Coronavirus Cell Entry Occurs through the Endo-/Lysosomal Pathway in a Proteolysis-Dependent Manner
Identifieur interne : 001120 ( Pmc/Checkpoint ); précédent : 001119; suivant : 001121Coronavirus Cell Entry Occurs through the Endo-/Lysosomal Pathway in a Proteolysis-Dependent Manner
Auteurs : Christine Burkard [Pays-Bas] ; Monique H. Verheije [Pays-Bas] ; Oliver Wicht [Pays-Bas] ; Sander I. Van Kasteren [Pays-Bas] ; Frank J. Van Kuppeveld [Pays-Bas] ; Bart L. Haagmans [Pays-Bas] ; Lucas Pelkmans [Suisse] ; Peter J. M. Rottier [Pays-Bas] ; Berend Jan Bosch [Pays-Bas] ; Cornelis A. M. De Haan [Pays-Bas]Source :
- PLoS Pathogens [ 1553-7366 ] ; 2014.
Abstract
Enveloped viruses need to fuse with a host cell membrane in order to deliver their genome into the host cell. While some viruses fuse with the plasma membrane, many viruses are endocytosed prior to fusion. Specific cues in the endosomal microenvironment induce conformational changes in the viral fusion proteins leading to viral and host membrane fusion. In the present study we investigated the entry of coronaviruses (CoVs). Using siRNA gene silencing, we found that proteins known to be important for late endosomal maturation and endosome-lysosome fusion profoundly promote infection of cells with mouse hepatitis coronavirus (MHV). Using recombinant MHVs expressing reporter genes as well as a novel, replication-independent fusion assay we confirmed the importance of clathrin-mediated endocytosis and demonstrated that trafficking of MHV to lysosomes is required for fusion and productive entry to occur. Nevertheless, MHV was shown to be less sensitive to perturbation of endosomal pH than vesicular stomatitis virus and influenza A virus, which fuse in early and late endosomes, respectively. Our results indicate that entry of MHV depends on proteolytic processing of its fusion protein S by lysosomal proteases. Fusion of MHV was severely inhibited by a pan-lysosomal protease inhibitor, while trafficking of MHV to lysosomes and processing by lysosomal proteases was no longer required when a furin cleavage site was introduced in the S protein immediately upstream of the fusion peptide. Also entry of feline CoV was shown to depend on trafficking to lysosomes and processing by lysosomal proteases. In contrast, MERS-CoV, which contains a minimal furin cleavage site just upstream of the fusion peptide, was negatively affected by inhibition of furin, but not of lysosomal proteases. We conclude that a proteolytic cleavage site in the CoV S protein directly upstream of the fusion peptide is an essential determinant of the intracellular site of fusion.
Url:
DOI: 10.1371/journal.ppat.1004502
PubMed: 25375324
PubMed Central: 4223067
Affiliations:
- Pays-Bas, Suisse
- Canton de Zurich, Hollande-Méridionale, Utrecht (province)
- Leyde, Rotterdam, Utrecht, Zurich
- Université d'Utrecht, Université de Zurich
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PMC:4223067Le document en format XML
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<front><div type="abstract" xml:lang="en"><p>Enveloped viruses need to fuse with a host cell membrane in order to deliver their genome into the host cell. While some viruses fuse with the plasma membrane, many viruses are endocytosed prior to fusion. Specific cues in the endosomal microenvironment induce conformational changes in the viral fusion proteins leading to viral and host membrane fusion. In the present study we investigated the entry of coronaviruses (CoVs). Using siRNA gene silencing, we found that proteins known to be important for late endosomal maturation and endosome-lysosome fusion profoundly promote infection of cells with mouse hepatitis coronavirus (MHV). Using recombinant MHVs expressing reporter genes as well as a novel, replication-independent fusion assay we confirmed the importance of clathrin-mediated endocytosis and demonstrated that trafficking of MHV to lysosomes is required for fusion and productive entry to occur. Nevertheless, MHV was shown to be less sensitive to perturbation of endosomal pH than vesicular stomatitis virus and influenza A virus, which fuse in early and late endosomes, respectively. Our results indicate that entry of MHV depends on proteolytic processing of its fusion protein S by lysosomal proteases. Fusion of MHV was severely inhibited by a pan-lysosomal protease inhibitor, while trafficking of MHV to lysosomes and processing by lysosomal proteases was no longer required when a furin cleavage site was introduced in the S protein immediately upstream of the fusion peptide. Also entry of feline CoV was shown to depend on trafficking to lysosomes and processing by lysosomal proteases. In contrast, MERS-CoV, which contains a minimal furin cleavage site just upstream of the fusion peptide, was negatively affected by inhibition of furin, but not of lysosomal proteases. We conclude that a proteolytic cleavage site in the CoV S protein directly upstream of the fusion peptide is an essential determinant of the intracellular site of fusion.</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">PLoS Pathog</journal-id>
