</subject></subj-group><subj-group subj-group-type="overline"><subject>Molecular Biology and Physiology</subject></subj-group></article-categories><title-group><article-title>Mapping the Global Network of Extracellular Protease Regulation in <named-content content-type="genus-species">Staphylococcus aureus</named-content></article-title><alt-title alt-title-type="running-head">Regulation of Protease Expression in <named-content content-type="genus-species">S. aureus</named-content></alt-title><alt-title alt-title-type="short-authors">Gimza et al.</alt-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Gimza</surname><given-names>Brittney D.</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref></contrib><contrib contrib-type="author"><name><surname>Larias</surname><given-names>Maria I.</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref></contrib><contrib contrib-type="author"><name><surname>Budny</surname><given-names>Bridget G.</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref></contrib><contrib contrib-type="author" corresp="yes"><contrib-id contrib-id-type="orcid" authenticated="false">https://orcid.org/0000-0002-0629-8990</contrib-id><name><surname>Shaw</surname><given-names>Lindsey N.</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref></contrib><aff id="aff1"><label>a</label><addr-line>Department of Cell Biology, Microbiology & Molecular Biology, University of South Florida, Tampa, Florida, USA</addr-line></aff></contrib-group><contrib-group><contrib contrib-type="editor"><name><surname>Fey</surname><given-names>Paul D.</given-names></name><role>Editor</role><aff>University of Nebraska Medical Center</aff></contrib></contrib-group><author-notes><corresp id="cor1">Address correspondence to Lindsey N. Shaw, <email>shaw@usf.edu</email>.</corresp><fn fn-type="other"><p><bold>Citation</bold> Gimza BD, Larias MI, Budny BG, Shaw LN. 2019. Mapping the global network of extracellular protease regulation in <italic>Staphylococcus aureus</italic>. mSphere 4:e00676-19. <ext-link ext-link-type="uri" xlink:href="https://doi.org/10.1128/mSphere.00676-19">https://doi.org/10.1128/mSphere.00676-19</ext-link>.</p></fn></author-notes><pub-date pub-type="epub"><day>23</day><month>10</month><year>2019</year></pub-date><pub-date pub-type="collection"><season>Sep-Oct</season><year>2019</year></pub-date><volume>4</volume><issue>5</issue><elocation-id>e00676-19</elocation-id><history><date date-type="received"><day>11</day><month>9</month><year>2019</year></date><date date-type="accepted"><day>7</day><month>10</month><year>2019</year></date></history><permissions><copyright-statement>Copyright © 2019 Gimza et al.</copyright-statement><copyright-year>2019</copyright-year><copyright-holder>Gimza et al.</copyright-holder><license license-type="open-access" xlink:href="https://creativecommons.org/licenses/by/4.0/"><license-p>This is an open-access article distributed under the terms of the <ext-link ext-link-type="uri" xlink:href="https://creativecommons.org/licenses/by/4.0/">Creative Commons Attribution 4.0 International license</ext-link>.</license-p></license></permissions><self-uri content-type="pdf" xlink:href="mSphere.00676-19.pdf"></self-uri><abstract abstract-type="precis"><p>The complex regulatory role of the proteases necessitates very tight coordination and control of their expression. While this process has been well studied, a major oversight has been the consideration of proteases as a single entity rather than as 10 enzymes produced from four different promoters. As such, in this study, we comprehensively characterized the regulation of each protease promoter, discovering vast differences in the way each protease operon is controlled. Additionally, we broaden the picture of protease regulation using a global screen to identify novel loci controlling protease activity, uncovering a cadre of new effectors of protease expression. The impact of these elements on the activity of proteases and known regulators was characterized by producing a comprehensive regulatory circuit that emphasizes the complexity of protease regulation in <named-content content-type="genus-species">Staphylococcus aureus</named-content>.</p></abstract><abstract><title>ABSTRACT</title><p>A primary function of the extracellular proteases of <named-content content-type="genus-species">Staphylococcus aureus</named-content> is to control the progression of infection by selectively modulating the stability of virulence factors. Consequently, a regulatory network exists to titrate protease abundance/activity to influence the accumulation, or lack thereof, of individual virulence factors. Herein, we comprehensively map this system, exploring the regulation of the four protease loci by known and novel factors. In so doing, we determined that seven major elements (SarS, SarR, Rot, MgrA, CodY, SaeR, and SarA) form the primary network of control, with the latter three being the most powerful. We note that expression of aureolysin is largely repressed by these factors, while the <italic>spl</italic> operon is subject to the strongest upregulation of any protease loci, particularly by SarR and SaeR. Furthermore, when exploring <italic>scpA</italic> expression, we find it to be profoundly influenced in opposing fashions by SarA (repressor) and SarR (activator). We also present the screening of >100 regulator mutants of <named-content content-type="genus-species">S. aureus</named-content>, identifying 7 additional factors (ArgR2, AtlR, MntR, Rex, XdrA, Rbf, and SarU) that form a secondary circuit of protease control. Primarily, these elements serve as activators, although we reveal XdrA as a new repressor of protease expression. With the exception or ArgR2, each of the new effectors appears to work through the primary network of regulation to influence protease production. Collectively, we present a comprehensive regulatory circuit that emphasizes the complexity of protease regulation and suggest that its existence speaks to the importance of these enzymes to <named-content content-type="genus-species">S. aureus</named-content> physiology and pathogenic potential.</p><p><bold>IMPORTANCE</bold> The complex regulatory role of the proteases necessitates very tight coordination and control of their expression. While this process has been well studied, a major oversight has been the consideration of proteases as a single entity rather than as 10 enzymes produced from four different promoters. As such, in this study, we comprehensively characterized the regulation of each protease promoter, discovering vast differences in the way each protease operon is controlled. Additionally, we broaden the picture of protease regulation using a global screen to identify novel loci controlling protease activity, uncovering a cadre of new effectors of protease expression. The impact of these elements on the activity of proteases and known regulators was characterized by producing a comprehensive regulatory circuit that emphasizes the complexity of protease regulation in <named-content content-type="genus-species">Staphylococcus aureus</named-content>.</p></abstract><kwd-group><title>KEYWORDS</title><kwd><italic>Staphylococcus aureus</italic></kwd><kwd>gene regulation</kwd><kwd>proteases</kwd><kwd>transcriptional regulation</kwd><kwd>virulence factors</kwd></kwd-group><funding-group><award-group id="award1"><funding-source><institution-wrap><institution>HHS | NIH | National Institute of Allergy and Infectious Diseases (NIAID)</institution><institution-id>https://doi.org/10.13039/100000060</institution-id></institution-wrap></funding-source><award-id>AI124458</award-id><principal-award-recipient><name><surname>Shaw</surname><given-names>Lindsey N.</given-names></name></principal-award-recipient></award-group></funding-group><counts><count count="5" count-type="supplementary-material"></count><fig-count count="9"></fig-count><table-count count="1"></table-count><equation-count count="0"></equation-count><ref-count count="93"></ref-count><page-count count="17"></page-count><word-count count="11117"></word-count></counts><custom-meta-group><custom-meta><meta-name>cover-date</meta-name><meta-value>September/October 2019</meta-value></custom-meta></custom-meta-group></article-meta></front><body><sec sec-type="intro" id="s1"><title>INTRODUCTION</title><p><named-content content-type="genus-species">Staphylococcus aureus</named-content> is an opportunistic human pathogen known for causing both hospital- and community-acquired infections. It is capable of causing a plethora of diseases that range from minor skin and soft tissue infections, such as boils and carbuncles, to septicemia, endocarditis, osteomyelitis, and toxic shock syndrome (<xref rid="B1" ref-type="bibr">1</xref><xref ref-type="bibr" rid="B2">–</xref><xref rid="B3" ref-type="bibr">3</xref>). This broad disease potential can be attributed to the coordinated production of a wealth of virulence factors by <named-content content-type="genus-species">S. aureus</named-content> within the human host. Collectively, these elements allow the pathogen to evade phagocytosis, promote abscess formation, travel from initial sites of infection to invade new tissues, and induce a variety of syndromes (<xref rid="B4" ref-type="bibr">4</xref>). These virulence-causing entities can be divided into two broad groups: adherence factors and exoproteins. Adherence factors are responsible for the attachment of <named-content content-type="genus-species">S. aureus</named-content> to host tissues so that colonization may occur (<xref rid="B5" ref-type="bibr">5</xref>) and can also interfere with the host immune system to facilitate immune evasion (<xref rid="B6" ref-type="bibr">6</xref>). Conversely, exoproteins are secreted by <named-content content-type="genus-species">S. aureus</named-content> and function to acquire nutrients by breaking down host tissues and, more importantly, target the immune system, engendering immune subversion (<xref rid="B7" ref-type="bibr">7</xref>).