Severe acute respiratory syndrome coronavirus ORF6 antagonizes STAT1 function by sequestering nuclear import factors on the rough endoplasmic reticulum/golgi membrane
Identifieur interne : 003B33 ( Main/Exploration ); précédent : 003B32; suivant : 003B34Severe acute respiratory syndrome coronavirus ORF6 antagonizes STAT1 function by sequestering nuclear import factors on the rough endoplasmic reticulum/golgi membrane
Auteurs : Matthew Frieman [États-Unis] ; Boyd Yount [États-Unis] ; Mark Heise [États-Unis] ; Sarah A. Kopecky-Bromberg [États-Unis] ; Peter Palese [États-Unis] ; Ralph S. Baric [États-Unis]Source :
- Journal of virology [ 0022-538X ] ; 2007.
Descripteurs français
- KwdFr :
- Animaux, Appareil de Golgi (génétique), Appareil de Golgi (immunologie), Appareil de Golgi (métabolisme), Cadres ouverts de lecture (physiologie), Cariophérines alpha (génétique), Cariophérines alpha (immunologie), Cariophérines alpha (métabolisme), Caryophérines bêta (génétique), Caryophérines bêta (immunologie), Caryophérines bêta (métabolisme), Cellules Caco-2, Cellules Vero, Facteur de transcription STAT-1 (génétique), Facteur de transcription STAT-1 (immunologie), Facteur de transcription STAT-1 (métabolisme), Humains, Immunité innée (génétique), Interférons (immunologie), Interférons (métabolisme), Mutation, Noyau de la cellule (génétique), Noyau de la cellule (immunologie), Noyau de la cellule (métabolisme), Protéines recombinantes (génétique), Protéines recombinantes (immunologie), Protéines recombinantes (métabolisme), Régulation de l'expression des gènes (génétique), Régulation de l'expression des gènes (immunologie), Réplication virale (physiologie), Réticulum endoplasmique (génétique), Réticulum endoplasmique (immunologie), Réticulum endoplasmique (métabolisme), Structure tertiaire des protéines (génétique), Transduction du signal (génétique), Transduction du signal (immunologie), Transport nucléaire actif (physiologie), Virus du SRAS (génétique), Virus du SRAS (immunologie), Virus du SRAS (métabolisme).
- MESH :
- génétique : Appareil de Golgi, Cariophérines alpha, Caryophérines bêta, Facteur de transcription STAT-1, Immunité innée, Noyau de la cellule, Protéines recombinantes, Régulation de l'expression des gènes, Réticulum endoplasmique, Structure tertiaire des protéines, Transduction du signal, Virus du SRAS.
- immunologie : Appareil de Golgi, Cariophérines alpha, Caryophérines bêta, Facteur de transcription STAT-1, Interférons, Noyau de la cellule, Protéines recombinantes, Régulation de l'expression des gènes, Réticulum endoplasmique, Transduction du signal, Virus du SRAS.
- métabolisme : Appareil de Golgi, Cariophérines alpha, Caryophérines bêta, Facteur de transcription STAT-1, Interférons, Noyau de la cellule, Protéines recombinantes, Réticulum endoplasmique, Virus du SRAS.
- physiologie : Cadres ouverts de lecture, Réplication virale, Transport nucléaire actif.
- Pascal (Inist)
English descriptors
- KwdEn :
- Active Transport, Cell Nucleus (physiology), Acute, Animals, Caco-2 Cells, Cell Nucleus (genetics), Cell Nucleus (immunology), Cell Nucleus (metabolism), Chlorocebus aethiops, Coronavirus, Endoplasmic Reticulum (genetics), Endoplasmic Reticulum (immunology), Endoplasmic Reticulum (metabolism), Endoplasmic reticulum, Gene Expression Regulation (genetics), Gene Expression Regulation (immunology), Golgi Apparatus (genetics), Golgi Apparatus (immunology), Golgi Apparatus (metabolism), Golgi apparatus, Humans, Immunity, Innate (genetics), Interferons (immunology), Interferons (metabolism), Mutation, Open Reading Frames (physiology), Protein Structure, Tertiary (genetics), Recombinant Proteins (genetics), Recombinant Proteins (immunology), Recombinant Proteins (metabolism), SARS Virus (genetics), SARS Virus (immunology), SARS Virus (metabolism), STAT1 Transcription Factor (genetics), STAT1 Transcription Factor (immunology), STAT1 Transcription Factor (metabolism), Signal Transduction (genetics), Signal Transduction (immunology), Vero Cells, Virology, Virus Replication (physiology), alpha Karyopherins (genetics), alpha Karyopherins (immunology), alpha Karyopherins (metabolism), beta Karyopherins (genetics), beta Karyopherins (immunology), beta Karyopherins (metabolism).
