Severe Acute Respiratory Syndrome Coronavirus Replication Is Severely Impaired by MG132 due to Proteasome-Independent Inhibition of M-Calpain
Identifieur interne : 000C72 ( Pmc/Corpus ); précédent : 000C71; suivant : 000C73Severe Acute Respiratory Syndrome Coronavirus Replication Is Severely Impaired by MG132 due to Proteasome-Independent Inhibition of M-Calpain
Auteurs : Martha Schneider ; Kerstin Ackermann ; Melissa Stuart ; Claudia Wex ; Ulrike Protzer ; Hermann M. Sch Tzl ; Sabine GilchSource :
- Journal of Virology [ 0022-538X ] ; 2012.
Abstract
The ubiquitin-proteasome system (UPS) is involved in the replication of a broad range of viruses. Since replication of the murine hepatitis virus (MHV) is impaired upon proteasomal inhibition, the relevance of the UPS for the replication of the severe acute respiratory syndrome coronavirus (SARS-CoV) was investigated in this study. We demonstrate that the proteasomal inhibitor MG132 strongly inhibits SARS-CoV replication by interfering with early steps of the viral life cycle. Surprisingly, other proteasomal inhibitors (e.g., lactacystin and bortezomib) only marginally affected viral replication, indicating that the effect of MG132 is independent of proteasomal impairment. Induction of autophagy by MG132 treatment was excluded from playing a role, and no changes in SARS-CoV titers were observed during infection of wild-type or autophagy-deficient ATG5−/− mouse embryonic fibroblasts overexpressing the human SARS-CoV receptor, angiotensin-converting enzyme 2 (ACE2). Since MG132 also inhibits the cysteine protease m-calpain, we addressed the role of calpains in the early SARS-CoV life cycle using calpain inhibitors III (MDL28170) and VI (SJA6017). In fact, m-calpain inhibition with MDL28170 resulted in an even more pronounced inhibition of SARS-CoV replication (>7 orders of magnitude) than did MG132. Additional m-calpain knockdown experiments confirmed the dependence of SARS-CoV replication on the activity of the cysteine protease m-calpain. Taken together, we provide strong experimental evidence that SARS-CoV has unique replication requirements which are independent of functional UPS or autophagy pathways compared to other coronaviruses. Additionally, this work highlights an important role for m-calpain during early steps of the SARS-CoV life cycle.
Url:
DOI: 10.1128/JVI.01001-12
PubMed: 22787216
PubMed Central: 3446591
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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Severe Acute Respiratory Syndrome Coronavirus Replication Is Severely Impaired by MG132 due to Proteasome-Independent Inhibition of M-Calpain</title><author><name sortKey="Schneider, Martha" sort="Schneider, Martha" uniqKey="Schneider M" first="Martha" last="Schneider">Martha Schneider</name><affiliation><nlm:aff id="aff1">Institute of Virology, Technische Universität München, Munich, Germany</nlm:aff></affiliation><affiliation><nlm:aff id="aff2">Institute of Virology, Helmholtz Zentrum München, Oberschleissheim, Germany</nlm:aff></affiliation></author><author><name sortKey="Ackermann, Kerstin" sort="Ackermann, Kerstin" uniqKey="Ackermann K" first="Kerstin" last="Ackermann">Kerstin Ackermann</name><affiliation><nlm:aff id="aff1">Institute of Virology, Technische Universität München, Munich, Germany</nlm:aff></affiliation></author><author><name sortKey="Stuart, Melissa" sort="Stuart, Melissa" uniqKey="Stuart M" first="Melissa" last="Stuart">Melissa Stuart</name><affiliation><nlm:aff id="aff3">Departments of Veterinary Sciences and Molecular Biology, University of Wyoming, Laramie, Wyoming, USA</nlm:aff></affiliation></author><author><name sortKey="Wex, Claudia" sort="Wex, Claudia" uniqKey="Wex C" first="Claudia" last="Wex">Claudia Wex</name><affiliation><nlm:aff id="aff1">Institute of Virology, Technische Universität München, Munich, Germany</nlm:aff></affiliation></author><author><name sortKey="Protzer, Ulrike" sort="Protzer, Ulrike" uniqKey="Protzer