<journal-id journal-id-type="iso-abbrev">PLoS Pathog</journal-id>
<journal-id journal-id-type="publisher-id">plos</journal-id>
<journal-id journal-id-type="pmc">plospath</journal-id>
<journal-title-group><journal-title>PLoS Pathogens</journal-title>
</journal-title-group>
<issn pub-type="ppub">1553-7366</issn>
<issn pub-type="epub">1553-7374</issn>
<publisher><publisher-name>Public Library of Science</publisher-name>
<publisher-loc>San Francisco, USA</publisher-loc>
</publisher>
</journal-meta>
<article-meta><article-id pub-id-type="pmid">25375324</article-id>
<article-id pub-id-type="pmc">4223067</article-id>
<article-id pub-id-type="publisher-id">PPATHOGENS-D-14-01221</article-id>
<article-id pub-id-type="doi">10.1371/journal.ppat.1004502</article-id>
<article-categories><subj-group subj-group-type="heading"><subject>Research Article</subject>
</subj-group>
<subj-group subj-group-type="Discipline-v2"><subject>Biology and life sciences</subject>
<subj-group><subject>Microbiology</subject>
<subj-group><subject>Medical Microbiology</subject>
<subj-group><subject>Microbial Pathogens</subject>
<subj-group><subject>Viral Pathogens</subject>
<subj-group><subject>Coronaviruses</subject>
<subj-group><subject>Feline Coronavirus</subject>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
<subj-group><subject>Virology</subject>
<subj-group><subject>Viral Transmission and Infection</subject>
<subj-group><subject>Host Cells</subject>
<subject>Viral Attachment</subject>
<subject>Viral Entry</subject>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
<subj-group><subject>Organisms</subject>
<subj-group><subject>Viruses</subject>
<subj-group><subject>RNA viruses</subject>
</subj-group>
</subj-group>
</subj-group>
</subj-group>
<subj-group subj-group-type="Discipline-v2"><subject>Medicine and Health Sciences</subject>
<subj-group><subject>Pathology and Laboratory Medicine</subject>
<subj-group><subject>Pathogens</subject>
</subj-group>
</subj-group>
</subj-group>
</article-categories>
<title-group><article-title>Coronavirus Cell Entry Occurs through the Endo-/Lysosomal Pathway in a Proteolysis-Dependent Manner</article-title>
<alt-title alt-title-type="running-head">Proteolysis-Dependent Coronavirus Entry via an Endo-/Lysosomal Pathway</alt-title>
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<contrib-group><contrib contrib-type="author"><name><surname>Burkard</surname>
<given-names>Christine</given-names>
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<xref ref-type="aff" rid="aff1"><sup>1</sup>
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<xref ref-type="author-notes" rid="fn1"><sup>¤a</sup>
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<given-names>Monique H.</given-names>
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<xref ref-type="aff" rid="aff1"><sup>1</sup>
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<xref ref-type="author-notes" rid="fn2"><sup>¤b</sup>
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<given-names>Oliver</given-names>
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<xref ref-type="aff" rid="aff1"><sup>1</sup>
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<given-names>Sander I.</given-names>
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<xref ref-type="aff" rid="aff2"><sup>2</sup>
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<given-names>Frank J.</given-names>
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<xref ref-type="aff" rid="aff1"><sup>1</sup>
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<given-names>Bart L.</given-names>
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<xref ref-type="aff" rid="aff3"><sup>3</sup>
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<given-names>Lucas</given-names>
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<xref ref-type="aff" rid="aff4"><sup>4</sup>
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<given-names>Peter J. M.</given-names>
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<xref ref-type="aff" rid="aff1"><sup>1</sup>
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<given-names>Berend Jan</given-names>
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<xref ref-type="aff" rid="aff1"><sup>1</sup>