</p><p>Parts of this cadre of secreted factors are 10 extracellular proteases, which are produced by almost every <named-content content-type="genus-species">S. aureus</named-content> strain (<xref ref-type="fig" rid="fig1">Fig. 1</xref>) (<xref rid="B8" ref-type="bibr">8</xref>, <xref rid="B9" ref-type="bibr">9</xref>). These include the following: a metalloprotease, aureolysin (<italic>aur</italic>); a serine protease, V8 (<italic>sspA</italic>); two cysteine proteases, staphopain B (<italic>sspB</italic>) and staphopain A (<italic>scpA</italic>); and six serine protease-like enzymes (<italic>splABCDEF</italic>) (<xref rid="B9" ref-type="bibr">9</xref>, <xref rid="B10" ref-type="bibr">10</xref>). The functions of these enzymes have been studied by ourselves and others and include their ability to hydrolyze a variety of host proteins as well as self-derived toxins. With regard to host factors, the secreted proteases have been demonstrated to proteolyze proteins such as fibrinogen, elastin, and the heavy chains of immunoglobulins to promote tissue invasion, immune system evasion, and the dissemination of infection (<xref rid="B11" ref-type="bibr">11</xref><xref ref-type="bibr" rid="B12">–</xref><xref rid="B13" ref-type="bibr">13</xref>). In the context of the self-degradome, these enzymes can cleave multiple virulence determinants to promote bacterial invasion, immune evasion, and survival. For example, aureolysin was shown to control the stability of both phenol-soluble modulins and alpha-toxin (<xref rid="B14" ref-type="bibr">14</xref>, <xref rid="B15" ref-type="bibr">15</xref>) as well as the adhesin clumping factor B (ClfB) (<xref rid="B16" ref-type="bibr">16</xref>), while SspA is able to cleave surface protein A (SpA) and the fibrinogen-binding proteins (FnBPs) (<xref rid="B17" ref-type="bibr">17</xref>, <xref rid="B18" ref-type="bibr">18</xref>).</p><fig id="fig1" orientation="portrait" position="float"><label>FIG 1</label><caption><p>Genetic organization of the <named-content content-type="genus-species">S. aureus</named-content> secreted protease loci. The colors of arrows are representative of catalytic activity classification: metalloprotease in pink; serine proteases in green; cysteine proteases in purple; and the inhibitors of the staphopains (the staphostatins) in blue.</p></caption><graphic xlink:href="mSphere.00676-19-f0001"></graphic></fig><p>Recently, our group assessed the importance of secreted proteases in <named-content content-type="genus-species">S. aureus</named-content> pathogenesis using a strain where all 10 enzymes were deleted (<xref rid="B19" ref-type="bibr">19</xref>). Here, we demonstrated that secreted proteases are required for growth in whole human blood, serum, peptide-rich medium, and in the presence of antimicrobial peptides. Additionally, these enzymes are also necessary for <named-content content-type="genus-species">S. aureus</named-content> to resist phagocytosis by human granulocytes and monocytes. Most striking, however, were the <italic>in vivo</italic> phenotypes of this mutant, where a decrease in dissemination and abscess formation were observed in infected mice compared to in the wild type. Conversely, when assessing mortality, the complete protease-null strain demonstrated pronounced hypervirulence. These contrasting phenotypes were explained using proteomics, where an increase in the stability of secreted and surface-associated virulence factors was demonstrated <italic>en masse</italic> in the mutant, thus facilitating more aggressive and deadly infections. Importantly, many of these findings were also demonstrated in a companion study by Zielinska et al. (<xref rid="B20" ref-type="bibr">20</xref>). As such, it would appear that secreted proteases have a biphasic role in infection, serving on the one hand to modulate the stability of self-derived pathogenic determinants, so as to control disease severity and progression, while at the same time playing their own direct role by cleaving host proteins to promote invasion, immune evasion, and survival.</p><p>Given the complex regulatory role of <named-content content-type="genus-species">S. aureus</named-content> proteases during infection, it follows that there must be, and indeed is, tight control of their expression mediated by a collection of different factors. This is evidenced by the number of elements that have been identified thus far as influencing protease production, including RNAIII SarS, SarR, SarA, SarV, SarX, SarZ, ArlRS, CodY, Rot, MgrA, and SaeRS (<xref rid="B21" ref-type="bibr">21</xref><xref ref-type="bibr" rid="B22">–</xref><xref rid="B33" ref-type="bibr">33</xref>). Of these factors, SarS, SarR, CodY, Rot, MgrA, SaeR, and SarA are considered the primary regulators, with each being shown to directly influence protease transcription (<xref rid="B21" ref-type="bibr">21</xref><xref ref-type="bibr" rid="B22">–</xref><xref rid="B27" ref-type="bibr">27</xref>). A major oversight when studying the control of protease production in <named-content content-type="genus-species">S. aureus</named-content>, however, has been the consideration of these factors as a single entity rather than as 10 enzymes produced from four different promoters. Of the seven major regulators, only SarA and Rot have been explored in the context of all four protease promoters (<xref rid="B9" ref-type="bibr">9</xref>, <xref rid="B10" ref-type="bibr">10</xref>), with SarA shown to specifically repress the transcription of <italic>aur</italic>, <italic>scpA</italic>, and <italic>ssp</italic> but not <italic>spl</italic> (<xref rid="B9" ref-type="bibr">9</xref>, <xref rid="B10" ref-type="bibr">10</xref>), while Rot has been described as a direct negative regulator of all secreted protease operons (<xref rid="B23" ref-type="bibr">23</xref>). For the other primary regulators, CodY has been shown to directly repress <italic>ssp</italic> transcription (<xref rid="B22" ref-type="bibr">22</xref>), while SarS and SarR have been explored only in the context of <italic>aur</italic> and <italic>ssp</italic> promoter binding (<xref rid="B21" ref-type="bibr">21</xref>). Finally, MgrA has been shown to activate <italic>aur</italic>, <italic>ssp</italic>, and <italic>spl</italic> transcription (<xref rid="B25" ref-type="bibr">25</xref>, <xref rid="B34" ref-type="bibr">34</xref>), while SaeR has been described as an activator for <italic>spl</italic> but a repressor for <italic>aur</italic> (<xref rid="B24" ref-type="bibr">24</xref>).</p><p>Consequently, the overarching goal of this study was to explore and further our understanding of the regulation of secreted proteases by known regulatory factors in <named-content content-type="genus-species">S. aureus</named-content> while concurrently uncovering new effectors of protease transcription. Accordingly, we present a comprehensive mapping of protease regulation by all known <named-content content-type="genus-species">S. aureus</named-content> transcription factors in community-acquired methicillin-resistant <named-content content-type="genus-species">S. aureus</named-content> (CA-MRSA) strain USA300.</p></sec><sec sec-type="results|discussion" id="s2"><title>RESULTS AND DISCUSSION</title><sec id="s2.1"><title>Exploring the differential regulation of protease expression by primary regulators.</title><p>To date, seven different transcriptional regulators (Rot, CodY, SarA, SarS, MgrA, SarR, and SaeR) (<xref rid="B21" ref-type="bibr">21</xref><xref ref-type="bibr" rid="B22">–</xref><xref rid="B27" ref-type="bibr">27</xref>) have been identified as being the primary modulators of secreted protease expression. An oversight, however, is the consideration of <named-content content-type="genus-species">S. aureus</named-content> proteases as a single entity rather than as 10 enzymes produced from four distinct loci (<xref ref-type="fig" rid="fig1">Fig. 1</xref>). Thus, although these elements do indeed have the capacity to regulate the expression of one or more proteases, only a few have been explored in the context of all four operons. Therefore, our initial goal was to fill in missing gaps using quantitative real-time PCR (qRT-PCR). To assess this, wild-type and regulator mutant strains were grown to postexponential phase (5 h), which is a known window of peak protease expression (<xref rid="B9" ref-type="bibr">9</xref>), and assessed for the expression of each protease operon.</p><p>We began with the best-studied regulator, SarA, whose ability to repress the transcription of <italic>aur</italic>, <italic>scpA</italic>, and <italic>ssp</italic> but not <italic>spl</italic> has been well established (<xref rid="B9" ref-type="bibr">9</xref>, <xref rid="B10" ref-type="bibr">10</xref>). Here, our analysis provided the expected results: in the absence of SarA, there was a 275-fold increase in <italic>aur</italic>, 10.9-fold increase in <italic>sspA</italic>, and a 23.7-fold increase in <italic>scpA</italic> transcript levels, with no changes in <italic>spl</italic> expression (<xref ref-type="fig" rid="fig2">Fig. 2A</xref>).</p><fig id="fig2" orientation="portrait" position="float"><label>FIG 2</label><caption><p>Individual protease loci are differentially controlled by major regulators of <named-content content-type="genus-species">S. aureus</named-content>. qRT-PCR was used to determine transcript levels for <italic>aur</italic>, <italic>scp</italic>, <italic>ssp</italic>, and <italic>spl</italic> in regulator mutants after 5 h of growth. The strains used were wild type (WT) USA300 Houston (HOU) and mutants for <italic>sarA</italic> (A), <italic>codY</italic> (B), <italic>rot</italic> (C), <italic>sarS</italic> (D), <italic>saeR</italic> (E), <italic>mgrA</italic> (F), and <italic>sarR</italic> (G). RNA was isolated from three independent cultures. The 16S rRNA gene was used as an internal control. Fold change from WT was determined using the 2<sup>−ΔΔ</sup><italic><sup>CT</sup></italic> method. Student’s <italic>t</italic> tests were used to determine statistical significance. *, <italic>P</italic> < 0.05; **, <italic>P</italic> < 0.01; ***, <italic>P</italic> < 0.001; ****, <italic>P</italic> < 0.0001 relative to the wild-type strain. Error bars show the standard deviations (SDs).