U" first="Ulrike" last="Protzer">Ulrike Protzer</name><affiliation><nlm:aff id="aff1">Institute of Virology, Technische Universität München, Munich, Germany</nlm:aff></affiliation><affiliation><nlm:aff id="aff2">Institute of Virology, Helmholtz Zentrum München, Oberschleissheim, Germany</nlm:aff></affiliation></author><author><name sortKey="Sch Tzl, Hermann M" sort="Sch Tzl, Hermann M" uniqKey="Sch Tzl H" first="Hermann M." last="Sch Tzl">Hermann M. Sch Tzl</name><affiliation><nlm:aff id="aff1">Institute of Virology, Technische Universität München, Munich, Germany</nlm:aff></affiliation><affiliation><nlm:aff id="aff3">Departments of Veterinary Sciences and Molecular Biology, University of Wyoming, Laramie, Wyoming, USA</nlm:aff></affiliation></author><author><name sortKey="Gilch, Sabine" sort="Gilch, Sabine" uniqKey="Gilch S" first="Sabine" last="Gilch">Sabine Gilch</name><affiliation><nlm:aff id="aff1">Institute of Virology, Technische Universität München, Munich, Germany</nlm:aff></affiliation><affiliation><nlm:aff id="aff3">Departments of Veterinary Sciences and Molecular Biology, University of Wyoming, Laramie, Wyoming, USA</nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">22787216</idno><idno type="pmc">3446591</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3446591</idno><idno type="RBID">PMC:3446591</idno><idno type="doi">10.1128/JVI.01001-12</idno><date when="2012">2012</date><idno type="wicri:Area/Pmc/Corpus">000C72</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000C72</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Severe Acute Respiratory Syndrome Coronavirus Replication Is Severely Impaired by MG132 due to Proteasome-Independent Inhibition of M-Calpain</title><author><name sortKey="Schneider, Martha" sort="Schneider, Martha" uniqKey="Schneider M" first="Martha" last="Schneider">Martha Schneider</name><affiliation><nlm:aff id="aff1">Institute of Virology, Technische Universität München, Munich, Germany</nlm:aff></affiliation><affiliation><nlm:aff id="aff2">Institute of Virology, Helmholtz Zentrum München, Oberschleissheim, Germany</nlm:aff></affiliation></author><author><name sortKey="Ackermann, Kerstin" sort="Ackermann, Kerstin" uniqKey="Ackermann K" first="Kerstin" last="Ackermann">Kerstin Ackermann</name><affiliation><nlm:aff id="aff1">Institute of Virology, Technische Universität München, Munich, Germany</nlm:aff></affiliation></author><author><name sortKey="Stuart, Melissa" sort="Stuart, Melissa" uniqKey="Stuart M" first="Melissa" last="Stuart">Melissa Stuart</name><affiliation><nlm:aff id="aff3">Departments of Veterinary Sciences and Molecular Biology, University of Wyoming, Laramie, Wyoming, USA</nlm:aff></affiliation></author><author><name sortKey="Wex, Claudia" sort="Wex, Claudia" uniqKey="Wex C" first="Claudia" last="Wex">Claudia Wex</name><affiliation><nlm:aff id="aff1">Institute of Virology, Technische Universität München, Munich, Germany</nlm:aff></affiliation></author><author><name sortKey="Protzer, Ulrike" sort="Protzer, Ulrike" uniqKey="Protzer U" first="Ulrike" last="Protzer">Ulrike Protzer</name><affiliation><nlm:aff id="aff1">Institute of Virology, Technische Universität München, Munich, Germany</nlm:aff></affiliation><affiliation><nlm:aff id="aff2">Institute of Virology, Helmholtz Zentrum München, Oberschleissheim, Germany</nlm:aff></affiliation></author><author><name sortKey="Sch Tzl, Hermann M" sort="Sch Tzl, Hermann M" uniqKey="Sch Tzl H" first="Hermann M." last="Sch Tzl">Hermann M. Sch Tzl</name><affiliation><nlm:aff id="aff1">Institute of Virology, Technische Universität München, Munich, Germany</nlm:aff></affiliation><affiliation><nlm:aff id="aff3">Departments of Veterinary Sciences and Molecular Biology, University of Wyoming, Laramie, Wyoming, USA</nlm:aff></affiliation></author><author><name sortKey="Gilch, Sabine" sort="Gilch, Sabine" uniqKey="Gilch S" first="Sabine" last="Gilch">Sabine