Inhibition of Proprotein Convertases Abrogates Processing of the Middle Eastern Respiratory Syndrome Coronavirus Spike Protein in Infected Cells but Does Not Reduce Viral Infectivity
Identifieur interne : 000E22 ( Pmc/Curation ); précédent : 000E21; suivant : 000E23Inhibition of Proprotein Convertases Abrogates Processing of the Middle Eastern Respiratory Syndrome Coronavirus Spike Protein in Infected Cells but Does Not Reduce Viral Infectivity
Auteurs : Stefanie Gierer ; Marcel A. Müller ; Adeline Heurich ; Daniel Ritz ; Benjamin L. Springstein ; Christina B. Karsten [Allemagne] ; Alexander Schendzielorz ; Kerstin Gnir ; Christian Drosten ; Stefan PöhlmannSource :
- The Journal of Infectious Diseases [ 0022-1899 ] ; 2014.
Abstract
Middle East respiratory syndrome coronavirus (MERS-CoV) infection is associated with a high case-fatality rate, and the potential pandemic spread of the virus is a public health concern. The spike protein of MERS-CoV (MERS-S) facilitates viral entry into host cells, which depends on activation of MERS-S by cellular proteases. Proteolytic activation of MERS-S during viral uptake into target cells has been demonstrated. However, it is unclear whether MERS-S is also cleaved during S protein synthesis in infected cells and whether cleavage is required for MERS-CoV infectivity. Here, we show that MERS-S is processed by proprotein convertases in MERS-S–transfected and MERS-CoV–infected cells and that several RXXR motifs located at the border between the surface and transmembrane subunit of MERS-S are required for efficient proteolysis. However, blockade of proprotein convertases did not impact MERS-S–dependent transduction of target cells expressing high amounts of the viral receptor, DPP4, and did not modulate MERS-CoV infectivity. These results show that MERS-S is a substrate for proprotein convertases and demonstrate that processing by these enzymes is dispensable for S protein activation. Efforts to inhibit MERS-CoV infection by targeting host cell proteases should therefore focus on enzymes that process MERS-S during viral uptake into target cells.
Url:
DOI: 10.1093/infdis/jiu407
PubMed: 25057042
PubMed Central: 7107327
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<front><div type="abstract" xml:lang="en"><title>Abstract</title>
<p>Middle East respiratory syndrome coronavirus (MERS-CoV) infection is associated with a high case-fatality rate, and the potential pandemic spread of the virus is a public health concern. The spike protein of MERS-CoV (MERS-S) facilitates viral entry into host cells, which depends on activation of MERS-S by cellular proteases. Proteolytic activation of MERS-S during viral uptake into target cells has been demonstrated. However, it is unclear whether MERS-S is also cleaved during S protein synthesis in infected cells and whether cleavage is required for MERS-CoV infectivity. Here, we show that MERS-S is processed by proprotein convertases in MERS-S–transfected and MERS-CoV–infected cells and that several RXXR motifs located at the border between the surface and transmembrane subunit of MERS-S are required for efficient proteolysis. However, blockade of proprotein convertases did not impact MERS-S–dependent transduction of target cells expressing high amounts of the viral receptor, DPP4, and did not modulate MERS-CoV infectivity. These results show that MERS-S is a substrate for proprotein convertases and demonstrate that processing by these enzymes is dispensable for S protein activation. Efforts to inhibit MERS-CoV infection by targeting host cell proteases should therefore focus on enzymes that process MERS-S during viral uptake into target cells.</p>
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<pmc article-type="research-article"><pmc-dir>properties open_access</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-ta">J Infect Dis</journal-id>
<journal-id journal-id-type="iso-abbrev">J. Infect. Dis</journal-id>
<journal-id journal-id-type="publisher-id">jid</journal-id>
<journal-id journal-id-type="hwp">jinfdis</journal-id>
<journal-title-group><journal-title>The Journal of Infectious Diseases</journal-title>
</journal-title-group>
<issn pub-type="ppub">0022-1899</issn>
<issn pub-type="epub">1537-6613</issn>
<publisher><publisher-name>Oxford University Press</publisher-name>
</publisher>
</journal-meta>
<article-meta><article-id pub-id-type="pmid">25057042</article-id>
<article-id pub-id-type="pmc">7107327</article-id>
<article-id pub-id-type="doi">10.1093/infdis/jiu407</article-id>
<article-id pub-id-type="publisher-id">jiu407</article-id>
<article-categories><subj-group subj-group-type="heading"><subject>Major Articles and Brief Reports</subject>
<subj-group subj-group-type="category-toc-heading"><subject>Viruses</subject>
</subj-group>
</subj-group>
</article-categories>
<title-group><article-title>Inhibition of Proprotein Convertases Abrogates Processing of the Middle Eastern Respiratory Syndrome Coronavirus Spike Protein in Infected Cells but Does Not Reduce Viral Infectivity</article-title>
</title-group>
<contrib-group><contrib contrib-type="author"><name><surname>Gierer</surname>
<given-names>Stefanie</given-names>
</name>
<xref ref-type="aff" rid="af1">1</xref>
