Severe Acute Respiratory Syndrome Coronavirus Replication Is Severely Impaired by MG132 due to Proteasome-Independent Inhibition of M-Calpain
Identifieur interne : 000037 ( PascalFrancis/Checkpoint ); précédent : 000036; suivant : 000038Severe Acute Respiratory Syndrome Coronavirus Replication Is Severely Impaired by MG132 due to Proteasome-Independent Inhibition of M-Calpain
Auteurs : Martha Schneider [Allemagne] ; Kerstin Ackermann [Allemagne] ; Melissa Stuart [États-Unis] ; Claudia Wex [Allemagne] ; Ulrike Protzer [Allemagne] ; Hermann M. Sch Tzl [Allemagne, États-Unis] ; Sabine Gilch [Allemagne, États-Unis]Source :
- Journal of virology [ 0022-538X ] ; 2012.
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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.
Affiliations:
- Allemagne, États-Unis
- Bavière, District de Haute-Bavière, Wyoming
- Munich
- Université technique de Munich
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aut.</sZ></inist:fA14><country>Allemagne</country><placeName><region type="land" nuts="1">Bavière</region><region type="district" nuts="2">District de Haute-Bavière</region><settlement type="city">Munich</settlement></placeName><orgName type="university">Université technique de Munich</orgName></affiliation><affiliation wicri:level="1"><inist:fA14 i1="02"><s1>Institute of Virology, Helmholtz Zentrum München</s1><s2>Oberschleissheim</s2><s3>DEU</s3><sZ>1 aut.</sZ><sZ>5 aut.</sZ></inist:fA14><country>Allemagne</country><wicri:noRegion>Oberschleissheim</wicri:noRegion><wicri:noRegion>Helmholtz Zentrum München</wicri:noRegion><wicri:noRegion>Oberschleissheim</wicri:noRegion></affiliation></author><author><name sortKey="Ackermann, Kerstin" sort="Ackermann, Kerstin" uniqKey="Ackermann K" first="Kerstin" last="Ackermann">Kerstin Ackermann</name><affiliation wicri:level="4"><inist:fA14 i1="01"><s1>Institute of Virology, Technische Universität München</s1><s2>Munich</s2><s3>DEU</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>6 aut.</sZ><sZ>7 aut.</sZ></inist:fA14><country>Allemagne</country><placeName><region type="land" nuts="1">Bavière</region><region type="district" nuts="2">District de Haute-Bavière</region><settlement type="city">Munich</settlement></placeName><orgName type="university">Université technique de Munich</orgName></affiliation></author><author><name sortKey="Stuart, Melissa" sort="Stuart, Melissa" uniqKey="Stuart M" first="Melissa" last="Stuart">Melissa Stuart</name><affiliation wicri:level="2"><inist:fA14 i1="03"><s1>Departments of Veterinary Sciences and Molecular Biology, University of Wyoming</s1><s2>Laramie, Wyoming</s2><s3>USA</s3><sZ>3 aut.</sZ><sZ>6 aut.</sZ><sZ>7 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Wyoming</region></placeName></affiliation></author><author><name sortKey="Wex, Claudia" sort="Wex, Claudia" uniqKey="Wex C" first="Claudia" last="Wex">Claudia Wex</name><affiliation wicri:level="4"><inist:fA14 i1="01"><s1>Institute of Virology, Technische Universität München</s1><s2>Munich</s2><s3>DEU</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>6 aut.</sZ><sZ>7 aut.