Integrity of the early secretory pathway promotes, but is not required for, severe acute respiratory syndrome coronavirus RNA synthesis and virus-induced remodeling of endoplasmic reticulum membranes.
Identifieur interne : 002512 ( Main/Exploration ); précédent : 002511; suivant : 002513Integrity of the early secretory pathway promotes, but is not required for, severe acute respiratory syndrome coronavirus RNA synthesis and virus-induced remodeling of endoplasmic reticulum membranes.
Auteurs : Kèvin Knoops [Pays-Bas] ; Cindy Swett-Tapia ; Sjoerd H E. Van Den Worm ; Aartjan J W. Te Velthuis ; Abraham J. Koster ; A Mieke Mommaas ; Eric J. Snijder ; Marjolein KikkertSource :
- Journal of virology [ 1098-5514 ] ; 2010.
Descripteurs français
- KwdFr :
- ARN viral (métabolisme), Animaux, Bréfeldine A (pharmacologie), Cellules Vero (ultrastructure), Cellules Vero (virologie), Humains, Interactions hôte-pathogène, Membranes intracellulaires (métabolisme), Membranes intracellulaires (ultrastructure), Membranes intracellulaires (virologie), Microscopie confocale, Protéines (), Protéines (génétique), Protéines (métabolisme), Protéines virales (métabolisme), Réplication virale, Réticulum endoplasmique (métabolisme), Réticulum endoplasmique (ultrastructure), Réticulum endoplasmique (virologie), Tomographie en microscopie électronique, Virus du SRAS (génétique), Virus du SRAS (métabolisme), Virus du SRAS (pathogénicité).
- MESH :
- génétique : Protéines, Virus du SRAS.
- métabolisme : ARN viral, Membranes intracellulaires, Protéines, Protéines virales, Réticulum endoplasmique, Virus du SRAS.
- pathogénicité : Virus du SRAS.
- pharmacologie : Bréfeldine A.
- virologie : Cellules Vero, Membranes intracellulaires, Réticulum endoplasmique.
- Animaux, Cellules Vero, Humains, Interactions hôte-pathogène, Membranes intracellulaires, Microscopie confocale, Protéines, Réplication virale, Réticulum endoplasmique, Tomographie en microscopie électronique.
English descriptors
- KwdEn :
- Animals, Brefeldin A (pharmacology), Chlorocebus aethiops, Electron Microscope Tomography, Endoplasmic Reticulum (metabolism), Endoplasmic Reticulum (ultrastructure), Endoplasmic Reticulum (virology), Host-Pathogen Interactions, Humans, Intracellular Membranes (metabolism), Intracellular Membranes (ultrastructure), Intracellular Membranes (virology), Microscopy, Confocal, Proteins (drug effects), Proteins (genetics), Proteins (metabolism), RNA, Viral (metabolism), SARS Virus (genetics), SARS Virus (metabolism), SARS Virus (pathogenicity), Vero Cells (ultrastructure), Vero Cells (virology), Viral Proteins (metabolism), Virus Replication.
- MESH :
- chemical , drug effects : Proteins.
- chemical , genetics : Proteins.
- chemical , metabolism : Proteins, RNA, Viral, Viral Proteins.
- chemical , pharmacology : Brefeldin A.
- genetics : SARS Virus.
- metabolism : Endoplasmic Reticulum, Intracellular Membranes, SARS Virus.
- pathogenicity : SARS Virus.
- ultrastructure : Endoplasmic Reticulum, Intracellular Membranes, Vero Cells.
- virology : Endoplasmic Reticulum, Intracellular Membranes, Vero Cells.
- Animals, Chlorocebus aethiops, Electron Microscope Tomography, Host-Pathogen Interactions, Humans, Microscopy, Confocal, Virus Replication.