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<given-names>Cornelis A. M.</given-names>
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<xref ref-type="aff" rid="aff1"><sup>1</sup>
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<xref ref-type="corresp" rid="cor1"><sup>*</sup>
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</contrib-group>
<aff id="aff1"><label>1</label>
<addr-line>Virology Division, Department of Infectious Diseases and Immunology, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands</addr-line>
</aff>
<aff id="aff2"><label>2</label>
<addr-line>Division of Bio-Organic Synthesis, Leiden Institute of Chemistry, Leiden University, Leiden, The Netherlands</addr-line>
</aff>
<aff id="aff3"><label>3</label>
<addr-line>Department of Viroscience, Erasmus MC, Rotterdam, The Netherlands</addr-line>
</aff>
<aff id="aff4"><label>4</label>
<addr-line>Institute of Molecular Life Sciences, University of Zurich, Zurich, Switzerland</addr-line>
</aff>
<contrib-group><contrib contrib-type="editor"><name><surname>Perlman</surname>
<given-names>Stanley</given-names>
</name>
<role>Editor</role>
<xref ref-type="aff" rid="edit1"></xref>
</contrib>
</contrib-group>
<aff id="edit1"><addr-line>University of Iowa, United States of America</addr-line>
</aff>
<author-notes><corresp id="cor1">* E-mail: <email>c.a.m.dehaan@uu.nl</email>
</corresp>
<fn fn-type="COI-statement"><p>The authors have declared that no competing interests exist.</p>
</fn>
<fn fn-type="con"><p>Conceived and designed the experiments: CB MHV BLH LP PJMR BJB CAMdH. Performed the experiments: CB MHV BLH. Analyzed the data: CB MHV. Contributed reagents/materials/analysis tools: OW SIvK LP BLH. Wrote the paper: CB PJMR BJB CAMdH. Provided scientific input: OW FJvK LP PJMR BJB CAMdH.</p>
</fn>
<fn id="fn1" fn-type="current-aff"><label>¤a</label>
<p>Current address: The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Easter Bush, Edinburgh, United Kingdom,</p>
</fn>
<fn id="fn2" fn-type="current-aff"><label>¤b</label>
<p>Current address: Department of Pathobiology, Division Pathology, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands</p>
</fn>
</author-notes>
<pub-date pub-type="collection"><month>11</month>
<year>2014</year>
</pub-date>
<pub-date pub-type="epub"><day>6</day>
<month>11</month>
<year>2014</year>
</pub-date>
<pub-date pub-type="ecorrected"><day>12</day>
<month>12</month>
<year>2014</year>
</pub-date>
<volume>10</volume>
<issue>11</issue>
<elocation-id>e1004502</elocation-id>
<history><date date-type="received"><day>26</day>
<month>5</month>
<year>2014</year>
</date>
<date date-type="accepted"><day>2</day>
<month>10</month>
<year>2014</year>
</date>
</history>
<permissions><copyright-statement>© 2014 Burkard et al</copyright-statement>
<copyright-year>2014</copyright-year>
<copyright-holder>Burkard et al</copyright-holder>
<license xlink:href="http://creativecommons.org/licenses/by/4.0/"><license-p>This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.</license-p>
</license>
</permissions>
<abstract><p>Enveloped viruses need to fuse with a host cell membrane in order to deliver their genome into the host cell. While some viruses fuse with the plasma membrane, many viruses are endocytosed prior to fusion. Specific cues in the endosomal microenvironment induce conformational changes in the viral fusion proteins leading to viral and host membrane fusion. In the present study we investigated the entry of coronaviruses (CoVs). Using siRNA gene silencing, we found that proteins known to be important for late endosomal maturation and endosome-lysosome fusion profoundly promote infection of cells with mouse hepatitis coronavirus (MHV). Using recombinant MHVs expressing reporter genes as well as a novel, replication-independent fusion assay we confirmed the importance of clathrin-mediated endocytosis and demonstrated that trafficking of MHV to lysosomes is required for fusion and productive entry to occur. Nevertheless, MHV was shown to be less sensitive to perturbation of endosomal pH than vesicular stomatitis virus and influenza A virus, which fuse in early and late endosomes, respectively. Our results indicate that entry of MHV depends on proteolytic processing of its fusion protein S by lysosomal proteases. Fusion of MHV was severely inhibited by a pan-lysosomal protease inhibitor, while trafficking of MHV to lysosomes and processing by lysosomal proteases was no longer required when a furin cleavage site was introduced in the S protein immediately upstream of the fusion peptide. Also entry of feline CoV was shown to depend on trafficking to lysosomes and processing by lysosomal proteases. In contrast, MERS-CoV, which contains a minimal furin cleavage site just upstream of the fusion peptide, was negatively affected by inhibition of furin, but not of lysosomal proteases. We conclude that a proteolytic cleavage site in the CoV S protein directly upstream of the fusion peptide is an essential determinant of the intracellular site of fusion.</p>