<pmc-comment>spoehlmann@dpz.eu </pmc-comment>
<xref ref-type="corresp" rid="d4747e220"></xref>
</contrib>
<contrib contrib-type="author"><name><surname>Müller</surname>
<given-names>Marcel A.</given-names>
</name>
<xref ref-type="aff" rid="af2">2</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Heurich</surname>
<given-names>Adeline</given-names>
</name>
<xref ref-type="aff" rid="af1">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Ritz</surname>
<given-names>Daniel</given-names>
</name>
<xref ref-type="aff" rid="af2">2</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Springstein</surname>
<given-names>Benjamin L.</given-names>
</name>
<xref ref-type="aff" rid="af1">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Karsten</surname>
<given-names>Christina B.</given-names>
</name>
<xref ref-type="aff" rid="af1">1</xref>
<xref ref-type="aff" rid="af3">3</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Schendzielorz</surname>
<given-names>Alexander</given-names>
</name>
<xref ref-type="aff" rid="af1">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Gnirß</surname>
<given-names>Kerstin</given-names>
</name>
<xref ref-type="aff" rid="af1">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Drosten</surname>
<given-names>Christian</given-names>
</name>
<xref ref-type="aff" rid="af2">2</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Pöhlmann</surname>
<given-names>Stefan</given-names>
</name>
<xref ref-type="aff" rid="af1">1</xref>
</contrib>
</contrib-group>
<aff id="af1"><label>1</label>
<addr-line>Infection Biology Unit</addr-line>
,<institution>German Primate Center</institution>
,<addr-line>Göttingen</addr-line>
</aff>
<aff id="af2"><label>2</label>
<addr-line>Institute of Virology</addr-line>
,<institution>University of Bonn Medical Center</institution>
</aff>
<aff id="af3"><label>3</label>
<addr-line>Institute for Cellular Chemistry</addr-line>
,<institution>Hannover Medical School</institution>
,<country>Germany</country>
</aff>
<author-notes><fn id="TN1" fn-type="con"><p>Presented in part: 7th European Meeting on Viral Zoonoses, St. Raphaël, France, 24–27 May 2014.</p>
</fn>
<corresp id="d4747e220">Correspondence: Stefan Pöhlmann, PhD, Infection Biology Unit, German Primate Center, Kellnerweg 4, 37077 Göttingen, Germany (<email>spoehlmann@dpz.eu</email>
).</corresp>
</author-notes>
<pub-date pub-type="ppub"><day>15</day>
<month>3</month>
<year>2015</year>
</pub-date>
<pub-date pub-type="epub" iso-8601-date="2014-07-23"><day>23</day>
<month>7</month>
<year>2014</year>
</pub-date>
<volume>211</volume>
<issue>6</issue>
<fpage>889</fpage>
<lpage>897</lpage>
<history><date date-type="received"><day>23</day>
<month>4</month>
<year>2014</year>
</date>
<date date-type="accepted"><day>10</day>
<month>7</month>
<year>2014</year>
</date>
</history>
<permissions><copyright-statement>© The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: <email>journals.permissions@oup.com</email>
.</copyright-statement>
<copyright-year>2014</copyright-year>
<license><license-p>This article is made available via the PMC Open Access Subset for unrestricted re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the COVID-19 pandemic or until permissions are revoked in writing. Upon expiration of these permissions, PMC is granted a perpetual license to make this article available via PMC and Europe PMC, consistent with existing copyright protections.</license-p>
</license>
</permissions>
<self-uri xlink:href="jiu407.pdf"></self-uri>
<abstract><title>Abstract</title>
<p>Middle East respiratory syndrome coronavirus (MERS-CoV) infection is associated with a high case-fatality rate, and the potential pandemic spread of the virus is a public health concern. The spike protein of MERS-CoV (MERS-S) facilitates viral entry into host cells, which depends on activation of MERS-S by cellular proteases. Proteolytic activation of MERS-S during viral uptake into target cells has been demonstrated. However, it is unclear whether MERS-S is also cleaved during S protein synthesis in infected cells and whether cleavage is required for MERS-CoV infectivity. Here, we show that MERS-S is processed by proprotein convertases in MERS-S–transfected and MERS-CoV–infected cells and that several RXXR motifs located at the border between the surface and transmembrane subunit of MERS-S are required for efficient proteolysis. However, blockade of proprotein convertases did not impact MERS-S–dependent transduction of target cells expressing high amounts of the viral receptor, DPP4, and did not modulate MERS-CoV infectivity. These results show that MERS-S is a substrate for proprotein convertases and demonstrate that processing by these enzymes is dispensable for S protein activation. Efforts to inhibit MERS-CoV infection by targeting host cell proteases should therefore focus on enzymes that process MERS-S during viral uptake into target cells.</p>
</abstract>
<kwd-group><kwd>MERS-coronavirus</kwd>
<kwd>protease</kwd>
<kwd>TMPRSS2</kwd>
<kwd>trypsin</kwd>
<kwd>proprotein convertase</kwd>
<kwd>spike</kwd>
<kwd>activation</kwd>
</kwd-group>
</article-meta>
</front>
</pmc>
</record>
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