Abstract
To accommodate its RNA synthesis in the infected cell, severe acute respiratory syndrome coronavirus (SARS-CoV) induces a cytoplasmic reticulovesicular network (RVN) that is derived from endoplasmic reticulum (ER) membranes. We set out to investigate how the early secretory pathway interacts with the RVN and the viral replication/transcription complex (RTC) that is anchored to it. When the secretory pathway was disrupted by brefeldin A (BFA) treatment at the start of infection, RVN formation and viral RTC activity were not blocked and continued up to 11 h postinfection, although RNA synthesis was reduced by ca. 80%. In vitro RTC assays, using membrane fractions from infected cells, demonstrated that BFA does not directly interfere with the activity of the viral RNA-synthesizing enzymes. Confocal microscopy studies showed that early secretory pathway components are not associated with SARS-CoV-induced replication sites, although our studies revealed that infection induces a remarkable redistribution of the translocon subunit Sec61alpha. Ultrastructural studies, including electron tomography, revealed that the formation of the RVN and all its previously documented features can occur in the presence of BFA, despite differences in the volume and morphology of the network. We therefore conclude that early secretory pathway proteins do not play a direct role in RVN morphogenesis or the functionality of the SARS-CoV RTC. The BFA-induced disruption of ER integrity and functionality probably affects the overall quality of the membrane scaffold that is needed to support the viral RTC and/or the availability of specific host factors, which in turn compromises viral RNA synthesis.
DOI: 10.1128/JVI.01826-09
PubMed: 19889777
Affiliations:
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Box 9600, 2300 RC Leiden</wicri:regionArea><wicri:noRegion>2300 RC Leiden</wicri:noRegion></affiliation></author><author><name sortKey="Swett Tapia, Cindy" sort="Swett Tapia, Cindy" uniqKey="Swett Tapia C" first="Cindy" last="Swett-Tapia">Cindy Swett-Tapia</name></author><author><name sortKey="Van Den Worm, Sjoerd H E" sort="Van Den Worm, Sjoerd H E" uniqKey="Van Den Worm S" first="Sjoerd H E" last="Van Den Worm">Sjoerd H E. Van Den Worm</name></author><author><name sortKey="Te Velthuis, Aartjan J W" sort="Te Velthuis, Aartjan J W" uniqKey="Te Velthuis A" first="Aartjan J W" last="Te Velthuis">Aartjan J W. Te Velthuis</name></author><author><name sortKey="Koster, Abraham J" sort="Koster, Abraham J" uniqKey="Koster A" first="Abraham J" last="Koster">Abraham J. Koster</name></author><author><name sortKey="Mommaas, A Mieke" sort="Mommaas, A Mieke" uniqKey="Mommaas A" first="A Mieke" last="Mommaas">A Mieke Mommaas</name></author><author><name sortKey="Snijder, Eric J" sort="Snijder, Eric J" uniqKey="Snijder E" first="Eric J" last="Snijder">Eric J. Snijder</name></author><author><name sortKey="Kikkert, Marjolein" sort="Kikkert, Marjolein" uniqKey="Kikkert M" first="Marjolein" last="Kikkert">Marjolein Kikkert</name></author></titleStmt><publicationStmt><idno type="wicri:source">PubMed</idno><date when="2010">2010</date><idno type="RBID">pubmed:19889777</idno><idno type="pmid">19889777</idno><idno type="doi">10.1128/JVI.01826-09</idno><idno type="wicri:Area/PubMed/Corpus">001800</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Corpus" wicri:corpus="PubMed">001800</idno><idno type="wicri:Area/PubMed/Curation">001800</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Curation">001800</idno><idno type="wicri:Area/PubMed/Checkpoint">001642</idno><idno type="wicri:explorRef" wicri:stream="Checkpoint" wicri:step="PubMed">001642</idno><idno type="wicri:Area/Ncbi/Merge">002027</idno><idno type="wicri:Area/Ncbi/Curation">002027</idno><idno type="wicri:Area/Ncbi/Checkpoint">002027</idno><idno type="wicri:Area/Main/Merge">002546</idno><idno type="wicri:Area/Main/Curation">002512</idno><idno type="wicri:Area/Main/Exploration">002512</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en">Integrity of the early secretory pathway promotes, but is not required for, severe acute respiratory syndrome coronavirus RNA synthesis and virus-induced remodeling of endoplasmic reticulum membranes.</title><author><name sortKey="Knoops, Kevin" sort="Knoops, Kevin" uniqKey="Knoops K" first="Kèvin" last="Knoops">Kèvin Knoops</name><affiliation wicri:level="1"><nlm:affiliation>Molecular Virology Laboratory, Department of Medical Microbiology, Leiden University Medical Center, LUMC E4-P, P.O. Box 9600, 2300 RC Leiden, The Netherlands.