</p></caption><graphic xlink:href="mSphere.00676-19-f0002"></graphic></fig><p>Next, we investigated CodY, whose ability to influence protease expression was identified by microarray analysis in UAMS-1 (<xref rid="B22" ref-type="bibr">22</xref>). There, Majerczyk et al. (<xref rid="B22" ref-type="bibr">22</xref>) found that in the absence of CodY, <italic>sspA</italic> had increased transcript levels. Additionally, in the same study, CodY was shown to bind the <italic>spl</italic>, <italic>sspA</italic>, and <italic>aur</italic> promoters; however, the binding to <italic>aur</italic> and <italic>spl</italic> was deemed biologically irrelevant, as changes in their expression were not observed upon <italic>codY</italic> deletion. As such, the ability of CodY to modulate expression of <italic>aur</italic>, <italic>scpA</italic>, and <italic>spl</italic> has not been previously described. Herein, in the absence of CodY, we observed a significant 324-fold increase in <italic>aur</italic>, 12.8-fold increase in <italic>sspA</italic>, 3.3-fold increase in <italic>scpA</italic>, and 6.2-fold increase in <italic>spl</italic> transcript levels (<xref ref-type="fig" rid="fig2">Fig. 2B</xref>). Collectively, these data suggest that CodY is a negative regulator of secreted protease expression that rivals SarA in its potency.</p><p>We next considered Rot, which was first shown to negatively regulate <italic>sspA</italic> and <italic>spl</italic> transcription in a RN6390 microarray (<xref rid="B35" ref-type="bibr">35</xref>). In another study assessing <italic>aur</italic> and <italic>sspA</italic> regulation in strain 8325-4, Rot functioned as a direct repressor of both loci (<xref rid="B25" ref-type="bibr">25</xref>). In support of these studies, others have demonstrated that Rot represses <italic>aur</italic> and <italic>sspA</italic> while also directly repressing <italic>spl</italic> through promoter binding in strain LAC (<xref rid="B23" ref-type="bibr">23</xref>). Additionally, in the same study, Rot was shown for the first time to directly repress <italic>scpA</italic> transcription. In our study, upon <italic>rot</italic> inactivation, there were significant increases of 6.2-fold for <italic>aur</italic> and 4.5-fold for <italic>sspA</italic> transcript levels, which is in line with previous research (<xref rid="B23" ref-type="bibr">23</xref>). Additionally, a significant 2.1-fold decrease in <italic>scpA</italic> expression along with no change for <italic>spl</italic> was observed, contradicting previous studies, where increased transcription for both was observed upon <italic>rot</italic> deletion (<xref ref-type="fig" rid="fig2">Fig. 2C</xref>). We note, however, that previous studies regarding Rot regulation differ from ours through the use of medium supplemented with different nutrients. Specifically, in work by Mootz et al. (<xref rid="B23" ref-type="bibr">23</xref>), growth medium was supplemented with glucose, which has been documented as repressing the <italic>agr</italic> quorum sensing system via the decreased pH produced from carbon metabolism (<xref rid="B23" ref-type="bibr">23</xref>, <xref rid="B36" ref-type="bibr">36</xref>, <xref rid="B37" ref-type="bibr">37</xref>). As such, this decrease in <italic>agr</italic> activity could alter the expression of downstream factors also capable of regulating the secreted proteases. Similarly, Said-Salim et al. (<xref rid="B35" ref-type="bibr">35</xref>) used Casamino Acids-yeast extract-glycerol phosphate broth for their studies. Here, the addition of glycerol, as well as the use of an entirely different complex medium, altered the activity of other transcriptional regulators such as CodY, CcpE, CcpA, and RpiRC, which are known to sense the carbon status of the cell (<xref rid="B38" ref-type="bibr">38</xref>). Therefore, while Rot has the potential to regulate all four protease loci, our data suggest that Rot primarily controls expression of <italic>aur</italic> and <italic>sspAB</italic>, likely in an <italic>agr</italic>-dependent manner.</p><p>SarS was formerly shown to have no significant effect on <italic>aur</italic> and <italic>ssp</italic> transcription during investigation in strain 8325-4 (<xref rid="B27" ref-type="bibr">27</xref>). Oscarsson et al., however, established that when <italic>sarS</italic> is overexpressed in 8325-4, <italic>aur</italic> and <italic>sspA</italic> transcription is suppressed (<xref rid="B25" ref-type="bibr">25</xref>). In support of a role in <italic>sspA</italic> regulation, another study showed that SarS could bind the <italic>sspA</italic> promoter (<xref rid="B27" ref-type="bibr">27</xref>). To date, the effects of SarS on <italic>scpA</italic> and <italic>spl</italic> transcription have not yet been investigated. Our analysis of protease transcription in the absence of SarS revealed significant increases for <italic>aur</italic> (6.9-fold), <italic>sspA</italic> (2.9-fold), and <italic>spl</italic> (1.6-fold) but a 1.7-fold decrease in <italic>scpA</italic> transcript levels (<xref ref-type="fig" rid="fig2">Fig. 2D</xref>). These data thus support a role for SarS as a repressor of <italic>aur</italic> and <italic>sspA</italic> expression and identify the <italic>spl</italic> operon as a new target of negative regulation by this factor. Conversely, we reveal <italic>scpA</italic> as a being activated by SarS, demonstrating, as with our data for Rot, that each of the four proteases are often subject to differential and opposing regulation by the same element.</p><p>The ability of SaeR to influence protease expression was previously described by microarray analysis, where, in the absence of SaeR/S in strain LAC, there was a decrease in <italic>spl</italic> transcription (<xref rid="B24" ref-type="bibr">24</xref>). Furthermore, in that same study, it was observed that this effect was direct, as SaeR was shown to bind to the <italic>spl</italic> promoter. Additionally, in the same background, Cassat et al. showed a decrease in SplA-F protein levels following <italic>sae</italic> inactivation (<xref rid="B39" ref-type="bibr">39</xref>). In support of this, we observed a striking 671-fold decrease in <italic>spl</italic> transcript levels upon <italic>saeR</italic> deletion, which is the most pronounced alteration in expression for any protease observed in this study (<xref ref-type="fig" rid="fig2">Fig. 2E</xref>). With regard to <italic>aur</italic>, the previously referenced studies revealed an increase in <italic>aur</italic> transcription (<xref rid="B24" ref-type="bibr">24</xref>) as well as an increase in Aur protein levels (<xref rid="B39" ref-type="bibr">39</xref>) in the absence of <italic>saeRS</italic>. In our study, however, no change in transcription was observed, which is in line with Oscarsson et al., who derived similar findings in strain RN6390 (<xref rid="B25" ref-type="bibr">25</xref>). Of note, the changes observed during microarray and proteomic analyses were during stationary phase rather than postexponential phase. Therefore, the disagreement regarding <italic>aur</italic> regulation could be a product of different time points used for assessment. This is supported by our observation that, when analyzed throughout growth, SaeRS is the only major regulator in <named-content content-type="genus-species">S. aureus</named-content> to demonstrate a rebound in transcriptional activity during stationary phase (our unpublished observation). This suggests that SaeRS may have various or biphasic functions with regard to virulence factor regulation during <named-content content-type="genus-species">S. aureus</named-content> growth. Regarding <italic>scpA</italic>, the effect of SaeR on transcription has not until now been investigated. Herein, we observed a 2.5-fold decrease in <italic>scpA</italic> transcription in the absence of SaeR, indicating that, similarly to the <italic>spl</italic>s, it is activated by this factor. Lastly, no change in <italic>sspA</italic> transcription was observed, which, while in line with Oscarsson et al. (<xref rid="B25" ref-type="bibr">25</xref>), contradicts Cassat et al. (<xref rid="B39" ref-type="bibr">39</xref>), who observed an increase in SspA and SspB protein levels during stationary phase. As previously suggested, this conflict is likely explained by the varying impact of SaeRS during different growth phases. As such, our data support a role for SaeR during postexponential growth in the activation of <italic>spl</italic> and identify <italic>scpA</italic> as a new target for SaeR upregulation.</p><p>We next investigated MgrA, which was previously shown to activate <italic>aur</italic> and <italic>sspA</italic> transcription in 8325-4 (<xref rid="B25" ref-type="bibr">25</xref>). Using RNA sequencing in LAC, others have shown that the absence of MgrA decreased <italic>aur</italic> and <italic>spl</italic> transcript levels (<xref rid="B34" ref-type="bibr">34</xref>). Herein, in agreement with previous studies, we observed a significant 7.6-fold decrease in <italic>aur</italic>, 3.2-fold decrease in <italic>sspA</italic>, and 26.7-fold decrease in <italic>spl</italic> transcript levels (<xref ref-type="fig" rid="fig2">Fig. 2F</xref>). Lastly, until now, the effect of MgrA on <italic>scpA</italic> had not been investigated. In our study, no changes in <italic>scpA</italic> transcript levels were identified, which again demonstrates differential regulation of the various protease loci. This is particularly interesting, as it is an additional example of the two staphopain enzymes (SspB and ScpA), which share strong homology (<xref rid="B40" ref-type="bibr">40</xref><xref ref-type="bibr" rid="B41">–</xref><xref rid="B42" ref-type="bibr">42</xref>) although quite different substrate specificities (<xref rid="B42" ref-type="bibr">42</xref>), as being regulated in opposing fashions.</p><p>Finally, we investigated SarR, which was formerly shown to positively affect <italic>aur</italic> and <italic>sspA</italic> transcript levels in 8325-4 (<xref rid="B21" ref-type="bibr">21</xref>). In contrast, in another study, it was shown to negatively affect <italic>aur</italic> when overexpressed in an 8325-4 <italic>agr sarA</italic> double mutant (<xref rid="B25" ref-type="bibr">25</xref>). Interestingly, however, in our study, no change in <italic>aur</italic> transcript levels was detected in the absence of <italic>sarR</italic>. When considering <italic>ssp</italic> expression, we observed a significant 1.6-fold decrease in transcript levels (<xref ref-type="fig" rid="fig2">Fig. 2G</xref>) in the <italic>sarR</italic> mutant, which is in agreement with Gustafsson et al. (<xref rid="B21" ref-type="bibr">21</xref>). With regard to <italic>scpA</italic> and <italic>spl</italic>, SarR was not previously investigated as controlling their transcription. Herein, we observed a significant 29.1-fold decrease in <italic>scpA</italic> and 48.8-fold decrease in <italic>spl</italic> transcript levels. Our data therefore support a role for SarR in upregulating the <italic>ssp</italic> operon to a minor extent while serving as one of the strongest activators of <italic>scpA</italic> and <italic>spl</italic> expression identified thus far.