- MESH :
- chemical , genetics : Recombinant Proteins, STAT1 Transcription Factor, alpha Karyopherins, beta Karyopherins.
- chemical , immunology : Interferons, Recombinant Proteins, STAT1 Transcription Factor, alpha Karyopherins, beta Karyopherins.
- genetics : Cell Nucleus, Endoplasmic Reticulum, Gene Expression Regulation, Golgi Apparatus, Immunity, Innate, Protein Structure, Tertiary, SARS Virus, Signal Transduction.
- immunology : Cell Nucleus, Endoplasmic Reticulum, Gene Expression Regulation, Golgi Apparatus, SARS Virus, Signal Transduction.
- metabolism : Cell Nucleus, Endoplasmic Reticulum, Golgi Apparatus, Interferons, Recombinant Proteins, SARS Virus, STAT1 Transcription Factor, alpha Karyopherins, beta Karyopherins.
- physiology : Active Transport, Cell Nucleus, Open Reading Frames, Virus Replication.
- Animals, Caco-2 Cells, Chlorocebus aethiops, Humans, Mutation, Vero Cells.
Abstract
The host innate immune response is an important deterrent of severe viral infection in humans and animals. Nuclear import factors function as key gatekeepers that regulate the transport of innate immune regulatory cargo to the nucleus of cells to activate the antiviral response. Using severe acute respiratory syndrome coronavirus (SARS-CoV) as a model, we demonstrate that SARS-COV ORF6 protein is localized to the endoplasmic reticulum (ER)/Golgi membrane in infected cells, where it binds to and disrupts nuclear import complex formation by tethering karyopherin alpha 2 and karyopherin beta 1 to the membrane. Retention of import factors at the ER/Golgi membrane leads to a loss of STAT1 transport into the nucleus in response to interferon signaling, thus blocking the expression of STAT1-activated genes that establish an antiviral state. We mapped the region of ORF6, which binds karyopherin alpha 2, to the C terminus of ORF6 and show that mutations in the C terminus no longer bind karyopherin alpha 2 or block the nuclear import of STAT1. We also show that N-terminal deletions of karyopherin alpha 2 that no longer bind to karyopherin beta 1 still retain ORF6 binding activity but no longer block STAT1 nuclear import. Recombinant SARS-CoV lacking ORF6 did not tether karyopherin alpha 2 to the ER/Golgi membrane and allowed the import of the STAT1 complex into the nucleus. We discuss the likely implications of these data on SARS-CoV replication and pathogenesis.
Affiliations:
- États-Unis
- Caroline du Nord, État de New York
- Chapel Hill (Caroline du Nord)
- Université de Caroline du Nord à Chapel Hill
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Le document en format XML
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sortKey="Yount, Boyd" sort="Yount, Boyd" uniqKey="Yount B" first="Boyd" last="Yount">Boyd Yount</name><affiliation wicri:level="4"><inist:fA14 i1="01"><s1>Department of Epidemiology, School of Public Health, University of North Carolina at Chapel Hill</s1><s3>USA</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>6 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><settlement type="city">Chapel Hill (Caroline du Nord)</settlement><region type="state">Caroline du Nord</region></placeName><orgName type="university">Université de Caroline du Nord à Chapel Hill</orgName></affiliation></author><author><name sortKey="Heise, Mark" sort="Heise, Mark" uniqKey="Heise M" first="Mark" last="Heise">Mark Heise</name><affiliation wicri:level="4"><inist:fA14 i1="02"><s1>Department of Microbiology and Immunology, School of Medicine, University of North Carolina at Chapel Hill</s1><s3>USA</s3><sZ>3 aut.</sZ><sZ>6 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><settlement type="city">Chapel Hill (Caroline du Nord)</settlement><region type="state">Caroline du Nord</region></placeName><orgName type="university">Université de Caroline du Nord à Chapel Hill</orgName></affiliation><affiliation wicri:level="4"><inist:fA14 i1="03"><s1>Department of Genetics, University of North Carolina at Chapel Hill</s1><s3>USA</s3><sZ>3 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><settlement type="city">Chapel Hill (Caroline du Nord)</settlement><region type="state">Caroline du Nord</region></placeName><orgName type="university">Université de Caroline du Nord à Chapel Hill</orgName></affiliation><affiliation wicri:level="4"><inist:fA14 i1="04"><s1>Carolina Vaccine Institute, School of Medicine, University of North Carolina at Chapel Hill</s1><s2>Chapel Hill, North Carolina</s2><s3>USA</s3><sZ>3 aut.