</abstract>
<abstract abstract-type="summary"><title>Author Summary</title>
<p>Enveloped viruses need to fuse with a host cell membrane in order to deliver their genome into the host cell. In the present study we investigated the entry of coronaviruses (CoVs). CoVs are important pathogens of animals and man with high zoonotic potential as demonstrated by the emergence of SARS- and MERS-CoVs. Previous studies resulted in apparently conflicting results with respect to CoV cell entry, particularly regarding the fusion-activating requirements of the CoV S protein. By combining cell-biological, infection, and fusion assays we demonstrated that murine hepatitis virus (MHV), a prototypic member of the CoV family, enters cells via clathrin-mediated endocytosis. Moreover, although MHV does not depend on a low pH for fusion, the virus was shown to rely on trafficking to lysosomes for proteolytic cleavage of its spike (S) protein and membrane fusion to occur. Based on these results we predicted and subsequently demonstrated that MERS- and feline CoV require cleavage by different proteases and escape the endo/lysosomal system from different compartments. In conclusion, we elucidated the MHV entry pathway in detail and demonstrate that a proteolytic cleavage site in the S protein of different CoVs is an essential determinant of the intracellular site of fusion.</p>
</abstract>
<funding-group><funding-statement>This work was supported by the EU 7th Framework Programme (Virus Entry, project 235649, PJMR) and by a Utrecht University High potential grant to CAMdH. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.</funding-statement>
</funding-group>
<counts><page-count count="17"></page-count>
</counts>
<custom-meta-group><custom-meta id="data-availability"><meta-name>Data Availability</meta-name>
<meta-value>The authors confirm that all data underlying the findings are fully available without restriction. All relevant data are within the paper and its Supporting Information files.</meta-value>
</custom-meta>
</custom-meta-group>
</article-meta>
<notes><title>Data Availability</title>
<p>The authors confirm that all data underlying the findings are fully available without restriction. All relevant data are within the paper and its Supporting Information files.</p>
</notes>
</front>
</pmc>
<affiliations><list><country><li>Pays-Bas</li>
<li>Suisse</li>
</country>
<region><li>Canton de Zurich</li>
<li>Hollande-Méridionale</li>
<li>Utrecht (province)</li>
</region>
<settlement><li>Leyde</li>
<li>Rotterdam</li>
<li>Utrecht</li>
<li>Zurich</li>
</settlement>
<orgName><li>Université d'Utrecht</li>
<li>Université de Zurich</li>
</orgName>
</list>
<tree><country name="Pays-Bas"><region name="Utrecht (province)"><name sortKey="Burkard, Christine" sort="Burkard, Christine" uniqKey="Burkard C" first="Christine" last="Burkard">Christine Burkard</name>
</region>
<name sortKey="Bosch, Berend Jan" sort="Bosch, Berend Jan" uniqKey="Bosch B" first="Berend Jan" last="Bosch">Berend Jan Bosch</name>
<name sortKey="De Haan, Cornelis A M" sort="De Haan, Cornelis A M" uniqKey="De Haan C" first="Cornelis A. M." last="De Haan">Cornelis A. M. De Haan</name>
<name sortKey="Haagmans, Bart L" sort="Haagmans, Bart L" uniqKey="Haagmans B" first="Bart L." last="Haagmans">Bart L. Haagmans</name>
<name sortKey="Rottier, Peter J M" sort="Rottier, Peter J M" uniqKey="Rottier P" first="Peter J. M." last="Rottier">Peter J. M. Rottier</name>
<name sortKey="Van Kasteren, Sander I" sort="Van Kasteren, Sander I" uniqKey="Van Kasteren S" first="Sander I." last="Van Kasteren">Sander I. Van Kasteren</name>
<name sortKey="Van Kuppeveld, Frank J" sort="Van Kuppeveld, Frank J" uniqKey="Van Kuppeveld F" first="Frank J." last="Van Kuppeveld">Frank J. Van Kuppeveld</name>
<name sortKey="Verheije, Monique H" sort="Verheije, Monique H" uniqKey="Verheije M" first="Monique H." last="Verheije">Monique H. Verheije</name>
<name sortKey="Wicht, Oliver" sort="Wicht, Oliver" uniqKey="Wicht O" first="Oliver" last="Wicht">Oliver Wicht</name>
</country>
<country name="Suisse"><region name="Canton de Zurich"><name sortKey="Pelkmans, Lucas" sort="Pelkmans, Lucas" uniqKey="Pelkmans L" first="Lucas" last="Pelkmans">Lucas Pelkmans</name>
</region>
</country>
</tree>
</affiliations>
</record>
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