The coronavirus spike protein induces endoplasmic reticulum stress and upregulation of intracellular chemokine mRNA concentrations
Identifieur interne : 000325 ( PascalFrancis/Checkpoint ); précédent : 000324; suivant : 000326The coronavirus spike protein induces endoplasmic reticulum stress and upregulation of intracellular chemokine mRNA concentrations
Auteurs : Gijs A. Versteeg [Pays-Bas] ; Paula S. Van De Nes [Pays-Bas] ; Peter J. Bredenbeek [Pays-Bas] ; Willy J. M. Spaan [Pays-Bas]Source :
- Journal of virology [ 0022-538X ] ; 2007.
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Abstract
Murine hepatitis virus (MHV) and severe acute respiratory syndrome (SARS) coronavirus (CoV) are two of the best-studied representatives of the family Coronaviridae. During CoV infection, numerous cytokines and chemokines are induced in vitro and in vivo. Human interleukin 8 and its mouse functional counterpart, CXCL2, are early-expressed chemokines. Here we show that SARS-CoV and MHV induce endoplasmic reticulum (ER) stress and Cxcl2 mRNA transcription during infection in vitro. Expression of the viral spike protein significantly induced ER stress and Cxcl2 mRNA upregulation, while expression of the other structural genes did not. Additional experiments with UV-inactivated virus, cell-cell fusion-blocking antibodies, and an MHV mutant with a defect in spike protein maturation demonstrated that spike-host interactions in the ER are responsible for the induction of ER stress and subsequent Cxcl2 mRNA transcription. Despite significant increases in levels of Cxcl2 mRNA and functional nucleus-to-cytoplasm RNA transport, no CXCL2 protein was released into the medium from MHV-infected cells. Yet Sendai virus-infected cells showed substantial Cxcl2 mRNA induction and a simultaneous increase in levels of secreted CXCL2 protein. Our results demonstrate that expression of CoV spike proteins induces ER stress, which could subsequently trigger innate immune responses. However, at that point in infection, translation of host mRNA is already severely reduced in infected cells, preventing the synthesis of CXCL2 and ER stress proteins despite their increased mRNA concentrations.
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Van De Nes</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Molecular Virology Laboratory, Department of Medical Microbiology, Center of Infectious Diseases, Leiden University Medical Center, P.O. Box 9600</s1><s2>2300 RC Leiden</s2><s3>NLD</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ></inist:fA14><country>Pays-Bas</country><wicri:noRegion>2300 RC Leiden</wicri:noRegion></affiliation></author><author><name sortKey="Bredenbeek, Peter J" sort="Bredenbeek, Peter J" uniqKey="Bredenbeek P" first="Peter J." last="Bredenbeek">Peter J. Bredenbeek</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Molecular Virology Laboratory, Department of Medical Microbiology, Center of Infectious Diseases, Leiden University Medical Center, P.O. 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Versteeg</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Molecular Virology Laboratory, Department of Medical Microbiology, Center of Infectious Diseases, Leiden University Medical Center, P.O. Box 9600</s1><s2>2300 RC Leiden</s2><s3>NLD</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ></inist:fA14><country>Pays-Bas</country><wicri:noRegion>2300 RC Leiden</wicri:noRegion></affiliation></author><author><name sortKey="Van De Nes, Paula S" sort="Van De Nes, Paula S" uniqKey="Van De Nes P" first="Paula S." last="Van De Nes">Paula S. Van De Nes</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Molecular Virology Laboratory, Department of Medical Microbiology, Center of Infectious Diseases, Leiden University Medical Center, P.O. Box 9600</s1><s2>2300 RC Leiden</s2><s3>NLD</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ></inist:fA14><country>Pays-Bas</country><wicri:noRegion>2300 RC Leiden</wicri:noRegion></affiliation></author><author><name sortKey="Bredenbeek, Peter J" sort="Bredenbeek, Peter J" uniqKey="Bredenbeek P" first="Peter J." last="Bredenbeek">Peter J. Bredenbeek</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Molecular Virology Laboratory, Department of Medical Microbiology, Center of Infectious Diseases, Leiden University Medical Center, P.O. Box 9600</s1><s2>2300 RC Leiden</s2><s3>NLD</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ></inist:fA14><country>Pays-Bas</country><wicri:noRegion>2300 RC Leiden</wicri:noRegion></affiliation></author><author><name sortKey="Spaan, Willy J M" sort="Spaan, Willy J M" uniqKey="Spaan W" first="Willy J. M." last="Spaan">Willy J. M. Spaan</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Molecular Virology Laboratory, Department of Medical Microbiology, Center of Infectious Diseases, Leiden University Medical Center, P.O. Box 9600</s1><s2>2300 RC Leiden</s2><s3>NLD</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ></inist:fA14><country>Pays-Bas</country><wicri:noRegion>2300 RC Leiden</wicri:noRegion></affiliation></author></analytic><series><title level="j" type="main">Journal of virology</title><title level="j" type="abbreviated">J. virol.</title><idno type="ISSN">0022-538X</idno><imprint><date when="2007">2007</date></imprint></series></biblStruct></sourceDesc><seriesStmt><title level="j" type="main">Journal of virology</title><title level="j" type="abbreviated">J. virol.