</nlm:affiliation><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>Molecular Virology Laboratory, Department of Medical Microbiology, Leiden University Medical Center, LUMC E4-P, P.O. Box 9600, 2300 RC Leiden</wicri:regionArea><wicri:noRegion>2300 RC Leiden</wicri:noRegion></affiliation></author><author><name sortKey="Swett Tapia, Cindy" sort="Swett Tapia, Cindy" uniqKey="Swett Tapia C" first="Cindy" last="Swett-Tapia">Cindy Swett-Tapia</name></author><author><name sortKey="Van Den Worm, Sjoerd H E" sort="Van Den Worm, Sjoerd H E" uniqKey="Van Den Worm S" first="Sjoerd H E" last="Van Den Worm">Sjoerd H E. Van Den Worm</name></author><author><name sortKey="Te Velthuis, Aartjan J W" sort="Te Velthuis, Aartjan J W" uniqKey="Te Velthuis A" first="Aartjan J W" last="Te Velthuis">Aartjan J W. Te Velthuis</name></author><author><name sortKey="Koster, Abraham J" sort="Koster, Abraham J" uniqKey="Koster A" first="Abraham J" last="Koster">Abraham J. Koster</name></author><author><name sortKey="Mommaas, A Mieke" sort="Mommaas, A Mieke" uniqKey="Mommaas A" first="A Mieke" last="Mommaas">A Mieke Mommaas</name></author><author><name sortKey="Snijder, Eric J" sort="Snijder, Eric J" uniqKey="Snijder E" first="Eric J" last="Snijder">Eric J. Snijder</name></author><author><name sortKey="Kikkert, Marjolein" sort="Kikkert, Marjolein" uniqKey="Kikkert M" first="Marjolein" last="Kikkert">Marjolein Kikkert</name></author></analytic><series><title level="j">Journal of virology</title><idno type="eISSN">1098-5514</idno><imprint><date when="2010" type="published">2010</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Animals</term><term>Brefeldin A (pharmacology)</term><term>Chlorocebus aethiops</term><term>Electron Microscope Tomography</term><term>Endoplasmic Reticulum (metabolism)</term><term>Endoplasmic Reticulum (ultrastructure)</term><term>Endoplasmic Reticulum (virology)</term><term>Host-Pathogen Interactions</term><term>Humans</term><term>Intracellular Membranes (metabolism)</term><term>Intracellular Membranes (ultrastructure)</term><term>Intracellular Membranes (virology)</term><term>Microscopy, Confocal</term><term>Proteins (drug effects)</term><term>Proteins (genetics)</term><term>Proteins (metabolism)</term><term>RNA, Viral (metabolism)</term><term>SARS Virus (genetics)</term><term>SARS Virus (metabolism)</term><term>SARS Virus (pathogenicity)</term><term>Vero Cells (ultrastructure)</term><term>Vero Cells (virology)</term><term>Viral Proteins (metabolism)</term><term>Virus Replication</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>ARN viral (métabolisme)</term><term>Animaux</term><term>Bréfeldine A (pharmacologie)</term><term>Cellules Vero (ultrastructure)</term><term>Cellules Vero (virologie)</term><term>Humains</term><term>Interactions hôte-pathogène</term><term>Membranes intracellulaires (métabolisme)</term><term>Membranes intracellulaires (ultrastructure)</term><term>Membranes intracellulaires (virologie)</term><term>Microscopie confocale</term><term>Protéines ()</term><term>Protéines (génétique)</term><term>Protéines (métabolisme)</term><term>Protéines virales (métabolisme)</term><term>Réplication virale</term><term>Réticulum endoplasmique (métabolisme)</term><term>Réticulum endoplasmique (ultrastructure)</term><term>Réticulum endoplasmique (virologie)</term><term>Tomographie en microscopie électronique</term><term>Virus du SRAS (génétique)</term><term>Virus du SRAS (métabolisme)</term><term>Virus du SRAS (pathogénicité)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="drug effects" xml:lang="en"><term>Proteins</term></keywords><keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>Proteins</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Proteins</term><term>RNA, Viral</term><term>Viral Proteins</term></keywords><keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Brefeldin A</term></keywords><keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>SARS Virus</term></keywords><keywords scheme="MESH" qualifier="génétique" xml:lang="fr"><term>Protéines</term><term>Virus du SRAS</term></keywords><keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Endoplasmic Reticulum</term><term>Intracellular Membranes</term><term>SARS Virus</term></keywords><keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>ARN viral</term><term>Membranes intracellulaires</term><term>Protéines</term><term>Protéines virales</term><term>Réticulum endoplasmique</term><term>Virus du SRAS</term></keywords><keywords