Severe acute respiratory syndrome coronavirus triggers apoptosis via protein kinase R but is resistant to its antiviral activity.
Identifieur interne : 002A15 ( Main/Exploration ); précédent : 002A14; suivant : 002A16Severe acute respiratory syndrome coronavirus triggers apoptosis via protein kinase R but is resistant to its antiviral activity.
Auteurs : Verena Kr Hling [Allemagne] ; David A. Stein ; Martin Spiegel ; Friedemann Weber ; Elke MühlbergerSource :
- Journal of virology [ 1098-5514 ] ; 2009.
Descripteurs français
- KwdFr :
- Animaux, Apoptose, Cellules Vero, Facteur-2 d'initiation eucaryote (métabolisme), Humains, Infections à coronavirus (métabolisme), Interféron bêta (pharmacologie), Morpholines (pharmacologie), Morpholinos, Phosphorylation, Poly (ADP-Ribose) polymerase-1, Poly(ADP-ribose) polymerases (métabolisme), Protein-Serine-Threonine Kinases (métabolisme), Virus du SRAS (), Virus du SRAS (génétique), Virus du SRAS (métabolisme), eIF-2 Kinase (génétique), eIF-2 Kinase (métabolisme).
- MESH :
- génétique : Virus du SRAS, eIF-2 Kinase.
- métabolisme : Facteur-2 d'initiation eucaryote, Infections à coronavirus, Poly(ADP-ribose) polymerases, Protein-Serine-Threonine Kinases, Virus du SRAS, eIF-2 Kinase.
- pharmacologie : Interféron bêta, Morpholines.
- Animaux, Apoptose, Cellules Vero, Humains, Morpholinos, Phosphorylation, Poly (ADP-Ribose) polymerase-1, Virus du SRAS.
English descriptors
- KwdEn :
- Animals, Apoptosis, Chlorocebus aethiops, Coronavirus Infections (metabolism), Eukaryotic Initiation Factor-2 (metabolism), Humans, Interferon-beta (pharmacology), Morpholines (pharmacology), Morpholinos, Phosphorylation, Poly (ADP-Ribose) Polymerase-1, Poly(ADP-ribose) Polymerases (metabolism), Protein-Serine-Threonine Kinases (metabolism), SARS Virus (drug effects), SARS Virus (genetics), SARS Virus (metabolism), Vero Cells, eIF-2 Kinase (genetics), eIF-2 Kinase (metabolism).
- MESH :
- chemical , genetics : eIF-2 Kinase.
- chemical , metabolism : Eukaryotic Initiation Factor-2, Poly(ADP-ribose) Polymerases, Protein-Serine-Threonine Kinases, eIF-2 Kinase.
- drug effects : SARS Virus.
- genetics : SARS Virus.
- metabolism : Coronavirus Infections, SARS Virus.
- chemical , pharmacology : Interferon-beta, Morpholines.
- Animals, Apoptosis, Chlorocebus aethiops, Humans, Morpholinos, Phosphorylation, Poly (ADP-Ribose) Polymerase-1, Vero Cells.
