Severe Acute Respiratory Syndrome Coronavirus Replication Is Severely Impaired by MG132 due to Proteasome-Independent Inhibition of M-Calpain
Identifieur interne : 001F64 ( Main/Exploration ); précédent : 001F63; suivant : 001F65Severe 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.
Descripteurs français
- KwdFr :
- Animaux, Autophagie (), Calpain (antagonistes et inhibiteurs), Calpain (génétique), Cellules Vero, Humains, Inhibiteurs de la cystéine protéinase (pharmacologie), Leupeptines (pharmacologie), Lignée cellulaire, Petit ARN interférent (génétique), Proteasome endopeptidase complex (métabolisme), Protéine-5 associée à l'autophagie, Protéines associées aux microtubules (déficit), Protéines associées aux microtubules (génétique), Pénétration virale (), Réplication virale (), Réplication virale (physiologie), Souris, Séquence nucléotidique, Techniques de knock-down de gènes, Virus du SRAS (), Virus du SRAS (physiologie).
- MESH :
- antagonistes et inhibiteurs : Calpain.
- déficit : Protéines associées aux microtubules.
- génétique : Calpain, Petit ARN interférent, Protéines associées aux microtubules.
- métabolisme : Proteasome endopeptidase complex.
- pharmacologie : Inhibiteurs de la cystéine protéinase, Leupeptines.
- physiologie : Réplication virale, Virus du SRAS.
- Pascal (Inist)
- Animaux, Autophagie, Cellules Vero, Coronavirus, Humains, Lignée cellulaire, Protéine-5 associée à l'autophagie, Pénétration virale, Réplication, Multicatalytic endopeptidase complex, Réplication virale, Souris, Syndrome respiratoire aigu sévère, Séquence nucléotidique, Techniques de knock-down de gènes, Virus du SRAS.
English descriptors
- KwdEn :
- Animals, Autophagy (drug effects), Autophagy-Related Protein 5, Base Sequence, Calpain (antagonists & inhibitors), Calpain (genetics), Cell Line, Chlorocebus aethiops, Coronavirus, Cysteine Proteinase Inhibitors (pharmacology), Gene Knockdown Techniques, Humans, Leupeptins (pharmacology), Mice, Microtubule-Associated Proteins (deficiency), Microtubule-Associated Proteins (genetics), Multicatalytic endopeptidase complex, Proteasome Endopeptidase Complex (metabolism), RNA, Small Interfering (genetics), Replication, SARS Virus (drug effects), SARS Virus (physiology), Severe acute respiratory syndrome, Vero Cells, Virus Internalization (drug effects), Virus Replication (drug effects), Virus Replication (physiology).
- MESH :
- chemical , antagonists & inhibitors : Calpain.
- chemical , deficiency : Microtubule-Associated Proteins.
- chemical , genetics : Calpain, Microtubule-Associated Proteins, RNA, Small Interfering.
- chemical , metabolism : Proteasome Endopeptidase Complex.
- chemical , pharmacology : Cysteine Proteinase Inhibitors, Leupeptins.
- chemical : Autophagy-Related Protein 5.
- drug effects : Autophagy, SARS Virus, Virus Internalization, Virus Replication.
- physiology : SARS Virus, Virus Replication.
- Animals, Base Sequence, Cell Line, Chlorocebus aethiops, Gene Knockdown Techniques, Humans, Mice, Vero Cells.
