SARS-Coronavirus Open Reading Frame-8b triggers intracellular stress pathways and activates NLRP3 inflammasomes.
Identifieur interne : 000860 ( Main/Exploration ); précédent : 000859; suivant : 000861SARS-Coronavirus Open Reading Frame-8b triggers intracellular stress pathways and activates NLRP3 inflammasomes.
Auteurs : Chong-Shan Shi [États-Unis] ; Neel R. Nabar [États-Unis] ; Ning-Na Huang [États-Unis] ; John H. Kehrl [États-Unis]Source :
- Cell death discovery [ 2058-7716 ] ; 2019.
Abstract
The SARS (severe acute respiratory syndrome) outbreak was caused by a coronavirus (CoV) named the SARS-CoV. SARS pathology is propagated both by direct cytotoxic effects of the virus and aberrant activation of the innate immune response. Here, we identify several mechanisms by which a SARS-CoV open reading frame (ORF) activates intracellular stress pathways and targets the innate immune response. We show that ORF8b forms insoluble intracellular aggregates dependent on a valine at residue 77. Aggregated ORF8b induces endoplasmic reticulum (ER) stress, lysosomal damage, and subsequent activation of the master regulator of the autophagy and lysosome machinery, Transcription factor EB (TFEB). ORF8b causes cell death in epithelial cells, which is partially rescued by reducing its ability to aggregate. In macrophages, ORF8b robustly activates the NLRP3 inflammasome by providing a potent signal 2 required for activation. Mechanistically, ORF8b interacts directly with the Leucine Rich Repeat domain of NLRP3 and localizes with NLRP3 and ASC in cytosolic dot-like structures. ORF8b triggers cell death consistent with pyroptotic cell death in macrophages. While in those cells lacking NLRP3 accumulating ORF8b cytosolic aggregates cause ER stress, mitochondrial dysfunction, and caspase-independent cell death.
DOI: 10.1038/s41420-019-0181-7
PubMed: 31231549
Affiliations:
Links toward previous steps (curation, corpus...)
- to stream PubMed, to step Corpus: 000197
- to stream PubMed, to step Curation: 000197
- to stream PubMed, to step Checkpoint: 000188
- to stream Ncbi, to step Merge: 000A28
- to stream Ncbi, to step Curation: 000A28
- to stream Ncbi, to step Checkpoint: 000A28
- to stream Main, to step Merge: 000861
- to stream Main, to step Curation: 000860
Le document en format XML
<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">SARS-Coronavirus Open Reading Frame-8b triggers intracellular stress pathways and activates NLRP3 inflammasomes.</title><author><name sortKey="Shi, Chong Shan" sort="Shi, Chong Shan" uniqKey="Shi C" first="Chong-Shan" last="Shi">Chong-Shan Shi</name><affiliation wicri:level="2"><nlm:affiliation>B Cell Molecular Immunology Section, Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892 USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Maryland</region></placeName><wicri:cityArea>B Cell Molecular Immunology Section, Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda</wicri:cityArea></affiliation></author><author><name sortKey="Nabar, Neel R" sort="Nabar, Neel R" uniqKey="Nabar N" first="Neel R" last="Nabar">Neel R. Nabar</name><affiliation wicri:level="2"><nlm:affiliation>B Cell Molecular Immunology Section, Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892 USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Maryland</region></placeName><wicri:cityArea>B Cell Molecular Immunology Section, Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda</wicri:cityArea></affiliation></author><author><name sortKey="Huang, Ning Na" sort="Huang, Ning Na" uniqKey="Huang N" first="Ning-Na" last="Huang">Ning-Na Huang</name><affiliation wicri:level="2"><nlm:affiliation>B Cell Molecular Immunology Section, Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892 USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Maryland</region></placeName><wicri:cityArea>B Cell Molecular Immunology Section, Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda</wicri:cityArea></affiliation></author><author><name sortKey="Kehrl, John H" sort="Kehrl, John H" uniqKey="Kehrl J" first="John H" last="Kehrl">John H. Kehrl</name><affiliation wicri:level="2"><nlm:affiliation>B Cell Molecular Immunology Section, Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892 USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Maryland</region></placeName><wicri:cityArea>B Cell Molecular Immunology Section, Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda</wicri:cityArea></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PubMed</idno><date when="2019">2019</date><idno type="RBID">pubmed:31231549</idno><idno type="pmid">31231549</idno><idno type="doi">10.1038/s41420-019-0181-7</idno><idno type="wicri:Area/PubMed/Corpus">000197</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Corpus" wicri:corpus="PubMed">000197</idno><idno type="wicri:Area/PubMed/Curation">000197</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Curation">000197</idno><idno type="wicri:Area/PubMed/Checkpoint">000188</idno><idno type="wicri:explorRef" wicri:stream="Checkpoint" wicri:step="PubMed">000188</idno><idno type="wicri:Area/Ncbi/Merge">000A28</idno><idno type="wicri:Area/Ncbi/Curation">000A28</idno><idno type="wicri:Area/Ncbi/Checkpoint">000A28</idno><idno type="wicri:doubleKey">2058-7716:2019:Shi C:sars:coronavirus:open</idno><idno type="wicri:Area/Main/Merge">000861</idno><idno type="wicri:Area/Main/Curation">000860</idno><idno type="wicri:Area/Main/Exploration">000860</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en">SARS-Coronavirus Open Reading Frame-8b triggers intracellular stress pathways and activates NLRP3 inflammasomes.