</sZ></inist:fA14><country>Allemagne</country><placeName><region type="land" nuts="1">Bavière</region><region type="district" nuts="2">District de Haute-Bavière</region><settlement type="city">Munich</settlement></placeName><orgName type="university">Université technique de Munich</orgName></affiliation></author><author><name sortKey="Protzer, Ulrike" sort="Protzer, Ulrike" uniqKey="Protzer U" first="Ulrike" last="Protzer">Ulrike Protzer</name><affiliation wicri:level="4"><inist:fA14 i1="01"><s1>Institute of Virology, Technische Universität München</s1><s2>Munich</s2><s3>DEU</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>6 aut.</sZ><sZ>7 aut.</sZ></inist:fA14><country>Allemagne</country><placeName><region type="land" nuts="1">Bavière</region><region type="district" nuts="2">District de Haute-Bavière</region><settlement type="city">Munich</settlement></placeName><orgName type="university">Université technique de Munich</orgName></affiliation><affiliation wicri:level="1"><inist:fA14 i1="02"><s1>Institute of Virology, Helmholtz Zentrum München</s1><s2>Oberschleissheim</s2><s3>DEU</s3><sZ>1 aut.</sZ><sZ>5 aut.</sZ></inist:fA14><country>Allemagne</country><wicri:noRegion>Oberschleissheim</wicri:noRegion><wicri:noRegion>Helmholtz Zentrum München</wicri:noRegion><wicri:noRegion>Oberschleissheim</wicri:noRegion></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 wicri:level="4"><inist:fA14 i1="01"><s1>Institute of Virology, Technische Universität München</s1><s2>Munich</s2><s3>DEU</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>6 aut.</sZ><sZ>7 aut.</sZ></inist:fA14><country>Allemagne</country><placeName><region type="land" nuts="1">Bavière</region><region type="district" nuts="2">District de Haute-Bavière</region><settlement type="city">Munich</settlement></placeName><orgName type="university">Université technique de Munich</orgName></affiliation><affiliation wicri:level="2"><inist:fA14 i1="03"><s1>Departments of Veterinary Sciences and Molecular Biology, University of Wyoming</s1><s2>Laramie, Wyoming</s2><s3>USA</s3><sZ>3 aut.</sZ><sZ>6 aut.</sZ><sZ>7 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Wyoming</region></placeName></affiliation></author><author><name sortKey="Gilch, Sabine" sort="Gilch, Sabine" uniqKey="Gilch S" first="Sabine" last="Gilch">Sabine Gilch</name><affiliation wicri:level="4"><inist:fA14 i1="01"><s1>Institute of Virology, Technische Universität München</s1><s2>Munich</s2><s3>DEU</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>6 aut.</sZ><sZ>7 aut.</sZ></inist:fA14><country>Allemagne</country><placeName><region type="land" nuts="1">Bavière</region><region type="district" nuts="2">District de Haute-Bavière</region><settlement type="city">Munich</settlement></placeName><orgName type="university">Université technique de Munich</orgName></affiliation><affiliation wicri:level="2"><inist:fA14 i1="03"><s1>Departments of Veterinary Sciences and Molecular Biology, University of Wyoming</s1><s2>Laramie, Wyoming</s2><s3>USA</s3><sZ>3 aut.</sZ><sZ>6 aut.</sZ><sZ>7 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Wyoming</region></placeName></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="2012">2012</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>Coronavirus</term><term>Multicatalytic endopeptidase complex</term><term>Replication</term><term>Severe acute respiratory syndrome</term></keywords><keywords scheme="Pascal" xml:lang="fr"><term>Coronavirus</term><term>Réplication</term><term>Multicatalytic endopeptidase complex</term><term>Syndrome respiratoire aigu sévère</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">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.