Abstract
In this study, infection of 293/ACE2 cells with severe acute respiratory syndrome coronavirus (SARS-CoV) activated several apoptosis-associated events, namely, cleavage of caspase-3, caspase-8, and poly(ADP-ribose) polymerase 1 (PARP), and chromatin condensation and the phosphorylation and hence inactivation of the eukaryotic translation initiation factor 2alpha (eIF2alpha). In addition, two of the three cellular eIF2alpha kinases known to be virus induced, protein kinase R (PKR) and PKR-like endoplasmic reticulum kinase (PERK), were activated by SARS-CoV. The third kinase, general control nonderepressible-2 kinase (GCN2), was not activated, but late in infection the level of GCN2 protein was significantly reduced. Reverse transcription-PCR analyses revealed that the reduction of GCN2 protein was not due to decreased transcription or stability of GCN2 mRNA. The specific reduction of PKR protein expression by antisense peptide-conjugated phosphorodiamidate morpholino oligomers strongly reduced cleavage of PARP in infected cells. Surprisingly, the knockdown of PKR neither enhanced SARS-CoV replication nor abrogated SARS-CoV-induced eIF2alpha phosphorylation. Pretreatment of cells with beta interferon prior to SARS-CoV infection led to a significant decrease in PERK activation, eIF2alpha phosphorylation, and SARS-CoV replication. The various effects of beta interferon treatment were found to function independently on the expression of PKR. Our results show that SARS-CoV infection activates PKR and PERK, leading to sustained eIF2alpha phosphorylation. However, virus replication was not impaired by these events, suggesting that SARS-CoV possesses a mechanism to overcome the inhibitory effects of phosphorylated eIF2alpha on viral mRNA translation. Furthermore, our data suggest that viral activation of PKR can lead to apoptosis via a pathway that is independent of eIF2alpha phosphorylation.
DOI: 10.1128/JVI.01245-08
PubMed: 19109397
Affiliations:
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Le document en format XML
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Stein</name></author><author><name sortKey="Spiegel, Martin" sort="Spiegel, Martin" uniqKey="Spiegel M" first="Martin" last="Spiegel">Martin Spiegel</name></author><author><name sortKey="Weber, Friedemann" sort="Weber, Friedemann" uniqKey="Weber F" first="Friedemann" last="Weber">Friedemann Weber</name></author><author><name sortKey="Muhlberger, Elke" sort="Muhlberger, Elke" uniqKey="Muhlberger E" first="Elke" last="Mühlberger">Elke Mühlberger</name></author></analytic><series><title level="j">Journal of virology</title><idno type="eISSN">1098-5514</idno><imprint><date when="2009" type="published">2009</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Animals</term><term>Apoptosis</term><term>Chlorocebus aethiops</term><term>Coronavirus Infections (metabolism)</term><term>Eukaryotic Initiation Factor-2 (metabolism)</term><term>Humans</term><term>Interferon-beta (pharmacology)</term><term>Morpholines (pharmacology)</term><term>Morpholinos</term><term>Phosphorylation</term><term>Poly (ADP-Ribose) Polymerase-1</term><term>Poly(ADP-ribose) Polymerases (metabolism)</term><term>Protein-Serine-Threonine Kinases (metabolism)</term><term>SARS Virus (drug effects)</term><term>SARS Virus (genetics)</term><term>SARS Virus (metabolism)</term><term>Vero Cells</term><term>eIF-2 Kinase (genetics)</term><term>eIF-2 Kinase (metabolism)</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Animaux</term><term>Apoptose</term><term>Cellules Vero</term><term>Facteur-2 d'initiation eucaryote (métabolisme)</term><term>Humains</term><term>Infections à coronavirus (métabolisme)</term><term>Interféron bêta (pharmacologie)</term><term>Morpholines (pharmacologie)</term><term>Morpholinos</term><term>Phosphorylation</term><term>Poly (ADP-Ribose) polymerase-1</term><term>Poly(ADP-ribose) polymerases (métabolisme)</term><term>Protein-Serine-Threonine Kinases (métabolisme)</term><term>Virus du SRAS ()</term><term>Virus du SRAS (génétique)</term><term>Virus du SRAS (métabolisme)</term><term>eIF-2 Kinase (génétique)</term><term>eIF-2 Kinase (métabolisme)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>eIF-2 Kinase</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Eukaryotic Initiation Factor-2</term><term>Poly(ADP-ribose) Polymerases</term><term>Protein-Serine-Threonine Kinases</term><term>eIF-2 