</p></sec><sec id="s2.2"><title>Defining the pathway of control for secreted protease expression by known major regulators.</title><p>Collectively, our findings confirm 14 regulatory pathways for secreted protease transcription while identifying eight new nodes of expression (<xref ref-type="fig" rid="fig3">Fig. 3</xref>). For <italic>aur</italic>, we found it was regulated by CodY in addition to SarA, Rot, SarS, and MgrA. Interestingly, with the exception of MgrA, each of these factors engenders repression of <italic>aur</italic> expression, with some (SarA and CodY) exerting profound influence. This is perhaps explained by the observation that aureolysin sits atop the protease activation cascade, which flows from Aur to V8 and then staphopain B (<xref rid="B11" ref-type="bibr">11</xref>, <xref rid="B43" ref-type="bibr">43</xref><xref ref-type="bibr" rid="B44">–</xref><xref rid="B45" ref-type="bibr">45</xref>). As such, repressing aureolysin would allow the <named-content content-type="genus-species">S. aureus</named-content> cell to keep the majority of proteases’ activity restrained by the single act of limiting expression from P<italic><sub>aur</sub></italic>. This would be to the cells advantage as, although proteases are undoubtedly valuable enzymes with important roles, they are also destructive in nature. Thus, limiting their activity until it is absolutely required is a major goal of living cells from all kingdoms (<xref rid="B46" ref-type="bibr">46</xref>, <xref rid="B47" ref-type="bibr">47</xref>). This would be particularly true of aureolysin, given that it has among the broadest substrate specificities of any <named-content content-type="genus-species">S. aureus</named-content> protease (<xref rid="B48" ref-type="bibr">48</xref>). In the context of enzymes from the <italic>ssp</italic> operon, we did not identify new regulatory nodes but confirmed their broad regulation, albeit at modest levels, in a fashion that closely resembles that of <italic>aur</italic> control. This finding is again logical, given that the enzymes produced from these loci are part of the protease activation cascade referenced above.</p><fig id="fig3" orientation="portrait" position="float"><label>FIG 3</label><caption><p>Primary network of control for individual protease loci. Shown are transcriptional regulation events for the seven primary protease regulators of <named-content content-type="genus-species">S. aureus</named-content> on the four individual protease loci. Bars indicate repression, and arrows represent activation. New regulatory pathways identified herein between the primary regulators and the protease loci are shown in green.</p></caption><graphic xlink:href="mSphere.00676-19-f0003"></graphic></fig><p>Interestingly, much of the new knowledge generated herein involves the regulation of the more underappreciated proteases, staphopain A and the Spls. While the importance of <italic>scpA</italic> in virulence has been shown through <italic>in vivo</italic> studies, as well as by its ability to cleave specific host proteins (<xref rid="B13" ref-type="bibr">13</xref>, <xref rid="B49" ref-type="bibr">49</xref>, <xref rid="B50" ref-type="bibr">50</xref>), its transcriptional regulation has been underexplored. While it has been shown previously that <italic>scpA</italic> is regulated by Rot and SarA, we identified herein that SarS, CodY, SaeR, and SarR also control its expression. While much of this regulation is at modest levels, <italic>scpA</italic> expression is profoundly influenced in opposing fashions by SarA (repressor) and SarR (activator). This presents a scenario whereby the presence of this enzyme during infection could be discretely titrated, with high SarA activity resulting in decreased staphopain A, while elevated SarR levels would engender significant production of this enzyme. This could then provide rapid niche-specific control of the pathogenic process through staphopain A activity (or lack thereof) toward self- and host-derived proteins. The need for such a network of opposing and stringent control is supported by the observation that staphopain A is one of only two <named-content content-type="genus-species">S. aureus</named-content> secreted proteases with a broad and promiscuous substrate specificity (aureolysin being the other) (<xref rid="B51" ref-type="bibr">51</xref>); thus, tightly modulating its influence is a necessity for a coordinated and controlled infectious process.</p><p>When exploring control of <italic>spl</italic> expression, we note that this operon is subject to some of the strongest regulation observed for any protease loci in this study. Specifically, MgrA, SarR, and SaeR each bring about profound upregulation of the <italic>spl</italic> operon, to levels that rival and, in the case of SaeR, exceed, that of SarA and CodY for protease control. This is of interest because the Spls are well known for their narrow substrate specificity (<xref rid="B52" ref-type="bibr">52</xref><xref ref-type="bibr" rid="B53">–</xref><xref rid="B54" ref-type="bibr">54</xref>). Indeed, these enzymes share strong homology and many enzymatic characteristics with the exfoliative toxins of <named-content content-type="genus-species">S. aureus</named-content>. In the case of these latter proteases, they have only a single known target, desmoglein-1 in the skin of humans, the cleavage of which results in scalded skin syndrome (<xref rid="B55" ref-type="bibr">55</xref>). The Spl enzymes are projected to have a similarly narrow range of substrates (<xref rid="B56" ref-type="bibr">56</xref>); thus, it is logical that the cell would limit the production of these enzymes until it finds itself in an environment where their activity would prove beneficial. As such, it is logical that the presence and activity of the Spl enzymes can be selectively and rapidly stimulated by these regulatory factors in response to environmental cues within the host to facilitate infection.</p></sec><sec id="s2.3"><title>Identification of a cadre of new effectors of protease activity.</title><p>Given the complex regulatory function of <named-content content-type="genus-species">S. aureus</named-content> secreted proteases, tight modulation of their expression is required. As such, we set out to more deeply characterize their network of control by uncovering novel effectors of their activity. This was achieved by screening all 108 available transcriptional regulator mutants within the Nebraska Transposon Mutant Library (NTML) (<xref rid="B57" ref-type="bibr">57</xref>) for alterations in proteolytic capacity. Culture supernatants from all strains grown for 15 h (a window of peak accumulation for secreted proteases) were prepared and subjected to zymography using gelatin as a substrate, as described by us previously (<xref rid="B9" ref-type="bibr">9</xref>). Of the 108 mutants screened, five of the seven primary regulators (<italic>sarS</italic>, <italic>saeR</italic>, <italic>rot</italic>, <italic>sarA</italic>, and <italic>codY</italic> mutants) were included as controls (<italic>sarR</italic> and <italic>mgrA</italic> mutants are not present in the NTML), along with two other major regulators of protease production: <italic>agrA</italic> and <italic>sigB</italic>. As expected, an increase in proteolytic activity was observed with <italic>sarS</italic>, <italic>rot</italic>, <italic>sarA</italic>, <italic>codY</italic>, and <italic>sigB</italic> mutants, while a decrease was observed for <italic>saeR</italic> and <italic>agrA</italic> mutants, in comparison to that in the wild type (<xref ref-type="fig" rid="fig4">Fig. 4</xref>). For all strains, the intensities of proteolytic banding resulting from gelatin degradation were assessed visually and by densitometry using ImageJ software (<xref ref-type="fig" rid="fig5">Fig. 5</xref>).</p><fig id="fig4" orientation="portrait" position="float"><label>FIG 4</label><caption><p>Impact of primary regulator mutation on protease activity. Gelatin zymography was performed to visualize protease activity on 15-h culture supernatants obtained from USA300 JE2 and mutants of <italic>sarS</italic>, <italic>saeR</italic>, <italic>codY</italic>, <italic>sigB</italic>, <italic>agrA</italic>, <italic>rot</italic>, and <italic>sarA</italic>. All strains were adjusted to equal optical densities prior to analysis.</p></caption><graphic xlink:href="mSphere.00676-19-f0004"></graphic></fig><fig id="fig5" orientation="portrait" position="float"><label>FIG 5</label><caption><p>Quantitative profiling of protease activity for all available regulator mutants of <named-content content-type="genus-species">S. aureus</named-content>. Zymogram band intensities from all 108 regulator mutants contained within the NTML were measured using densitometry (ImageJ). Depicted is fold change of band intensity relative to that of the USA300 JE2 wild-type strain.</p></caption><graphic xlink:href="mSphere.00676-19-f0005"></graphic></fig><p>Excluding the known major regulators, a total of 45 mutants were identified as having notable alterations in proteolytic activity from our screen, with 26 found to have decreased proteolysis (see <xref ref-type="supplementary-material" rid="tabS1">Table S1</xref> in the supplemental material), while 19 had an increase (<xref ref-type="supplementary-material" rid="tabS2">Table S2</xref>). When assessing mutants that showed increased proteolysis, we identified SarX and NsaR, which were both previously identified as regulating proteases. SarX has been shown to repress <italic>sspA</italic> transcription in strain RN6390 (<xref rid="B31" ref-type="bibr">31</xref>), while NsaR was shown to be a repressor of <italic>scpA</italic>, <italic>sspA</italic>, and <italic>splA-F</italic> in strain SH1000 (<xref rid="B58" ref-type="bibr">58</xref>). When considering mutants that had decreased proteolysis, we noted SarV and CcpE, both of which have been implicated in modulating protease activity. Specifically, <italic>sarV</italic> disruption in RN6390 led to a decrease in transcription for <italic>aur</italic>, <italic>scpA</italic>, and <italic>splA</italic> (<xref rid="B32" ref-type="bibr">32</xref>), while loss of <italic>ccpE</italic> in strain Newman results in impaired expression of all protease loci (<xref rid="B59" ref-type="bibr">59</xref>).