</sZ><sZ>6 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Caroline du Nord</region><settlement type="city">Chapel Hill (Caroline du Nord)</settlement></placeName><orgName type="university">Université de Caroline du Nord à Chapel Hill</orgName></affiliation></author><author><name sortKey="Kopecky Bromberg, Sarah A" sort="Kopecky Bromberg, Sarah A" uniqKey="Kopecky Bromberg S" first="Sarah A." last="Kopecky-Bromberg">Sarah A. Kopecky-Bromberg</name><affiliation wicri:level="2"><inist:fA14 i1="05"><s1>Department of Microbiology, Mount Sinai School of Medicine</s1><s2>New York, New York</s2><s3>USA</s3><sZ>4 aut.</sZ><sZ>5 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">État de New York</region></placeName></affiliation></author><author><name sortKey="Palese, Peter" sort="Palese, Peter" uniqKey="Palese P" first="Peter" last="Palese">Peter Palese</name><affiliation wicri:level="2"><inist:fA14 i1="05"><s1>Department of Microbiology, Mount Sinai School of Medicine</s1><s2>New York, New York</s2><s3>USA</s3><sZ>4 aut.</sZ><sZ>5 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">État de New York</region></placeName></affiliation></author><author><name sortKey="Baric, Ralph S" sort="Baric, Ralph S" uniqKey="Baric R" first="Ralph S." last="Baric">Ralph S. Baric</name><affiliation wicri:level="4"><inist:fA14 i1="01"><s1>Department of Epidemiology, School of Public Health, University of North Carolina at Chapel Hill</s1><s3>USA</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>6 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><settlement type="city">Chapel Hill (Caroline du Nord)</settlement><region type="state">Caroline du Nord</region></placeName><orgName type="university">Université de Caroline du Nord à Chapel Hill</orgName></affiliation><affiliation wicri:level="4"><inist:fA14 i1="02"><s1>Department of Microbiology and Immunology, School of Medicine, University of North Carolina at Chapel Hill</s1><s3>USA</s3><sZ>3 aut.</sZ><sZ>6 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><settlement type="city">Chapel Hill (Caroline du Nord)</settlement><region type="state">Caroline du Nord</region></placeName><orgName type="university">Université de Caroline du Nord à Chapel Hill</orgName></affiliation><affiliation wicri:level="4"><inist:fA14 i1="04"><s1>Carolina Vaccine Institute, School of Medicine, University of North Carolina at Chapel Hill</s1><s2>Chapel Hill, North Carolina</s2><s3>USA</s3><sZ>3 aut.</sZ><sZ>6 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Caroline du Nord</region><settlement type="city">Chapel Hill (Caroline du Nord)</settlement></placeName><orgName type="university">Université de Caroline du Nord à Chapel Hill</orgName></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>Active Transport, Cell Nucleus (physiology)</term><term>Acute</term><term>Animals</term><term>Caco-2 Cells</term><term>Cell Nucleus (genetics)</term><term>Cell Nucleus (immunology)</term><term>Cell Nucleus (metabolism)</term><term>Chlorocebus aethiops</term><term>Coronavirus</term><term>Endoplasmic Reticulum (genetics)</term><term>Endoplasmic Reticulum (immunology)</term><term>Endoplasmic Reticulum (metabolism)</term><term>Endoplasmic reticulum</term><term>Gene Expression Regulation (genetics)</term><term>Gene Expression Regulation (immunology)</term><term>Golgi Apparatus (genetics)</term><term>Golgi Apparatus (immunology)</term><term>Golgi Apparatus (metabolism)</term><term>Golgi apparatus</term><term>Humans</term><term>Immunity, Innate (genetics)</term><term>Interferons (immunology)</term><term>Interferons (metabolism)</term><term>Mutation</term><term>Open Reading Frames (physiology)</term><term>Protein Structure, Tertiary (genetics)</term><term>Recombinant Proteins (genetics)</term><term>Recombinant Proteins (immunology)</term><term>Recombinant Proteins (metabolism)</term><term>SARS Virus (genetics)</term><term>SARS Virus (immunology)</term><term>SARS Virus (metabolism)</term><term>STAT1 Transcription Factor (genetics)</term><term>STAT1 Transcription Factor (immunology)</term><term>STAT1 Transcription Factor (metabolism)</term><term>Signal Transduction (genetics)</term><term>Signal Transduction (immunology)</term><term>Vero Cells</term><term>Virology</term><term>Virus Replication (physiology)</term><term>alpha Karyopherins (genetics)</term><term>alpha Karyopherins (immunology)</term><term>alpha Karyopherins (metabolism)</term><term>beta Karyopherins (genetics)</term><term>beta Karyopherins (immunology)</term><term>beta Karyopherins (metabolism)</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Animaux</term><term>Appareil de Golgi (génétique)</term><term>Appareil de Golgi (immunologie)</term><term>Appareil de Golgi (métabolisme)</term><term>Cadres ouverts de lecture (physiologie)</term><term>Cariophérines alpha (génétique)</term><term>Cariophérines alpha (immunologie)</term><term>Cariophérines alpha (métabolisme)</term><term>Caryophérines bêta (génétique)</term><term>Caryophérines bêta (immunologie)</term><term>Caryophérines bêta (métabolisme)</term><term>Cellules Caco-2</term><term>Cellules Vero</term><term>Facteur de transcription STAT-1 (génétique)</term><term>Facteur de transcription STAT-1 (immunologie)</term><term>Facteur de transcription STAT-1 (métabolisme)</term><term>Humains</term><term>Immunité innée (génétique)</term><term>Interférons (immunologie)</term><term>Interférons (métabolisme)</term><term>Mutation</term><term>Noyau de la cellule (génétique)</term><term>Noyau de la cellule (immunologie)</term><term>Noyau de la cellule (métabolisme)</term><term>Protéines recombinantes (génétique)</term><term>Protéines recombinantes (immunologie)</term><term>Protéines recombinantes (métabolisme)</term><term>Régulation de l'expression des gènes (génétique)</term><term>Régulation de l'expression des gènes (immunologie)</term><term>Réplication virale (physiologie)</term><term>Réticulum endoplasmique (génétique)</term><term>Réticulum endoplasmique (immunologie)</term><term>Réticulum endoplasmique (métabolisme)</term><term>Structure tertiaire des protéines (génétique)</term><term>Transduction du signal (génétique)</term><term>Transduction du signal (immunologie)</term><term>Transport nucléaire actif (physiologie)</term><term>Virus du SRAS (génétique)</term><term>Virus du SRAS (immunologie)</term><term>Virus du SRAS (métabolisme)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>Recombinant Proteins</term><term>STAT1 Transcription Factor</term><term>alpha Karyopherins</term><term>beta Karyopherins</term></keywords><keywords scheme="MESH" type="chemical" qualifier="immunology" xml:lang="en"><term>Interferons</term><term>Recombinant Proteins</term><term>STAT1 Transcription Factor</term><term>alpha Karyopherins</term><term>beta Karyopherins</term></keywords><keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>Cell Nucleus</term><term>Endoplasmic Reticulum</term><term>Gene Expression Regulation</term><term>Golgi Apparatus</term><term>Immunity, Innate</term><term>Protein Structure, Tertiary</term><term>SARS Virus</term><term>Signal Transduction</term></keywords><keywords scheme="MESH" qualifier="génétique" xml:lang="fr"><term>Appareil de Golgi</term><term>Cariophérines alpha</term><term>Caryophérines bêta</term><term>Facteur de transcription STAT-1</term><term>Immunité innée</term><term>Noyau de la cellule</term><term>Protéines recombinantes</term><term>Régulation de l'expression des gènes</term><term>Réticulum endoplasmique</term><term>Structure tertiaire des protéines</term><term>Transduction du signal</term><term>Virus du SRAS</term></keywords><keywords scheme="MESH" qualifier="immunologie" xml:lang="fr"><term>Appareil de Golgi</term><term>Cariophérines alpha</term><term>Caryophérines bêta</term><term>Facteur de transcription STAT-1</term><term>Interférons</term><term>Noyau de la cellule</term><term>Protéines recombinantes</term><term>Régulation de l'expression des gènes</term><term>Réticulum endoplasmique</term><term>Transduction du signal</term><term>Virus du SRAS</term></keywords><keywords scheme="MESH" qualifier="immunology" xml:lang="en"><term>Cell Nucleus</term><term>Endoplasmic Reticulum</term><term>Gene Expression Regulation</term><term>Golgi Apparatus</term><term>SARS Virus</term><term>Signal Transduction</term></keywords><keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Cell Nucleus</term><term>Endoplasmic Reticulum</term><term>Golgi Apparatus</term><term>Interferons</term><term>Recombinant Proteins</term><term>SARS Virus</term><term>STAT1 Transcription Factor</term><term>alpha Karyopherins</term><term>beta