Gilch</name><affiliation><nlm:aff id="aff1">Institute of Virology, Technische Universität München, Munich, Germany</nlm:aff></affiliation><affiliation><nlm:aff id="aff3">Departments of Veterinary Sciences and Molecular Biology, University of Wyoming, Laramie, Wyoming, USA</nlm:aff></affiliation></author></analytic><series><title level="j">Journal of Virology</title><idno type="ISSN">0022-538X</idno><idno type="eISSN">1098-5514</idno><imprint><date when="2012">2012</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>The ubiquitin-proteasome system (UPS) is involved in the replication of a broad range of viruses. Since replication of the murine hepatitis virus (MHV) is impaired upon proteasomal inhibition, the relevance of the UPS for the replication of the severe acute respiratory syndrome coronavirus (SARS-CoV) was investigated in this study. We demonstrate that the proteasomal inhibitor MG132 strongly inhibits SARS-CoV replication by interfering with early steps of the viral life cycle. Surprisingly, other proteasomal inhibitors (e.g., lactacystin and bortezomib) only marginally affected viral replication, indicating that the effect of MG132 is independent of proteasomal impairment. Induction of autophagy by MG132 treatment was excluded from playing a role, and no changes in SARS-CoV titers were observed during infection of wild-type or autophagy-deficient ATG5<sup>−/−</sup> mouse embryonic fibroblasts overexpressing the human SARS-CoV receptor, angiotensin-converting enzyme 2 (ACE2). Since MG132 also inhibits the cysteine protease m-calpain, we addressed the role of calpains in the early SARS-CoV life cycle using calpain inhibitors III (MDL28170) and VI (SJA6017). In fact, m-calpain inhibition with MDL28170 resulted in an even more pronounced inhibition of SARS-CoV replication (>7 orders of magnitude) than did MG132. Additional m-calpain knockdown experiments confirmed the dependence of SARS-CoV replication on the activity of the cysteine protease m-calpain. Taken together, we provide strong experimental evidence that SARS-CoV has unique replication requirements which are independent of functional UPS or autophagy pathways compared to other coronaviruses. Additionally, this work highlights an important role for m-calpain during early steps of the SARS-CoV life cycle.</p></div></front></TEI><pmc article-type="research-article"><pmc-comment>The publisher of this article does not allow downloading of the full text in XML form.</pmc-comment>
<front><journal-meta><journal-id journal-id-type="nlm-ta">J Virol</journal-id><journal-id journal-id-type="iso-abbrev">J. Virol</journal-id><journal-id journal-id-type="hwp">jvi</journal-id><journal-id journal-id-type="pmc">jvi</journal-id><journal-id journal-id-type="publisher-id">JVI</journal-id><journal-title-group><journal-title>Journal of Virology</journal-title></journal-title-group><issn pub-type="ppub">0022-538X</issn><issn pub-type="epub">1098-5514</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">22787216</article-id><article-id pub-id-type="pmc">3446591</article-id><article-id pub-id-type="publisher-id">01001-12</article-id><article-id pub-id-type="doi">10.1128/JVI.01001-12</article-id><article-categories><subj-group subj-group-type="heading"><subject>Virus-Cell Interactions</subject></subj-group></article-categories><title-group><article-title>Severe Acute Respiratory Syndrome Coronavirus Replication Is Severely Impaired by MG132 due to Proteasome-Independent Inhibition of M-Calpain</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Schneider</surname><given-names>Martha</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref><xref ref-type="aff" rid="aff2"><sup>b</sup></xref></contrib><contrib contrib-type="author"><name><surname>Ackermann</surname><given-names>Kerstin</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref></contrib><contrib contrib-type="author"><name><surname>Stuart</surname><given-names>Melissa</given-names></name><xref ref-type="aff" rid="aff3"><sup>c</sup></xref></contrib><contrib contrib-type="author"><name><surname>Wex</surname><given-names>Claudia</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref></contrib><contrib contrib-type="author"><name><surname>Protzer</surname><given-names>Ulrike</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref><xref ref-type="aff" rid="aff2"><sup>b</sup></xref></contrib><contrib contrib-type="author"><name><surname>Schätzl</surname><given-names>Hermann M.