</title><author><name sortKey="Shi, Chong Shan" sort="Shi, Chong Shan" uniqKey="Shi C" first="Chong-Shan" last="Shi">Chong-Shan Shi</name><affiliation wicri:level="2"><nlm:affiliation>B Cell Molecular Immunology Section, Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892 USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Maryland</region></placeName><wicri:cityArea>B Cell Molecular Immunology Section, Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda</wicri:cityArea></affiliation></author><author><name sortKey="Nabar, Neel R" sort="Nabar, Neel R" uniqKey="Nabar N" first="Neel R" last="Nabar">Neel R. Nabar</name><affiliation wicri:level="2"><nlm:affiliation>B Cell Molecular Immunology Section, Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892 USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Maryland</region></placeName><wicri:cityArea>B Cell Molecular Immunology Section, Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda</wicri:cityArea></affiliation></author><author><name sortKey="Huang, Ning Na" sort="Huang, Ning Na" uniqKey="Huang N" first="Ning-Na" last="Huang">Ning-Na Huang</name><affiliation wicri:level="2"><nlm:affiliation>B Cell Molecular Immunology Section, Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892 USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Maryland</region></placeName><wicri:cityArea>B Cell Molecular Immunology Section, Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda</wicri:cityArea></affiliation></author><author><name sortKey="Kehrl, John H" sort="Kehrl, John H" uniqKey="Kehrl J" first="John H" last="Kehrl">John H. Kehrl</name><affiliation wicri:level="2"><nlm:affiliation>B Cell Molecular Immunology Section, Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892 USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Maryland</region></placeName><wicri:cityArea>B Cell Molecular Immunology Section, Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda</wicri:cityArea></affiliation></author></analytic><series><title level="j">Cell death discovery</title><idno type="ISSN">2058-7716</idno><imprint><date when="2019" type="published">2019</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">The SARS (severe acute respiratory syndrome) outbreak was caused by a coronavirus (CoV) named the SARS-CoV. SARS pathology is propagated both by direct cytotoxic effects of the virus and aberrant activation of the innate immune response. Here, we identify several mechanisms by which a SARS-CoV open reading frame (ORF) activates intracellular stress pathways and targets the innate immune response. We show that ORF8b forms insoluble intracellular aggregates dependent on a valine at residue 77. Aggregated ORF8b induces endoplasmic reticulum (ER) stress, lysosomal damage, and subsequent activation of the master regulator of the autophagy and lysosome machinery, Transcription factor EB (TFEB). ORF8b causes cell death in epithelial cells, which is partially rescued by reducing its ability to aggregate. In macrophages, ORF8b robustly activates the NLRP3 inflammasome by providing a potent signal 2 required for activation. Mechanistically, ORF8b interacts directly with the Leucine Rich Repeat domain of NLRP3 and localizes with NLRP3 and ASC in cytosolic dot-like structures. ORF8b triggers cell death consistent with pyroptotic cell death in macrophages. While in those cells lacking NLRP3 accumulating ORF8b cytosolic aggregates cause ER stress, mitochondrial dysfunction, and caspase-independent cell death.</div></front></TEI><affiliations><list><country><li>États-Unis</li></country><region><li>Maryland</li></region></list><tree><country name="États-Unis"><region name="Maryland"><name sortKey="Shi, Chong Shan" sort="Shi, Chong Shan" uniqKey="Shi C" first="Chong-Shan" last="Shi">Chong-Shan Shi</name></region><name sortKey="Huang, Ning Na" sort="Huang, Ning Na" uniqKey="Huang N" first="Ning-Na" last="Huang">Ning-Na Huang</name><name sortKey="Kehrl, John H" sort="Kehrl, John H" uniqKey="Kehrl J" first="John H" last="Kehrl">John H. Kehrl</name><name sortKey="Nabar, Neel R" sort="Nabar, Neel R" uniqKey="Nabar N" first="Neel R" last="Nabar">Neel R. Nabar</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
EXPLOR_STEP=$WICRI_ROOT/Sante/explor/StressCovidV1/Data/Main/Exploration
HfdSelect -h $EXPLOR_STEP/biblio.hfd -nk 000860 | SxmlIndent | more
Ou
HfdSelect -h $EXPLOR_AREA/Data/Main/Exploration/biblio.hfd -nk 000860 | SxmlIndent | more
Pour mettre un lien sur cette page dans le réseau Wicri
{{Explor lien
|wiki= Sante
|area= StressCovidV1
|flux= Main
|étape= Exploration
|type= RBID
|clé= pubmed:31231549
|texte= SARS-Coronavirus Open Reading Frame-8b triggers intracellular stress pathways and activates NLRP3 inflammasomes.
}}
Pour générer des pages wiki
HfdIndexSelect -h $EXPLOR_AREA/Data/Main/Exploration/RBID.i -Sk "pubmed:31231549" \
| HfdSelect -Kh $EXPLOR_AREA/Data/Main/Exploration/biblio.hfd \
| NlmPubMed2Wicri -a StressCovidV1
| This area was generated with Dilib version V0.6.33. |  |