</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>86</s2></fA05><fA06><s2>18</s2></fA06><fA08 i1="01" i2="1" l="ENG"><s1>Severe Acute Respiratory Syndrome Coronavirus Replication Is Severely Impaired by MG132 due to Proteasome-Independent Inhibition of M-Calpain</s1></fA08><fA11 i1="01" i2="1"><s1>SCHNEIDER (Martha)</s1></fA11><fA11 i1="02" i2="1"><s1>ACKERMANN (Kerstin)</s1></fA11><fA11 i1="03" i2="1"><s1>STUART (Melissa)</s1></fA11><fA11 i1="04" i2="1"><s1>WEX (Claudia)</s1></fA11><fA11 i1="05" i2="1"><s1>PROTZER (Ulrike)</s1></fA11><fA11 i1="06" i2="1"><s1>SCHÄTZL (Hermann M.)</s1></fA11><fA11 i1="07" i2="1"><s1>GILCH (Sabine)</s1></fA11><fA14 i1="01"><s1>Institute of Virology, Technische Universität München</s1><s2>Munich</s2><s3>DEU</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>4 aut.</sZ><sZ>5 aut.</sZ><sZ>6 aut.</sZ><sZ>7 aut.</sZ></fA14><fA14 i1="02"><s1>Institute of Virology, Helmholtz Zentrum München</s1><s2>Oberschleissheim</s2><s3>DEU</s3><sZ>1 aut.</sZ><sZ>5 aut.</sZ></fA14><fA14 i1="03"><s1>Departments of Veterinary Sciences and Molecular Biology, University of Wyoming</s1><s2>Laramie, Wyoming</s2><s3>USA</s3><sZ>3 aut.</sZ><sZ>6 aut.</sZ><sZ>7 aut.</sZ></fA14><fA20><s1>10112-10122</s1></fA20><fA21><s1>2012</s1></fA21><fA23 i1="01"><s0>ENG</s0></fA23><fA43 i1="01"><s1>INIST</s1><s2>13592</s2><s5>354000504481340520</s5></fA43><fA44><s0>0000</s0><s1>© 2012 INIST-CNRS. All rights reserved.</s1></fA44><fA45><s0>73 ref.</s0></fA45><fA47 i1="01" i2="1"><s0>12-0360875</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>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.</s0></fC01><fC02 i1="01" i2="X"><s0>002A05C10</s0></fC02><fC03 i1="01" i2="X" l="FRE"><s0>Coronavirus</s0><s2>NW</s2><s5>01</s5></fC03><fC03 i1="01" i2="X" l="ENG"><s0>Coronavirus</s0><s2>NW</s2><s5>01</s5></fC03><fC03 i1="01" i2="X" l="SPA"><s0>Coronavirus</s0><s2>NW</s2><s5>01</s5></fC03><fC03 i1="02" i2="X" l="FRE"><s0>Réplication</s0><s5>05</s5></fC03><fC03 i1="02" i2="X" l="ENG"><s0>Replication</s0><s5>05</s5></fC03><fC03 i1="02" i2="X" l="SPA"><s0>Replicación</s0><s5>05</s5></fC03><fC03 i1="03" i2="X" l="FRE"><s0>Multicatalytic endopeptidase complex</s0><s2>FE</s2><s5>06</s5></fC03><fC03 i1="03" i2="X" l="ENG"><s0>Multicatalytic endopeptidase complex</s0><s2>FE</s2><s5>06</s5></fC03><fC03 i1="03" i2="X" l="SPA"><s0>Multicatalytic endopeptidase complex</s0><s2>FE</s2><s5>06</s5></fC03><fC03 i1="04" i2="X" l="FRE"><s0>Syndrome respiratoire aigu sévère</s0><s2>NM</s2><s5>14</s5></fC03><fC03 i1="04" i2="X" l="ENG"><s0>Severe acute respiratory syndrome</s0><s2>NM</s2><s5>14</s5></fC03><fC03 i1="04" i2="X" l="SPA"><s0>Síndrome respiratorio agudo severo</s0><s2>NM</s2><s5>14</s5></fC03><fC07 i1="01" i2="X" l="FRE"><s0>Coronaviridae</s0><s2>NW</s2></fC07><fC07 i1="01" i2="X" l="ENG"><s0>Coronaviridae</s0><s2>NW</s2></fC07><fC07 i1="01" i2="X" l="SPA"><s0>Coronaviridae</s0><s2>NW</s2></fC07><fC07 i1="02" i2="X" l="FRE"><s0>Nidovirales</s0><s2>NW</s2></fC07><fC07 i1="02" i2="X" l="ENG"><s0>Nidovirales</s0><s2>NW</s2></fC07><fC07 i1="02" i2="X" l="SPA"><s0>Nidovirales</s0><s2>NW</s2></fC07><fC07 i1="03" i2="X" l="FRE"><s0>Virus</s0><s2>NW</s2></fC07><fC07 