Kinase</term></keywords><keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>SARS Virus</term></keywords><keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>SARS Virus</term></keywords><keywords scheme="MESH" qualifier="génétique" xml:lang="fr"><term>Virus du SRAS</term><term>eIF-2 Kinase</term></keywords><keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Coronavirus Infections</term><term>SARS Virus</term></keywords><keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Facteur-2 d'initiation eucaryote</term><term>Infections à coronavirus</term><term>Poly(ADP-ribose) polymerases</term><term>Protein-Serine-Threonine Kinases</term><term>Virus du SRAS</term><term>eIF-2 Kinase</term></keywords><keywords scheme="MESH" qualifier="pharmacologie" xml:lang="fr"><term>Interféron bêta</term><term>Morpholines</term></keywords><keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Interferon-beta</term><term>Morpholines</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Animals</term><term>Apoptosis</term><term>Chlorocebus aethiops</term><term>Humans</term><term>Morpholinos</term><term>Phosphorylation</term><term>Poly (ADP-Ribose) Polymerase-1</term><term>Vero Cells</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Animaux</term><term>Apoptose</term><term>Cellules Vero</term><term>Humains</term><term>Morpholinos</term><term>Phosphorylation</term><term>Poly (ADP-Ribose) polymerase-1</term><term>Virus du SRAS</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">In this study, infection of 293/ACE2 cells with severe acute respiratory syndrome coronavirus (SARS-CoV) activated several apoptosis-associated events, namely, cleavage of caspase-3, caspase-8, and poly(ADP-ribose) polymerase 1 (PARP), and chromatin condensation and the phosphorylation and hence inactivation of the eukaryotic translation initiation factor 2alpha (eIF2alpha). In addition, two of the three cellular eIF2alpha kinases known to be virus induced, protein kinase R (PKR) and PKR-like endoplasmic reticulum kinase (PERK), were activated by SARS-CoV. The third kinase, general control nonderepressible-2 kinase (GCN2), was not activated, but late in infection the level of GCN2 protein was significantly reduced. Reverse transcription-PCR analyses revealed that the reduction of GCN2 protein was not due to decreased transcription or stability of GCN2 mRNA. The specific reduction of PKR protein expression by antisense peptide-conjugated phosphorodiamidate morpholino oligomers strongly reduced cleavage of PARP in infected cells. Surprisingly, the knockdown of PKR neither enhanced SARS-CoV replication nor abrogated SARS-CoV-induced eIF2alpha phosphorylation. Pretreatment of cells with beta interferon prior to SARS-CoV infection led to a significant decrease in PERK activation, eIF2alpha phosphorylation, and SARS-CoV replication. The various effects of beta interferon treatment were found to function independently on the expression of PKR. Our results show that SARS-CoV infection activates PKR and PERK, leading to sustained eIF2alpha phosphorylation. However, virus replication was not impaired by these events, suggesting that SARS-CoV possesses a mechanism to overcome the inhibitory effects of phosphorylated eIF2alpha on viral mRNA translation. Furthermore, our data suggest that viral activation of PKR can lead to apoptosis via a pathway that is independent of eIF2alpha phosphorylation.</div></front></TEI><affiliations><list><country><li>Allemagne</li></country><region><li>District de Giessen</li><li>Hesse (Land)</li></region><settlement><li>Marbourg</li></settlement></list><tree><noCountry><name sortKey="Muhlberger, Elke" sort="Muhlberger, Elke" uniqKey="Muhlberger E" first="Elke" last="Mühlberger">Elke Mühlberger</name><name sortKey="Spiegel, Martin" sort="Spiegel, Martin" uniqKey="Spiegel M" first="Martin" last="Spiegel">Martin Spiegel</name><name sortKey="Stein, David A" sort="Stein, David A" uniqKey="Stein D" first="David A" last="Stein">David A. Stein</name><name sortKey="Weber, Friedemann" sort="Weber, Friedemann" uniqKey="Weber F" first="Friedemann" last="Weber">Friedemann Weber</name></noCountry><country name="Allemagne"><region name="Hesse (Land)"><name sortKey="Kr Hling, Verena" sort="Kr Hling, Verena" uniqKey="Kr Hling V" first="Verena" last="Kr Hling">Verena Kr Hling</name></region></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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