</p><supplementary-material content-type="local-data" id="tabS1"><object-id pub-id-type="doi">10.1128/mSphere.00676-19.3</object-id><label>TABLE S1</label><p>Transcriptional regulators identified as producing a decrease in protease activity upon transposon disruption. <italic><sup>a</sup></italic> Strains chosen for further study are highlighted in grey. <italic><sup>b</sup></italic> NE#, NTML strain number. <italic><sup>c</sup></italic> N/A, gene name has not yet been assigned. <italic><sup>d</sup></italic> Transcriptional regulator family assignment is from reference <xref rid="B93" ref-type="bibr">93</xref>. Download <inline-supplementary-material id="tS1" mimetype="application" mime-subtype="pdf" xlink:href="mSphere.00676-19-st001.pdf" content-type="local-data">Table S1, PDF file, 0.03 MB</inline-supplementary-material>.</p><permissions><copyright-statement>Copyright © 2019 Gimza et al.</copyright-statement><copyright-year>2019</copyright-year><copyright-holder>Gimza et al.</copyright-holder><license license-type="open-access" xlink:href="https://creativecommons.org/licenses/by/4.0/"><license-p>This content is distributed under the terms of the <ext-link ext-link-type="uri" xlink:href="https://creativecommons.org/licenses/by/4.0/">Creative Commons Attribution 4.0 International license</ext-link>.</license-p></license></permissions></supplementary-material><supplementary-material content-type="local-data" id="tabS2"><object-id pub-id-type="doi">10.1128/mSphere.00676-19.4</object-id><label>TABLE S2</label><p>Transcriptional regulators identified as producing an increase in protease activity upon transposon disruption. <italic><sup>a</sup></italic> Strains chosen for further study are highlighted in grey. <italic><sup>b</sup></italic> NE#, NTML strain number. <italic><sup>c</sup></italic> N/A, gene name has not yet been assigned. <italic><sup>d</sup></italic> Transcriptional regulator family assignment is from reference <xref rid="B93" ref-type="bibr">93</xref>. Download <inline-supplementary-material id="tS2" mimetype="application" mime-subtype="pdf" xlink:href="mSphere.00676-19-st002.pdf" content-type="local-data">Table S2, PDF file, 0.02 MB</inline-supplementary-material>.</p><permissions><copyright-statement>Copyright © 2019 Gimza et al.</copyright-statement><copyright-year>2019</copyright-year><copyright-holder>Gimza et al.</copyright-holder><license license-type="open-access" xlink:href="https://creativecommons.org/licenses/by/4.0/"><license-p>This content is distributed under the terms of the <ext-link ext-link-type="uri" xlink:href="https://creativecommons.org/licenses/by/4.0/">Creative Commons Attribution 4.0 International license</ext-link>.</license-p></license></permissions></supplementary-material><p>Beyond these known factors, we identified a number of intriguing regulators which have yet to be implicated in protease regulation. Of these, several displayed a prominent decrease in protease activity, including SarU. This regulator is an understudied transcription factor belonging to the Sar family, with many of its counterparts already known to have a role in regulating protease production (<xref rid="B60" ref-type="bibr">60</xref>). In addition, a notable decrease in protease activity was also observed for mutants of <italic>rbf</italic> and <italic>atlR</italic>, which encode regulators known to control biofilm formation (<xref rid="B61" ref-type="bibr">61</xref><xref ref-type="bibr" rid="B62">–</xref><xref rid="B63" ref-type="bibr">63</xref>). Further, Rex and MntR, both of which regulate different aspects of cellular metabolism, also caused pronounced decreases in protease activity upon ablation. We also observed a decrease in protease activity upon disruption of <italic>argR2</italic>, which is located within the arginine catabolism metabolic element (ACME) found in USA300 strains (<xref rid="B64" ref-type="bibr">64</xref>). Finally, XdrA/<italic>xdrA</italic>, which has a role in immune evasion via its involvement in the production of protein A (<xref rid="B65" ref-type="bibr">65</xref>), was found to produce a notable increase in protease activity upon disruption.</p></sec><sec id="s2.4"><title>Exploring protease control via a secondary network of regulation.</title><p>To more deeply explore the new protease regulatory factors identified herein, the seven referenced above were chosen for more detailed study. First, each mutation was transduced into a clean USA300 HOU background, and protease activity was continuously monitored throughout growth (see <xref ref-type="supplementary-material" rid="figS1">Fig. S1</xref>). In agreement with results from our zymography screen, a decrease in protease activity was observed at all time points for mutants of <italic>argR2</italic>, <italic>mntR</italic>, <italic>atlR</italic>, <italic>rbf</italic>, <italic>sarU</italic>, and <italic>rex</italic>, while the <italic>xdrA</italic> mutant demonstrated a minor decrease in protease activity at early times points, but produced the expected increase in proteolysis thereafter. To ensure that the changes observed were not the result of a simple growth defect, growth curves were performed for all strains, revealing no notable alterations compared to the growth of the wild type (see <xref ref-type="supplementary-material" rid="figS2">Fig. S2</xref>).</p><supplementary-material content-type="local-data" id="figS1"><object-id pub-id-type="doi">10.1128/mSphere.00676-19.1</object-id><label>FIG S1</label><p>Protease activity profiling of novel regulator mutants during growth. Gelatin zymography was performed on USA300 HOU WT and mutant strain culture supernatants obtained at the times specified. Culture supernatants were concentrated and ran on an SDS-PAGE gel containing 0.1% gelatin. Strains used are indicated on each gel. Download <inline-supplementary-material id="fS1" mimetype="application" mime-subtype="pdf" xlink:href="mSphere.00676-19-sf001.pdf" content-type="local-data">FIG S1, PDF file, 8.3 MB</inline-supplementary-material>.</p><permissions><copyright-statement>Copyright © 2019 Gimza et al.</copyright-statement><copyright-year>2019</copyright-year><copyright-holder>Gimza et al.</copyright-holder><license license-type="open-access" xlink:href="https://creativecommons.org/licenses/by/4.0/"><license-p>This content is distributed under the terms of the <ext-link ext-link-type="uri" xlink:href="https://creativecommons.org/licenses/by/4.0/">Creative Commons Attribution 4.0 International license</ext-link>.</license-p></license></permissions></supplementary-material><supplementary-material content-type="local-data" id="figS2"><object-id pub-id-type="doi">10.1128/mSphere.00676-19.2</object-id><label>FIG S2</label><p>Growth analysis of novel protease regulator mutants. USA300 HOU WT and regulator mutants of <italic>argR2</italic>, <italic>mntR</italic>, <italic>atlR</italic>, <italic>rbf</italic>, <italic>sarU</italic>, <italic>xdrA</italic>, and <italic>rex</italic> were grown under standard conditions in TSB. Data are from three biological replicates with error bars showing SDs. Download <inline-supplementary-material id="fS2" mimetype="application" mime-subtype="pdf" xlink:href="mSphere.00676-19-sf002.pdf" content-type="local-data">FIG S2, PDF file, 0.1 MB</inline-supplementary-material>.</p><permissions><copyright-statement>Copyright © 2019 Gimza et al.</copyright-statement><copyright-year>2019</copyright-year><copyright-holder>Gimza et al.</copyright-holder><license license-type="open-access" xlink:href="https://creativecommons.org/licenses/by/4.0/"><license-p>This content is distributed under the terms of the <ext-link ext-link-type="uri" xlink:href="https://creativecommons.org/licenses/by/4.0/">Creative Commons Attribution 4.0 International license</ext-link>.</license-p></license></permissions></supplementary-material><p>Our next step was to determine if the changes observed in the novel regulatory mutants were driven by changes at the level of transcription. Thus, qRT-PCR analysis for each protease loci was performed for the wild-type and regulator mutant strains during postexponential phase, with the exception of the <italic>argR2</italic> mutant, which appears to most notably alter proteolysis at 3 h of growth; thus, this time point was used for this strain. When studying changes in the <italic>argR2</italic> mutant, a 1.6-fold decrease in <italic>aur</italic>, 1.8-fold increase in <italic>sspA</italic>, and 1.7-fold increase in <italic>spl</italic> transcripts were observed (<xref ref-type="fig" rid="fig6">Fig. 6A</xref>), along with no change in <italic>scpA</italic> transcription. Next, with the mutant of <italic>atlR</italic>, we observed a significant 2-fold decrease in <italic>aur</italic> and a 2.2-fold decrease in <italic>spl</italic> transcripts (<xref ref-type="fig" rid="fig6">Fig. 6B</xref>), whereas with <italic>scpA</italic> and <italic>sspA</italic>, no changes in transcript levels were noted. For the <italic>mntR</italic> mutant, we observed a significant 2.5-fold decrease in <italic>sspA</italic> and 1.7-fold decrease in <italic>spl</italic> transcript levels (<xref ref-type="fig" rid="fig6">Fig. 6C</xref>), with no changes detected for <italic>aur</italic> and <italic>scpA</italic>. In the context of <italic>rex</italic>, a significant 3.3-fold decrease was seen with <italic>sspA</italic> transcript levels, while there were no changes in transcription for the other protease loci in this mutant (<xref ref-type="fig" rid="fig6">Fig. 6D</xref>). Following this, we investigated the <italic>xdrA</italic> mutant, in which we observed a significant 1.9-fold increase for <italic>aur</italic> and 4.2-fold increase in <italic>scpA</italic> transcript levels (<xref ref-type="fig" rid="fig6">Fig. 6E</xref>); however, with <italic>spl</italic>, we observed a significant 2.4-fold decrease in expression. When studying the <italic>rbf</italic> mutant, there was a significant 1.7-fold decrease for <italic>aur</italic>, 2-fold decrease for <italic>sspA</italic>, and 1.8-fold decrease for <italic>spl</italic> transcript levels (<xref ref-type="fig" rid="fig6">Fig. 6F</xref>), along with no changes for <italic>scpA</italic> transcription. Lastly, for the <italic>sarU</italic> mutant, we observed a significant 2.3-fold decrease for <italic>sspA</italic> and 1.7-fold decrease for <italic>aur</italic> transcript levels (<xref ref-type="fig" rid="fig6">Fig. 6G</xref>), while no changes were noted for <italic>scpA</italic> and <italic>spl</italic> transcription. Collectively, almost all of the regulators solely activate protease transcription, with the exception of XdrA, which differentially regulates protease loci in opposing fashions, akin to that observed with Rot and SarS.