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:
Affiliations:
- Allemagne, États-Unis
- Bavière, District de Haute-Bavière, Wyoming
- Munich
- Université technique de Munich
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Le document en format XML
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type="wicri:Area/Main/Exploration">001F64</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a">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 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="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>Animals</term><term>Autophagy (drug effects)</term><term>Autophagy-Related Protein 5</term><term>Base Sequence</term><term>Calpain (antagonists & inhibitors)</term><term>Calpain (genetics)</term><term>Cell Line</term><term>Chlorocebus aethiops</term><term>Coronavirus</term><term>Cysteine Proteinase Inhibitors (pharmacology)</term><term>Gene Knockdown Techniques</term><term>Humans</term><term>Leupeptins (pharmacology)</term><term>Mice</term><term>Microtubule-Associated Proteins (deficiency)</term><term>Microtubule-Associated Proteins (genetics)</term><term>Multicatalytic endopeptidase complex</term><term>Proteasome Endopeptidase Complex (metabolism)</term><term>RNA, Small Interfering (genetics)</term><term>Replication</term><term>SARS Virus (drug effects)</term><term>SARS Virus (physiology)</term><term>Severe acute respiratory syndrome</term><term>Vero Cells</term><term>Virus Internalization (drug effects)</term><term>Virus Replication (drug effects)</term><term>Virus Replication (physiology)</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Animaux</term><term>Autophagie ()</term><term>Calpain (antagonistes et inhibiteurs)</term><term>Calpain (génétique)</term><term>Cellules Vero</term><term>Humains</term><term>Inhibiteurs de la cystéine protéinase (pharmacologie)</term><term>Leupeptines (pharmacologie)</term><term>Lignée cellulaire</term><term>Petit ARN interférent (génétique)</term><term>Proteasome endopeptidase complex (métabolisme)</term><term>Protéine-5 associée à l'autophagie</term><term>Protéines associées aux microtubules (déficit)</term><term>Protéines associées aux microtubules (génétique)</term><term>Pénétration virale ()</term><term>Réplication virale ()</term><term>Réplication virale (physiologie)</term><term>Souris</term><term>Séquence nucléotidique</term><term>Techniques de knock-down de gènes</term><term>Virus du SRAS ()</term><term>Virus du SRAS (physiologie)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="antagonists & inhibitors" xml:lang="en"><term>Calpain</term></keywords><keywords scheme="MESH" type="chemical" qualifier="deficiency" xml:lang="en"><term>Microtubule-Associated Proteins</term></keywords><keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>Calpain</term><term>Microtubule-Associated Proteins</term><term>RNA, Small Interfering</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Proteasome Endopeptidase Complex</term></keywords><keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Cysteine Proteinase Inhibitors</term><term>Leupeptins</term></keywords><keywords scheme="MESH" type="chemical" xml:lang="en"><term>Autophagy-Related Protein 5</term></keywords><keywords scheme="MESH" qualifier="antagonistes et inhibiteurs" xml:lang="fr"><term>Calpain</term></keywords><keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>Autophagy</term><term>SARS Virus</term><term>Virus Internalization</term><term>Virus Replication</term></keywords><keywords scheme="MESH" qualifier="déficit" xml:lang="fr"><term>Protéines associées aux microtubules</term></keywords><keywords scheme="MESH" qualifier="génétique" xml:lang="fr"><term>Calpain</term><term>Petit ARN interférent</term><term>Protéines associées aux microtubules</term></keywords><keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Proteasome endopeptidase complex</term></keywords><keywords scheme="MESH" qualifier="pharmacologie" xml:lang="fr"><term>Inhibiteurs de la cystéine protéinase</term><term>Leupeptines</term></keywords><keywords scheme="MESH" qualifier="physiologie" xml:lang="fr"><term>Réplication virale</term><term>Virus du SRAS</term></keywords><keywords scheme="MESH" qualifier="physiology" xml:lang="en"><term>SARS Virus</term><term>Virus Replication</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Animals</term><term>Base Sequence</term><term>Cell Line</term><term>Chlorocebus aethiops</term><term>Gene Knockdown Techniques</term><term>Humans</term><term>Mice</term><term>Vero Cells</term></keywords><keywords scheme="Pascal" xml:lang="fr"><term>Animaux</term><term>Autophagie</term><term>Cellules Vero</term><term>Coronavirus</term><term>Humains</term><term>Lignée cellulaire</term><term>Protéine-5 associée à l'autophagie</term><term>Pénétration virale</term><term>Réplication</term><term>Multicatalytic endopeptidase complex</term><term>Réplication virale</term><term>Souris</term><term>Syndrome respiratoire aigu sévère</term><term>Séquence nucléotidique</term><term>Techniques de knock-down de gènes</term><term>Virus du SRAS</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><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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