i1="03" i2="X" l="ENG"><s0>Virus</s0><s2>NW</s2></fC07><fC07 i1="03" i2="X" l="SPA"><s0>Virus</s0><s2>NW</s2></fC07><fC07 i1="04" i2="X" l="FRE"><s0>Peptidases</s0><s2>FE</s2></fC07><fC07 i1="04" i2="X" l="ENG"><s0>Peptidases</s0><s2>FE</s2></fC07><fC07 i1="04" i2="X" l="SPA"><s0>Peptidases</s0><s2>FE</s2></fC07><fC07 i1="05" i2="X" l="FRE"><s0>Hydrolases</s0><s2>FE</s2></fC07><fC07 i1="05" i2="X" l="ENG"><s0>Hydrolases</s0><s2>FE</s2></fC07><fC07 i1="05" i2="X" l="SPA"><s0>Hydrolases</s0><s2>FE</s2></fC07><fC07 i1="06" i2="X" l="FRE"><s0>Enzyme</s0><s2>FE</s2></fC07><fC07 i1="06" i2="X" l="ENG"><s0>Enzyme</s0><s2>FE</s2></fC07><fC07 i1="06" i2="X" l="SPA"><s0>Enzima</s0><s2>FE</s2></fC07><fC07 i1="07" i2="X" l="FRE"><s0>Pathologie de l'appareil respiratoire</s0><s5>13</s5></fC07><fC07 i1="07" i2="X" l="ENG"><s0>Respiratory disease</s0><s5>13</s5></fC07><fC07 i1="07" i2="X" l="SPA"><s0>Aparato respiratorio patología</s0><s5>13</s5></fC07><fC07 i1="08" i2="X" l="FRE"><s0>Virose</s0></fC07><fC07 i1="08" i2="X" l="ENG"><s0>Viral disease</s0></fC07><fC07 i1="08" i2="X" l="SPA"><s0>Virosis</s0></fC07><fC07 i1="09" i2="X" l="FRE"><s0>Infection</s0></fC07><fC07 i1="09" i2="X" l="ENG"><s0>Infection</s0></fC07><fC07 i1="09" i2="X" l="SPA"><s0>Infección</s0></fC07><fC07 i1="10" i2="X" l="FRE"><s0>Pathologie des poumons</s0><s5>16</s5></fC07><fC07 i1="10" i2="X" l="ENG"><s0>Lung disease</s0><s5>16</s5></fC07><fC07 i1="10" i2="X" l="SPA"><s0>Pulmón patología</s0><s5>16</s5></fC07><fN21><s1>282</s1></fN21><fN44 i1="01"><s1>OTO</s1></fN44><fN82><s1>OTO</s1></fN82></pA></standard></inist><affiliations><list><country><li>Allemagne</li><li>États-Unis</li></country><region><li>Bavière</li><li>District de Haute-Bavière</li><li>Wyoming</li></region><settlement><li>Munich</li></settlement><orgName><li>Université technique de Munich</li></orgName></list><tree><country name="Allemagne"><region name="Bavière"><name sortKey="Schneider, Martha" sort="Schneider, Martha" uniqKey="Schneider M" first="Martha" last="Schneider">Martha Schneider</name></region><name sortKey="Ackermann, Kerstin" sort="Ackermann, Kerstin" uniqKey="Ackermann K" first="Kerstin" last="Ackermann">Kerstin Ackermann</name><name sortKey="Gilch, Sabine" sort="Gilch, Sabine" uniqKey="Gilch S" first="Sabine" last="Gilch">Sabine Gilch</name><name sortKey="Protzer, Ulrike" sort="Protzer, Ulrike" uniqKey="Protzer U" first="Ulrike" last="Protzer">Ulrike Protzer</name><name sortKey="Protzer, Ulrike" sort="Protzer, Ulrike" uniqKey="Protzer U" first="Ulrike" last="Protzer">Ulrike Protzer</name><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><name sortKey="Schneider, Martha" sort="Schneider, Martha" uniqKey="Schneider M" first="Martha" last="Schneider">Martha Schneider</name><name sortKey="Wex, Claudia" sort="Wex, Claudia" uniqKey="Wex C" first="Claudia" last="Wex">Claudia Wex</name></country><country name="États-Unis"><region name="Wyoming"><name sortKey="Stuart, Melissa" sort="Stuart, Melissa" uniqKey="Stuart M" first="Melissa" last="Stuart">Melissa Stuart</name></region><name sortKey="Gilch, Sabine" sort="Gilch, Sabine" uniqKey="Gilch S" first="Sabine" last="Gilch">Sabine Gilch</name><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></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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