</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref><xref ref-type="aff" rid="aff3"><sup>c</sup></xref></contrib><contrib contrib-type="author" corresp="yes"><name><surname>Gilch</surname><given-names>Sabine</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref><xref ref-type="aff" rid="aff3"><sup>c</sup></xref></contrib><aff id="aff1"><label>a</label>Institute of Virology, Technische Universität München, Munich, Germany</aff><aff id="aff2"><label>b</label>Institute of Virology, Helmholtz Zentrum München, Oberschleissheim, Germany</aff><aff id="aff3"><label>c</label>Departments of Veterinary Sciences and Molecular Biology, University of Wyoming, Laramie, Wyoming, USA</aff></contrib-group><author-notes><corresp>Address correspondence to Sabine Gilch, <email>sgilch@uwyo.edu</email>.</corresp></author-notes><pub-date pub-type="ppub"><month>9</month><year>2012</year></pub-date><volume>86</volume><issue>18</issue><fpage>10112</fpage><lpage>10122</lpage><history><date date-type="received"><day>23</day><month>4</month><year>2012</year></date><date date-type="accepted"><day>3</day><month>7</month><year>2012</year></date></history><permissions><copyright-statement>Copyright © 2012, American Society for Microbiology. All Rights Reserved.</copyright-statement><copyright-year>2012</copyright-year><copyright-holder>American Society for Microbiology</copyright-holder></permissions><self-uri xlink:title="pdf" xlink:type="simple" xlink:href="zjv01812010112.pdf"></self-uri><abstract><p>The ubiquitin-proteasome system (UPS) is involved in the replication of a broad range of viruses. Since replication of the murine hepatitis virus (MHV) is impaired upon proteasomal inhibition, the relevance of the UPS for the replication of the severe acute respiratory syndrome coronavirus (SARS-CoV) was investigated in this study. We demonstrate that the proteasomal inhibitor MG132 strongly inhibits SARS-CoV replication by interfering with early steps of the viral life cycle. Surprisingly, other proteasomal inhibitors (e.g., lactacystin and bortezomib) only marginally affected viral replication, indicating that the effect of MG132 is independent of proteasomal impairment. Induction of autophagy by MG132 treatment was excluded from playing a role, and no changes in SARS-CoV titers were observed during infection of wild-type or autophagy-deficient ATG5<sup>−/−</sup> mouse embryonic fibroblasts overexpressing the human SARS-CoV receptor, angiotensin-converting enzyme 2 (ACE2). Since MG132 also inhibits the cysteine protease m-calpain, we addressed the role of calpains in the early SARS-CoV life cycle using calpain inhibitors III (MDL28170) and VI (SJA6017). In fact, m-calpain inhibition with MDL28170 resulted in an even more pronounced inhibition of SARS-CoV replication (>7 orders of magnitude) than did MG132. Additional m-calpain knockdown experiments confirmed the dependence of SARS-CoV replication on the activity of the cysteine protease m-calpain. Taken together, we provide strong experimental evidence that SARS-CoV has unique replication requirements which are independent of functional UPS or autophagy pathways compared to other coronaviruses. Additionally, this work highlights an important role for m-calpain during early steps of the SARS-CoV life cycle.</p></abstract></article-meta></front></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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