</title><idno type="ISSN">0022-538X</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Chemokine</term><term>Coronavirus</term><term>Endoplasmic reticulum</term><term>Intracellular</term><term>Messenger RNA</term><term>Protein</term><term>Stress</term><term>Virology</term></keywords><keywords scheme="Pascal" xml:lang="fr"><term>Coronavirus</term><term>Protéine</term><term>Réticulum endoplasmique</term><term>Stress</term><term>Intracellulaire</term><term>Chimiokine</term><term>RNA messager</term><term>Virologie</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Murine hepatitis virus (MHV) and severe acute respiratory syndrome (SARS) coronavirus (CoV) are two of the best-studied representatives of the family Coronaviridae. During CoV infection, numerous cytokines and chemokines are induced in vitro and in vivo. Human interleukin 8 and its mouse functional counterpart, CXCL2, are early-expressed chemokines. Here we show that SARS-CoV and MHV induce endoplasmic reticulum (ER) stress and Cxcl2 mRNA transcription during infection in vitro. Expression of the viral spike protein significantly induced ER stress and Cxcl2 mRNA upregulation, while expression of the other structural genes did not. Additional experiments with UV-inactivated virus, cell-cell fusion-blocking antibodies, and an MHV mutant with a defect in spike protein maturation demonstrated that spike-host interactions in the ER are responsible for the induction of ER stress and subsequent Cxcl2 mRNA transcription. Despite significant increases in levels of Cxcl2 mRNA and functional nucleus-to-cytoplasm RNA transport, no CXCL2 protein was released into the medium from MHV-infected cells. Yet Sendai virus-infected cells showed substantial Cxcl2 mRNA induction and a simultaneous increase in levels of secreted CXCL2 protein. Our results demonstrate that expression of CoV spike proteins induces ER stress, which could subsequently trigger innate immune responses. However, at that point in infection, translation of host mRNA is already severely reduced in infected cells, preventing the synthesis of CXCL2 and ER stress proteins despite their increased mRNA concentrations.</div></front></TEI><inist><standard h6="B"><pA><fA01 i1="01" i2="1"><s0>0022-538X</s0></fA01><fA03 i2="1"><s0>J. virol.</s0></fA03><fA05><s2>81</s2></fA05><fA06><s2>20</s2></fA06><fA08 i1="01" i2="1" l="ENG"><s1>The coronavirus spike protein induces endoplasmic reticulum stress and upregulation of intracellular chemokine mRNA concentrations</s1></fA08><fA11 i1="01" i2="1"><s1>VERSTEEG (Gijs A.)</s1></fA11><fA11 i1="02" i2="1"><s1>VAN DE NES (Paula S.)</s1></fA11><fA11 i1="03" i2="1"><s1>BREDENBEEK (Peter J.)</s1></fA11><fA11 i1="04" i2="1"><s1>SPAAN (Willy J. M.)</s1></fA11><fA14 i1="01"><s1>Molecular Virology Laboratory, Department of Medical Microbiology, Center of Infectious Diseases, Leiden University Medical Center, P.O. Box 9600</s1><s2>2300 RC Leiden</s2><s3>NLD</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ></fA14><fA20><s1>10981-10990</s1></fA20><fA21><s1>2007</s1></fA21><fA23 i1="01"><s0>ENG</s0></fA23><fA43 i1="01"><s1>INIST</s1><s2>13592</s2><s5>354000143477600150</s5></fA43><fA44><s0>0000</s0><s1>© 2007 INIST-CNRS. All rights reserved.</s1></fA44><fA45><s0>52 ref.</s0></fA45><fA47 i1="01" i2="1"><s0>07-0485996</s0></fA47><fA60><s1>P</s1></fA60><fA61><s0>A</s0></fA61><fA64 i1="01" i2="1"><s0>Journal of virology</s0></fA64><fA66 i1="01"><s0>USA</s0></fA66><fC01 i1="01" l="ENG"><s0>Murine hepatitis virus (MHV) and severe acute respiratory syndrome (SARS) coronavirus (CoV) are two of the best-studied representatives of the family Coronaviridae. During CoV infection, numerous cytokines and chemokines are induced in vitro and in vivo. Human interleukin 8 and its mouse functional counterpart, CXCL2, are early-expressed chemokines. Here we show that SARS-CoV and MHV induce endoplasmic reticulum (ER) stress and Cxcl2 mRNA transcription during infection in vitro. Expression of the viral spike protein significantly induced ER stress and Cxcl2 mRNA upregulation, while expression of the other structural genes did not. Additional experiments with UV-inactivated virus, cell-cell fusion-blocking antibodies, and an MHV mutant with a defect in spike protein maturation demonstrated that spike-host interactions in the ER are responsible for the induction of ER stress and subsequent Cxcl2 mRNA transcription. Despite significant increases in levels of Cxcl2 mRNA and functional nucleus-to-cytoplasm RNA transport, no CXCL2 protein was released into the medium from MHV-infected cells. Yet Sendai virus-infected cells showed substantial Cxcl2 mRNA induction and a simultaneous increase in levels of secreted CXCL2 protein. Our results demonstrate that expression of CoV spike proteins induces ER stress, which could subsequently trigger innate immune responses. 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Versteeg</name></noRegion><name sortKey="Bredenbeek, Peter J" sort="Bredenbeek, Peter J" uniqKey="Bredenbeek P" first="Peter J." last="Bredenbeek">Peter J. Bredenbeek</name><name sortKey="Spaan, Willy J M" sort="Spaan, Willy J M" uniqKey="Spaan W" first="Willy J. M." last="Spaan">Willy J. M. Spaan</name><name sortKey="Van De Nes, Paula S" sort="Van De Nes, Paula S" uniqKey="Van De Nes P" first="Paula S." last="Van De Nes">Paula S. Van De Nes</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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