Karyopherins</term></keywords><keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Appareil de Golgi</term><term>Cariophérines alpha</term><term>Caryophérines bêta</term><term>Facteur de transcription STAT-1</term><term>Interférons</term><term>Noyau de la cellule</term><term>Protéines recombinantes</term><term>Réticulum endoplasmique</term><term>Virus du SRAS</term></keywords><keywords scheme="MESH" qualifier="physiologie" xml:lang="fr"><term>Cadres ouverts de lecture</term><term>Réplication virale</term><term>Transport nucléaire actif</term></keywords><keywords scheme="MESH" qualifier="physiology" xml:lang="en"><term>Active Transport, Cell Nucleus</term><term>Open Reading Frames</term><term>Virus Replication</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Animals</term><term>Caco-2 Cells</term><term>Chlorocebus aethiops</term><term>Humans</term><term>Mutation</term><term>Vero Cells</term></keywords><keywords scheme="Pascal" xml:lang="fr"><term>Animaux</term><term>Cellules Caco-2</term><term>Cellules Vero</term><term>Coronavirus</term><term>Aigu</term><term>Humains</term><term>Mutation</term><term>Réticulum endoplasmique</term><term>Appareil Golgi</term><term>Virologie</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">The host innate immune response is an important deterrent of severe viral infection in humans and animals. Nuclear import factors function as key gatekeepers that regulate the transport of innate immune regulatory cargo to the nucleus of cells to activate the antiviral response. Using severe acute respiratory syndrome coronavirus (SARS-CoV) as a model, we demonstrate that SARS-COV ORF6 protein is localized to the endoplasmic reticulum (ER)/Golgi membrane in infected cells, where it binds to and disrupts nuclear import complex formation by tethering karyopherin alpha 2 and karyopherin beta 1 to the membrane. Retention of import factors at the ER/Golgi membrane leads to a loss of STAT1 transport into the nucleus in response to interferon signaling, thus blocking the expression of STAT1-activated genes that establish an antiviral state. We mapped the region of ORF6, which binds karyopherin alpha 2, to the C terminus of ORF6 and show that mutations in the C terminus no longer bind karyopherin alpha 2 or block the nuclear import of STAT1. We also show that N-terminal deletions of karyopherin alpha 2 that no longer bind to karyopherin beta 1 still retain ORF6 binding activity but no longer block STAT1 nuclear import. Recombinant SARS-CoV lacking ORF6 did not tether karyopherin alpha 2 to the ER/Golgi membrane and allowed the import of the STAT1 complex into the nucleus. We discuss the likely implications of these data on SARS-CoV replication and pathogenesis.</div></front></TEI><affiliations><list><country><li>États-Unis</li></country><region><li>Caroline du Nord</li><li>État de New York</li></region><settlement><li>Chapel Hill (Caroline du Nord)</li></settlement><orgName><li>Université de Caroline du Nord à Chapel Hill</li></orgName></list><tree><country name="États-Unis"><region name="Caroline du Nord"><name sortKey="Frieman, Matthew" sort="Frieman, Matthew" uniqKey="Frieman M" first="Matthew" last="Frieman">Matthew Frieman</name></region><name sortKey="Baric, Ralph S" sort="Baric, Ralph S" uniqKey="Baric R" first="Ralph S." last="Baric">Ralph S. Baric</name><name sortKey="Baric, Ralph S" sort="Baric, Ralph S" uniqKey="Baric R" first="Ralph S." last="Baric">Ralph S. Baric</name><name sortKey="Baric, Ralph S" sort="Baric, Ralph S" uniqKey="Baric R" first="Ralph S." last="Baric">Ralph S. Baric</name><name sortKey="Heise, Mark" sort="Heise, Mark" uniqKey="Heise M" first="Mark" last="Heise">Mark Heise</name><name sortKey="Heise, Mark" sort="Heise, Mark" uniqKey="Heise M" first="Mark" last="Heise">Mark Heise</name><name sortKey="Heise, Mark" sort="Heise, Mark" uniqKey="Heise M" first="Mark" last="Heise">Mark Heise</name><name sortKey="Kopecky Bromberg, Sarah A" sort="Kopecky Bromberg, Sarah A" uniqKey="Kopecky Bromberg S" first="Sarah A." last="Kopecky-Bromberg">Sarah A. Kopecky-Bromberg</name><name sortKey="Palese, Peter" sort="Palese, Peter" uniqKey="Palese P" first="Peter" last="Palese">Peter Palese</name><name sortKey="Yount, Boyd" sort="Yount, Boyd" uniqKey="Yount B" first="Boyd" last="Yount">Boyd Yount</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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