scheme="MESH" qualifier="pathogenicity" xml:lang="en"><term>SARS Virus</term></keywords><keywords scheme="MESH" qualifier="pathogénicité" xml:lang="fr"><term>Virus du SRAS</term></keywords><keywords scheme="MESH" qualifier="pharmacologie" xml:lang="fr"><term>Bréfeldine A</term></keywords><keywords scheme="MESH" qualifier="ultrastructure" xml:lang="en"><term>Endoplasmic Reticulum</term><term>Intracellular Membranes</term><term>Vero Cells</term></keywords><keywords scheme="MESH" qualifier="virologie" xml:lang="fr"><term>Cellules Vero</term><term>Membranes intracellulaires</term><term>Réticulum endoplasmique</term></keywords><keywords scheme="MESH" qualifier="virology" xml:lang="en"><term>Endoplasmic Reticulum</term><term>Intracellular Membranes</term><term>Vero Cells</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Animals</term><term>Chlorocebus aethiops</term><term>Electron Microscope Tomography</term><term>Host-Pathogen Interactions</term><term>Humans</term><term>Microscopy, Confocal</term><term>Virus Replication</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Animaux</term><term>Cellules Vero</term><term>Humains</term><term>Interactions hôte-pathogène</term><term>Membranes intracellulaires</term><term>Microscopie confocale</term><term>Protéines</term><term>Réplication virale</term><term>Réticulum endoplasmique</term><term>Tomographie en microscopie électronique</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">To accommodate its RNA synthesis in the infected cell, severe acute respiratory syndrome coronavirus (SARS-CoV) induces a cytoplasmic reticulovesicular network (RVN) that is derived from endoplasmic reticulum (ER) membranes. We set out to investigate how the early secretory pathway interacts with the RVN and the viral replication/transcription complex (RTC) that is anchored to it. When the secretory pathway was disrupted by brefeldin A (BFA) treatment at the start of infection, RVN formation and viral RTC activity were not blocked and continued up to 11 h postinfection, although RNA synthesis was reduced by ca. 80%. In vitro RTC assays, using membrane fractions from infected cells, demonstrated that BFA does not directly interfere with the activity of the viral RNA-synthesizing enzymes. Confocal microscopy studies showed that early secretory pathway components are not associated with SARS-CoV-induced replication sites, although our studies revealed that infection induces a remarkable redistribution of the translocon subunit Sec61alpha. Ultrastructural studies, including electron tomography, revealed that the formation of the RVN and all its previously documented features can occur in the presence of BFA, despite differences in the volume and morphology of the network. We therefore conclude that early secretory pathway proteins do not play a direct role in RVN morphogenesis or the functionality of the SARS-CoV RTC. The BFA-induced disruption of ER integrity and functionality probably affects the overall quality of the membrane scaffold that is needed to support the viral RTC and/or the availability of specific host factors, which in turn compromises viral RNA synthesis.</div></front></TEI><affiliations><list><country><li>Pays-Bas</li></country></list><tree><noCountry><name sortKey="Kikkert, Marjolein" sort="Kikkert, Marjolein" uniqKey="Kikkert M" first="Marjolein" last="Kikkert">Marjolein Kikkert</name><name sortKey="Koster, Abraham J" sort="Koster, Abraham J" uniqKey="Koster A" first="Abraham J" last="Koster">Abraham J. Koster</name><name sortKey="Mommaas, A Mieke" sort="Mommaas, A Mieke" uniqKey="Mommaas A" first="A Mieke" last="Mommaas">A Mieke Mommaas</name><name sortKey="Snijder, Eric J" sort="Snijder, Eric J" uniqKey="Snijder E" first="Eric J" last="Snijder">Eric J. Snijder</name><name sortKey="Swett Tapia, Cindy" sort="Swett Tapia, Cindy" uniqKey="Swett Tapia C" first="Cindy" last="Swett-Tapia">Cindy Swett-Tapia</name><name sortKey="Te Velthuis, Aartjan J W" sort="Te Velthuis, Aartjan J W" uniqKey="Te Velthuis A" first="Aartjan J W" last="Te Velthuis">Aartjan J W. Te Velthuis</name><name sortKey="Van Den Worm, Sjoerd H E" sort="Van Den Worm, Sjoerd H E" uniqKey="Van Den Worm S" first="Sjoerd H E" last="Van Den Worm">Sjoerd H E. Van Den Worm</name></noCountry><country name="Pays-Bas"><noRegion><name sortKey="Knoops, Kevin" sort="Knoops, Kevin" uniqKey="Knoops K" first="Kèvin" last="Knoops">Kèvin Knoops</name></noRegion></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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