</p><fig id="fig6" orientation="portrait" position="float"><label>FIG 6</label><caption><p>Differential control of individual protease loci by a secondary network of regulatory factors. qRT-qPCR was performed to determine transcript levels for <italic>aur</italic>, <italic>ssp</italic>, <italic>scp</italic>, and <italic>spl</italic> in the regulator mutants. The strains used were WT USA300 HOU and mutants of <italic>argR2</italic> (A), <italic>atlR</italic> (B), <italic>mntR</italic> (C), <italic>rex</italic> (D), <italic>xdrA</italic> (E), <italic>rbf</italic> (F), and <italic>sarU</italic> (G). RNA was isolated from three independent cultures. The 16S rRNA gene was used as an internal control. Fold change from WT was determined using the 2<sup>−ΔΔ</sup><italic><sup>CT</sup></italic> method. Student’s <italic>t</italic> tests were used to determine statistical significance. *, <italic>P</italic> < 0.05; **, <italic>P</italic> < 0.01; ***, <italic>P</italic> < 0.001 relative to the wild-type strain. Error bars are SDs.</p></caption><graphic xlink:href="mSphere.00676-19-f0006"></graphic></fig></sec><sec id="s2.5"><title>Determining the pathway of control for the novel protease regulators.</title><p>In the work described above, we identified 14 new regulatory pathways for secreted protease transcription. These data allow us to construct a map of protease regulation for these factors, detailing specific effects on individual protease loci (<xref ref-type="fig" rid="fig7">Fig. 7</xref>). To delineate the pathway by which these regulators exert their effects, we next assessed their impact on the primary regulators of protease expression considered previously. As such, qRT-PCR analysis was performed on the seven novel protease regulator mutants for <italic>sarA</italic>, <italic>codY</italic>, <italic>rot</italic>, <italic>sarS</italic>, <italic>saeR</italic>, <italic>mgrA</italic>, and <italic>sarR</italic> at the respective time points in which their protease transcripts were previously assessed. SarA, SarR, MgrA, and CodY are able to regulate protease production by direct action, but can also act via control of the Agr quorum sensing system (<xref rid="B26" ref-type="bibr">26</xref>, <xref rid="B66" ref-type="bibr">66</xref><xref ref-type="bibr" rid="B67">–</xref><xref rid="B72" ref-type="bibr">72</xref>). Agr in turn activates secreted protease production during postexponential phase by inhibiting translation of the negative regulator Rot (<xref rid="B73" ref-type="bibr">73</xref><xref ref-type="bibr" rid="B74">–</xref><xref rid="B75" ref-type="bibr">75</xref>). As such, for completeness, we also included analysis of the <italic>agr</italic> operon in these studies.</p><fig id="fig7" orientation="portrait" position="float"><label>FIG 7</label><caption><p>Novel regulatory network controlling expression of extracellular proteases. Shown are transcriptional regulation events for the seven novel protease regulators on the four individual protease loci. Bars indicate repression, and arrows indicate activation.</p></caption><graphic xlink:href="mSphere.00676-19-f0007"></graphic></fig><p>When data for the <italic>argR2</italic> mutant were analyzed, we found no significant changes in expression for any of the primary protease regulators (<xref ref-type="fig" rid="fig8">Fig. 8A</xref>). As such, the changes in <italic>ssp</italic> transcript levels in the <italic>argR2</italic> mutant are either the result of direct action by ArgR2 or are mediated by an as yet unknown circuit. When assessing the <italic>atlR</italic> mutant, a significant 1.4-fold decrease in <italic>saeR</italic> and a 1.5-fold increase in <italic>sarS</italic> transcripts were observed (<xref ref-type="fig" rid="fig8">Fig. 8B</xref>). The decrease in <italic>saeR</italic> could explain the observed decrease in <italic>spl</italic> expression, as SaeR was shown by ourselves and others to activate <italic>spl</italic> transcription (<xref rid="B24" ref-type="bibr">24</xref>, <xref rid="B39" ref-type="bibr">39</xref>). In addition, the increase in <italic>sarS</italic> expression could explain the decrease in both <italic>aur</italic> and <italic>spl</italic> transcripts, as SarS was shown in this study to repress transcription of <italic>spl</italic> and was shown here and elsewhere to repress <italic>aur</italic> expression (<xref rid="B25" ref-type="bibr">25</xref>).</p><fig id="fig8" orientation="portrait" position="float"><label>FIG 8</label><caption><p>Determining the pathway of control for the novel protease regulators. qRT-PCR was performed to determine transcript levels for <italic>agrB</italic>, <italic>sarA</italic>, <italic>mgrA</italic>, <italic>rot</italic>, <italic>codY</italic>, <italic>saeR</italic>, <italic>sarR</italic>, and <italic>sarS</italic> in the regulator mutants. The strains used were WT USA300 HOU and mutants of <italic>argR2</italic> (A), <italic>atlR</italic> (B), <italic>mntR</italic> (C), <italic>rex</italic> (D), <italic>xdrA</italic> (E), <italic>rbf</italic> (F), and <italic>sarU</italic> (G). RNA was isolated from three independent cultures. The 16S rRNA gene was used as an internal control. Fold change from the WT was determined using the 2<sup>−ΔΔ</sup><italic><sup>CT</sup></italic> method. Student’s <italic>t</italic> tests were used to determine statistical significance. *, <italic>P</italic> < 0.05; **, <italic>P</italic> < 0.01; ***, <italic>P</italic> < 0.001 relative to the wild-type strain. Error bars are SDs.</p></caption><graphic xlink:href="mSphere.00676-19-f0008"></graphic></fig><p>Next, with the <italic>mntR</italic> mutant, we observed a significant 1.4-fold decrease in <italic>mgrA</italic>, 1.5-fold decrease in <italic>codY</italic>, 1.5-fold decrease in <italic>saeR</italic>, and 1.8-fold decrease in <italic>sarR</italic> transcript levels (<xref ref-type="fig" rid="fig8">Fig. 8C</xref>). With regard to the decrease in <italic>ssp</italic> and <italic>spl</italic> transcripts, these changes cannot be explained by the decrease in transcription for <italic>codY</italic>, as we show that CodY represses both of these loci. The decrease in the <italic>saeR</italic> transcript, however, could result in a decrease in <italic>spl</italic> transcription, as it has been shown by ourselves and others to be an activator of this operon (<xref rid="B24" ref-type="bibr">24</xref>, <xref rid="B39" ref-type="bibr">39</xref>). Furthermore, the decrease in <italic>mgrA</italic> and <italic>sarR</italic> transcripts could lead to a decrease in <italic>ssp</italic> and <italic>spl</italic> expression, as we confirm the work of others demonstrating that MgrA activates expression for both proteases (<xref rid="B25" ref-type="bibr">25</xref>, <xref rid="B34" ref-type="bibr">34</xref>) while newly identifying SarR as acting in a similar fashion.</p><p>When exploring the influence of Rex, we observed a significant 1.4-fold decrease in <italic>agrB</italic>, 1.3-fold decrease in <italic>sarA</italic>, 1.3-fold decrease in <italic>mgrA</italic>, 1.5-fold decrease in <italic>saeR</italic>, 2-fold decrease in <italic>sarR</italic>, and 1.5-fold decrease in <italic>sarS</italic> transcript levels (<xref ref-type="fig" rid="fig8">Fig. 8D</xref>). The changes in <italic>sarA</italic>, <italic>saeR</italic>, and <italic>sarS</italic> cannot explain the decrease we observed for the <italic>ssp</italic> transcript, because as shown by ourselves and others, both are repressors of <italic>ssp</italic> (<xref rid="B9" ref-type="bibr">9</xref>, <xref rid="B10" ref-type="bibr">10</xref>, <xref rid="B25" ref-type="bibr">25</xref>). However, as we and others have shown that MgrA, SarR, and Agr are activators of <italic>ssp</italic> transcription (<xref rid="B9" ref-type="bibr">9</xref>, <xref rid="B21" ref-type="bibr">21</xref>, <xref rid="B25" ref-type="bibr">25</xref>), decreases in their expression could explain our data. When assessing the <italic>xdrA</italic> mutant, a significant 2.1-fold decrease in <italic>agrB</italic> and 1.5-fold decrease in <italic>codY</italic> transcript levels were observed (<xref ref-type="fig" rid="fig8">Fig. 8E</xref>). Additionally, a significant 1.8-fold increase in <italic>mgrA</italic>, 4-fold increase in <italic>saeR</italic>, 1.7-fold increase in <italic>sarR</italic>, and 3-fold increase in <italic>sarS</italic> transcripts were observed. The increase in <italic>mgrA</italic> transcript could explain the increase in <italic>aur</italic> expression as MgrA has been shown here and by others to activate its transcription (<xref rid="B25" ref-type="bibr">25</xref>, <xref rid="B34" ref-type="bibr">34</xref>). Next, as we showed SaeR, SarR, and SarS are activators of <italic>scp</italic> expression, increases in the transcription of each could result in enhanced <italic>scp</italic> transcript abundance. Additionally, the decrease in <italic>codY</italic> expression could explain the increase in transcript for <italic>aur</italic> and <italic>scp</italic>, as we showed CodY is a repressor of both. Lastly, the decrease in <italic>spl</italic> transcript levels in the <italic>xdrA</italic> mutant could be explained by either the increase in <italic>sarS</italic> or by the decrease in <italic>agrB</italic> expression, as we show that SarS is a repressor of this locus, while it is well known that Agr is an activator of <italic>spl</italic> transcription (<xref rid="B10" ref-type="bibr">10</xref>). Next, with the <italic>rbf</italic> mutant, we observed a significant 1.3-fold increase in <italic>rot</italic> transcription as well as a 2.1-fold increase for <italic>sarS</italic> (<xref ref-type="fig" rid="fig8">Fig. 8F</xref>). The decrease in <italic>aur</italic> and <italic>ssp</italic> transcript levels observed in the <italic>rbf</italic> mutant could be explained by the increase in <italic>sarS</italic> expression, as it was shown by ourselves and others to be a repressor for both loci (<xref rid="B25" ref-type="bibr">25</xref>). Furthermore, we show SarS is a repressor of <italic>spl</italic>, and as such, the increase in <italic>sarS</italic> could have resulted in the decrease in the <italic>spl</italic> transcript. In addition, Rot was shown herein, and by others, to be a repressor for <italic>aur</italic> and <italic>ssp</italic>; therefore, the increase in <italic>rot</italic> transcription could result in the decrease of <italic>aur</italic> and <italic>ssp</italic> expression (<xref rid="B23" ref-type="bibr">23</xref>). Lastly, with the <italic>sarU</italic> mutant, we observed a significant 1.6-fold increase in <italic>rot</italic> transcription (<xref ref-type="fig" rid="fig8">Fig. 8G</xref>). In the <italic>sarU</italic> mutant, the decrease in <italic>aur</italic> and <italic>ssp</italic> transcription could be explained by the increase in <italic>rot</italic> transcription, as it has been shown by ourselves and others to be a repressor of both (<xref rid="B23" ref-type="bibr">23</xref>).</p></sec><sec id="s2.6"><title>Integrating the novel secondary protease regulators into the global picture of protease control.</title><p>Using the findings from this study, along with existing knowledge, we put forward a comprehensive map of secreted protease regulation (<xref ref-type="fig" rid="fig9">Fig. 9</xref>). With this knowledge, we are able to identify specific regulatory pathways connecting our novel protease effectors with the major protease regulators. Specifically, with regard to Rbf, it is possible that its repressive effect on <italic>sarS</italic> transcription is through Rot, as it was previously shown to activate <italic>sarS</italic> transcription (<xref rid="B35" ref-type="bibr">35</xref>, <xref rid="B71" ref-type="bibr">71</xref>) and <italic>rot</italic> transcription is increased in the <italic>rbf</italic> mutant. Next, with MntR, its positive effect on <italic>sarR</italic> transcription is likely occurring through MgrA, as it was previously shown that MgrA activates <italic>sarR</italic> transcription (<xref rid="B34" ref-type="bibr">34</xref>) and <italic>mgrA</italic> expression is decreased in the <italic>mntR</italic> mutant. As for Rex, its activation of <italic>sarR</italic> transcription could be occurring through MgrA, as it has been shown that MgrA activates <italic>sarR</italic> (<xref rid="B35" ref-type="bibr">35</xref>, <xref rid="B71" ref-type="bibr">71</xref>) and <italic>mgrA</italic> transcription is decreased in the absence of <italic>rex</italic>. Lastly, with XrdA, it is possible that its represses <italic>saeR</italic> via CodY, as it has been shown that CodY represses <italic>saeR</italic> transcription (<xref rid="B76" ref-type="bibr">76</xref>, <xref rid="B77" ref-type="bibr">77</xref>) and <italic>codY</italic> transcription is decreased in the <italic>xdrA</italic> mutant. Additionally, the negative effect of XdrA on <italic>sarR</italic> and <italic>sarS</italic> transcription could be occurring via MgrA, as it was previously shown that MgrA activates <italic>sarR</italic> and <italic>sarS</italic> transcription (<xref rid="B34" ref-type="bibr">34</xref>, <xref rid="B71" ref-type="bibr">71</xref>) and <italic>mgrA</italic> transcription is increased in the <italic>xdrA</italic> mutant. Finally, the activation of <italic>agr</italic> by XdrA could by occurring via the MgrA-SarR pathway, as SarR has been shown to repress <italic>agr</italic> transcription (<xref rid="B68" ref-type="bibr">68</xref>) and, as already noted, <italic>sarR</italic> transcription is increased in the <italic>xdrA</italic> mutant.</p><fig id="fig9" orientation="portrait" position="float"><label>FIG 9</label><caption><p>Mapping the global network of extracellular protease regulation in <named-content content-type="genus-species">Staphylococcus aureus</named-content>. The seven primary regulators of protease expression are shown in blue, while factors known to, in turn, regulate their expression are shown in dark green (activators) or dark red (repressors). The novel regulators identified in this study are shown in light green (activators) or light red (repressors). New regulatory pathways identified herein between the primary regulators and the protease loci are shown in green. New regulatory pathways identified herein between the primary regulators and the novel regulators are shown in blue.</p></caption><graphic xlink:href="mSphere.00676-19-f0009"></graphic></fig></sec><sec id="s2.7"><title>Concluding remarks.</title><p>In this study, we set out to completely characterize the locus-specific effects of regulatory factors on secreted protease expression. In so doing, we have identified an abundance of novel regulatory nodes controlling their production and present a comprehensive regulatory circuit that emphasizes the complexity of protease regulation (<xref ref-type="fig" rid="fig9">Fig. 9</xref>). When one compares this regulatory overview with the literature on virulence factor control in <named-content content-type="genus-species">S. aureus</named-content>, it becomes clear that the expansive and complex regulatory circuits that exist to oversee secreted protease expression rivals that of alpha-toxin and protein A, which are arguably some of the most important virulence-affecting entities produced by this organism (<xref rid="B35" ref-type="bibr">35</xref>, <xref rid="B65" ref-type="bibr">65</xref>, <xref rid="B78" ref-type="bibr">78</xref><xref ref-type="bibr" rid="B79">–</xref><xref rid="B85" ref-type="bibr">85</xref>). Indeed, we suggest that the existence of such a broad network of control speaks to the importance of the secreted proteases to <named-content content-type="genus-species">S. aureus</named-content> physiology and pathogenic potential. We also contend that there is a clear and obvious need for such a network, so as to limit or enhance the abundance (and thus activity) of these enzymes. The rationale for this is that a primary function of these enzymes is to control the progression of infection by selectively modulating the stability of individual virulence factors produced by the cell (<xref rid="B19" ref-type="bibr">19</xref>). Thus, in this context, it makes sense that a network of control exists to selectively titrate in or out a given protease (and thus its activity), so as to specifically influence the abundance (or lack thereof) of an individual virulence factor(s). This would then facilitate the selective and niche-specific pathogenic behaviors of <named-content content-type="genus-species">S. aureus</named-content> and provide a basis for control of the broad and varied infection types that is the hallmark of this organism’s disease-causing nature. In addition to this, there is abundant evidence in the literature implicating the secreted proteases as facilitating the infectious process by attacking the host and cleaving host proteins. It is thus in line with the above hypothesis that tightly controlling protease activity, by selectively limiting or enhancing their activity in specific niches, is to the advantage of <named-content content-type="genus-species">S. aureus</named-content> and its highly effective and efficient infectious process.</p></sec></sec><sec sec-type="materials|methods" id="s3"><title>MATERIALS AND METHODS</title><sec id="s3.1"><title>Media and growth conditions.</title><p>All cultures were grown overnight at 37°C with shaking at 250 rpm in 5 ml of either tryptic soy broth (TSB) or lysogeny broth (LB). When required, antibiotics were added at the following concentrations: for <named-content content-type="genus-species">Escherichia coli</named-content>, 100 μg ml<sup>−1</sup> ampicillin, 12.5 μg ml<sup>−1</sup> tetracycline; for <named-content content-type="genus-species">S. aureus</named-content>, 5 μg ml<sup>−1</sup> tetracycline, 5 μg ml<sup>−1</sup> erythromycin, 25 μg ml<sup>−1</sup> lincomycin, and 2.5 μg ml<sup>−1</sup> chloramphenicol. To obtain synchronous cultures, overnight <named-content content-type="genus-species">S. aureus</named-content> cultures were diluted 1:100 into 5 ml of fresh medium and grown for 3 h before being standardized to an optical density at 600 nm (OD<sub>600</sub>) of 0.05 in 100 ml of fresh TSB. When assessing growth, OD<sub>600</sub> was measured hourly using a Synergy 2 plate reader (Bio-Tek).</p></sec><sec id="s3.2"><title>Bacterial strains.</title><p>All bacterial strains and plasmids used in this study are listed in <xref rid="tab1" ref-type="table">Table 1</xref>. Transposon mutants for all available transcriptional regulators in <named-content content-type="genus-species">S. aureus</named-content> USA300 JE2 were obtained from the Nebraska Transposon Mutant Library (NTML). Those subjected to further study were transduced into USA300 Houston, as described by us previously (<xref rid="B86" ref-type="bibr">86</xref>), using ϕ11. The construction of an <italic>mgrA</italic> mutant in <named-content content-type="genus-species">S. aureus</named-content> Becker was previously described (<xref rid="B87" ref-type="bibr">87</xref>). This mutation was transduced into USA300 Houston using ϕ85.</p><table-wrap id="tab1" orientation="portrait" position="float"><label>TABLE 1</label><caption><p>Strains and plasmids used in this study</p></caption><alternatives><table frame="hsides" rules="groups"><colgroup span="1"><col span="1"></col><col span="1"></col><col span="1"></col></colgroup><thead><tr><th rowspan="1" colspan="1">Strain or plasmid</th><th rowspan="1" colspan="1">Description<xref ref-type="table-fn" rid="ngtab1.1"><sup><italic>a</italic></sup></xref></th><th rowspan="1" colspan="1">Reference or source</th></tr></thead><tbody><tr><td rowspan="1" colspan="1">Strains</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1"></td></tr><tr><td rowspan="1" colspan="1"> <named-content content-type="genus-species">E. coli</named-content></td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1"></td></tr><tr><td rowspan="1" colspan="1"> DH5α</td><td rowspan="1" colspan="1">Cloning strain</td><td rowspan="1" colspan="1"><xref rid="B92" ref-type="bibr">92</xref></td></tr><tr><td rowspan="1" colspan="1"> <named-content content-type="genus-species">S. aureus</named-content></td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1"></td></tr><tr><td rowspan="1" colspan="1"> RN4220</td><td rowspan="1" colspan="1">Restriction-deficient strain</td><td rowspan="1" colspan="1">Lab stock</td></tr><tr><td rowspan="1" colspan="1"> USA300 HOU</td><td rowspan="1" colspan="1">USA300 HOU MRSA isolate</td><td rowspan="1" colspan="1"><xref rid="B58" ref-type="bibr">58</xref></td></tr><tr><td rowspan="1" colspan="1"> BDG2625</td><td rowspan="1" colspan="1">USA300 HOU <italic>codY</italic>::Tn::<italic>erm</italic> Δ<italic>codY</italic></td><td rowspan="1" colspan="1">This study</td></tr><tr><td rowspan="1" colspan="1"> BDG2623</td><td rowspan="1" colspan="1">USA300 HOU <italic>sarS</italic>::Tn::<italic>erm</italic> Δ<italic>sarS</italic></td><td rowspan="1" colspan="1">This study</td></tr><tr><td rowspan="1" colspan="1"> BDG2621</td><td rowspan="1" colspan="1">USA300 HOU <italic>sarA</italic>::Tn::<italic>erm</italic> Δ<italic>sarA</italic></td><td rowspan="1" colspan="1">This study</td></tr><tr><td rowspan="1" colspan="1"> BDG2624</td><td rowspan="1" colspan="1">USA300 HOU <italic>rot</italic>::Tn::<italic>erm</italic> Δ<italic>rot</italic></td><td rowspan="1" colspan="1">This study</td></tr><tr><td rowspan="1" colspan="1"> BDG2622</td><td rowspan="1" colspan="1">USA300 HOU <italic>saeR</italic>::Tn::<italic>erm</italic> Δ<italic>saeR</italic></td><td rowspan="1" colspan="1">This study</td></tr><tr><td rowspan="1" colspan="1"> CYL1040</td><td rowspan="1" colspan="1">Becker <italic>mgrA</italic>::<italic>cm</italic> Δ<italic>mgrA</italic></td><td rowspan="1" colspan="1"><xref rid="B87" ref-type="bibr">87</xref></td></tr><tr><td rowspan="1" colspan="1"> BDG2626</td><td rowspan="1" colspan="1">USA300 HOU <italic>mgrA</italic>::<italic>cm</italic> Δ<italic>mgrA</italic></td><td rowspan="1" colspan="1">This study</td></tr><tr><td rowspan="1" colspan="1"> BDG2479</td><td rowspan="1" colspan="1">USA300 HOU <italic>sarR</italic>::<italic>tet</italic> Δ<italic>sarR</italic></td><td rowspan="1" colspan="1">This study</td></tr><tr><td rowspan="1" colspan="1"> BDG2331</td><td rowspan="1" colspan="1">USA300 HOU <italic>sarU</italic>::Tn::<italic>erm</italic> Δ<italic>sarU</italic></td><td rowspan="1" colspan="1">This study</td></tr><tr><td rowspan="1" colspan="1"> BDG2333</td><td rowspan="1" colspan="1">USA300 HOU <italic>rex</italic>::Tn::<italic>erm</italic> Δ<italic>rex</italic></td><td rowspan="1" colspan="1">This study</td></tr><tr><td rowspan="1" colspan="1"> BDG2329</td><td rowspan="1" colspan="1">USA300 HOU <italic>rbf</italic>::Tn::<italic>erm</italic> Δ<italic>rbf</italic></td><td rowspan="1" colspan="1">This study</td></tr><tr><td rowspan="1" colspan="1"> BDG2334</td><td rowspan="1" colspan="1">USA300 HOU <italic>argR2</italic>::Tn::<italic>erm</italic> Δ<italic>argR2</italic></td><td rowspan="1" colspan="1">This study</td></tr><tr><td rowspan="1" colspan="1"> BDG2336</td><td rowspan="1" colspan="1">USA300 HOU <italic>atlR</italic>::Tn::<italic>erm</italic> Δ<italic>atlR</italic></td><td rowspan="1" colspan="1">This study</td></tr><tr><td rowspan="1" colspan="1"> BDG2328</td><td rowspan="1" colspan="1">USA300 HOU <italic>mntR</italic>::Tn::<italic>erm</italic> Δ<italic>mntR</italic></td><td rowspan="1" colspan="1">This study</td></tr><tr><td rowspan="1" colspan="1"> BDG2332</td><td rowspan="1" colspan="1">USA300 HOU <italic>xdrA</italic>::Tn::<italic>erm</italic> Δ<italic>xdrA</italic></td><td rowspan="1" colspan="1">This study</td></tr><tr><td rowspan="1" colspan="1"> LES55</td><td rowspan="1" colspan="1">SH1000 <italic>sigS</italic>::<italic>tet</italic> Δ<italic>sigS</italic></td><td rowspan="1" colspan="1"><xref rid="B89" ref-type="bibr">89</xref></td></tr><tr><td rowspan="1" colspan="1">Plasmids</td><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1"></td></tr><tr><td rowspan="1" colspan="1"> pJB38</td><td rowspan="1" colspan="1">Plasmid to create mutants in <named-content content-type="genus-species">S. aureus</named-content></td><td rowspan="1" colspan="1"><xref rid="B88" ref-type="bibr">88</xref></td></tr><tr><td rowspan="1" colspan="1"> pBDG01</td><td rowspan="1" colspan="1">pJB38 construct for <italic>sarR</italic> mutation, Amp<sup>r</sup> CM<sup>r</sup></td><td rowspan="1" colspan="1">This study</td></tr></tbody></table><graphic xlink:href="mSphere.00676-19-t0001"></graphic></alternatives><table-wrap-foot><fn fn-type="other" id="ngtab1.1"><label>a</label><p>Erm, erythromycin; CM, chloramphenicol; Tet, tetracycline; Amp, ampicillin.</p></fn></table-wrap-foot></table-wrap></sec><sec id="s3.3"><title>Construction of a <italic>sarR</italic> mutant strain.</title><p>A tetracycline-marked disruption of <italic>sarR</italic> was generated using pJB38, as described by Bose et al. (<xref rid="B88" ref-type="bibr">88</xref>). Regions up- and downstream of <italic>sarR</italic>, including portions of the 5′ and 3′ ends of the coding gene, were amplified via PCR using primers OL4208/OL4209 and OL4210/OL4211. A tetracycline resistance cassette was amplified using OL4299/OL4300 from a SH1000 <italic>sigS</italic>::<italic>tet</italic> mutant (<xref rid="B89" ref-type="bibr">89</xref>). Using MluI sites, the tetracycline cassette was ligated between the upstream and downstream fragments of <italic>sarR</italic> and ligated directly into pJB38 using EcoRI and KpnI sites. Using the established protocol, the majority of <italic>sarR</italic> was deleted in USA300 Houston using allelic replacement (<xref rid="B88" ref-type="bibr">88</xref>). Strains were confirmed by PCR and sequencing (Eurofins Genomics) using primers OL4577/OL4578, which amplify across the deleted region where the tetracycline cassette was inserted.</p></sec><sec id="s3.4"><title>Quantitative real-time PCR analysis.</title><p>To quantify expression changes for target genes (primers are listed in <xref ref-type="supplementary-material" rid="tabS3">Table S3</xref> in the supplemental material), quantitative real-time PCR (qRT-PCR) was performed, as described by us previously (<xref rid="B90" ref-type="bibr">90</xref>). All targets were normalized using 16S rRNA expression, and fold change from the wild-type was determined using the threshold cycle (2<sup>−ΔΔ</sup><italic><sup>CT</sup></italic>) method (<xref rid="B91" ref-type="bibr">91</xref>). All graphical representations of fold changes are relative to the wild-type, ±1.</p><supplementary-material content-type="local-data" id="tabS3"><object-id pub-id-type="doi">10.1128/mSphere.00676-19.5</object-id><label>TABLE S3</label><p>Primers used in this study. <italic><sup>a</sup></italic> Restriction sites present in primers are denoted by underlining. <italic><sup>b</sup></italic> KO, knockout. Download <inline-supplementary-material id="tS3" mimetype="application" mime-subtype="pdf" xlink:href="mSphere.00676-19-st003.pdf" content-type="local-data">Table S3, PDF file, 0.03 MB</inline-supplementary-material>.</p><permissions><copyright-statement>Copyright © 2019 Gimza et al.</copyright-statement><copyright-year>2019</copyright-year><copyright-holder>Gimza et al.</copyright-holder><license license-type="open-access" xlink:href="https://creativecommons.org/licenses/by/4.0/"><license-p>This content is distributed under the terms of the <ext-link ext-link-type="uri" xlink:href="https://creativecommons.org/licenses/by/4.0/">Creative Commons Attribution 4.0 International license</ext-link>.</license-p></license></permissions></supplementary-material></sec><sec id="s3.5"><title>Zymography.</title><p>Strains grown for 15 h overnight were adjusted to equal optical densities and pelleted. When assessing proteolytic activity over time, synchronized cultures were grown to exponential phase and standardized to an OD<sub>600</sub> of 0.05 in 100 ml of TSB. At the desired time points, cells were pelleted. Thereafter, for all samples, 2 ml of supernatant was processed through an Amicon Ultra 3K centrifugal filter for 60 min at 4,000 × <italic>g</italic>. Concentrated supernatants were recovered by removing filtrate collection tubes, inverting filter devices, and spinning again for 2 min at 1,000 × <italic>g</italic>. Equal volumes of Laemmli loading buffer were added to the concentrated supernatants and incubated for 30 min at 37°C. Next, 20 μl of each sample was loaded onto preprepared SDS-PAGE gels containing 0.1% gelatin and run until the dye front reached the edge of the plates. Gels were washed twice using 2.5% Triton X-100 at room temperature. Following a rinse with distilled water (dH<sub>2</sub>O), developing buffer (0.2 M Tris, 5 mM CaCl<sub>2</sub>, 1 mM dithiothreitol [DTT], pH 7.6) was added and gels were incubated overnight at 37°C static. After incubation, gels were rinsed with dH<sub>2</sub>O and covered with 0.1% amido black for 1 h. Once gels were stained, destain 1 (30% methanol, 10% acetic acid) was added for 5 to 10 min, replaced with destain 2 (10% acetic acid) until bands became clear, and then replaced with destain 3 (1% acetic acid) for storage. Changes in band intensity were quantified using ImageJ software.</p></sec></sec></body><back><ack><title>ACKNOWLEDGMENT</title><p>This study was supported by grant AI124458 (to L.N.S.) from the National Institute of Allergy and Infectious Diseases.</p></ack><ref-list><title>REFERENCES</title><ref id="B1"><label>1.</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name name-style="western"><surname>Torres</surname><given-names>VJ</given-names></name>, <name name-style="western"><surname>Stauff</surname><given-names>DL</given-names></name>, <name name-style="western"><surname>Pishchany</surname><given-names>G</given-names></name>, <name name-style="western"><surname>Bezbradica</surname><given-names>JS</given-names></name>, <name name-style="western"><surname>Gordy</surname><given-names>LE</given-names></name>, <name name-style="western"><surname>Iturregui</surname><given-names>J</given-names></name>, <name 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