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Article: Severe acute respiratory syndrome coronavirus ORF3a protein activates the NLRP3 inflammasome by promoting TRAF3-dependent ubiquitination of ASC

TitleSevere acute respiratory syndrome coronavirus ORF3a protein activates the NLRP3 inflammasome by promoting TRAF3-dependent ubiquitination of ASC
Authors
KeywordsSARS coronavirus
Issue Date2019
PublisherFederation of American Societies for Experimental Biology. The Journal's web site is located at http://www.fasebj.org/
Citation
The FASEB Journal, 2019, v. 33 n. 8, p. 8865-8877 How to Cite?
AbstractSevere acute respiratory syndrome coronavirus (SARS-CoV) is capable of inducing a storm of proinflammatory cytokines. In this study, we show that the SARS-CoV open reading frame 3a (ORF3a) accessory protein activates the NLRP3 inflammasome by promoting TNF receptor-associated factor 3 (TRAF3)–mediated ubiquitination of apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC). SARS-CoV and its ORF3a protein were found to be potent activators of pro–IL-1β gene transcription and protein maturation, the 2 signals required for activation of the NLRP3 inflammasome. ORF3a induced pro–IL-1β transcription through activation of NF-κB, which was mediated by TRAF3-dependent ubiquitination and processing of p105. ORF3a-induced elevation of IL-1β secretion was independent of its ion channel activity or absent in melanoma 2 but required NLRP3, ASC, and TRAF3. ORF3a interacted with TRAF3 and ASC, colocalized with them in discrete punctate structures in the cytoplasm, and facilitated ASC speck formation. TRAF3-dependent K63-linked ubiquitination of ASC was more pronounced in SARS-CoV–infected cells or when ORF3a was expressed. Taken together, our findings reveal a new mechanism by which SARS-CoV ORF3a protein activates NF-κB and the NLRP3 inflammasome by promoting TRAF3-dependent ubiquitination of p105 and ASC.—Siu, K.-L., Yuen, K.-S., Castaño-Rodriguez, C., Ye, Z.-W., Yeung, M.-L., Fung, S.-Y., Yuan, S., Chan, C.-P., Yuen, K.-Y., Enjuanes, L., Jin, D.-Y. Severe acute respiratory syndrome coronavirus ORF3a protein activates the NLRP3 inflammasome by promoting TRAF3-dependent ubiquitination of ASC.
Persistent Identifierhttp://hdl.handle.net/10722/274571
ISSN
2017 Impact Factor: 5.595
2015 SCImago Journal Rankings: 2.775
PubMed Central ID

 

DC FieldValueLanguage
dc.contributor.authorSiu, KL-
dc.contributor.authorYuen, KS-
dc.contributor.authorCastaño-Rodriguez, C-
dc.contributor.authorYe, ZW-
dc.contributor.authorYeung, ML-
dc.contributor.authorFung, SY-
dc.contributor.authorYuan, S-
dc.contributor.authorChan, CP-
dc.contributor.authorYuen, KY-
dc.contributor.authorEnjuanes, L-
dc.contributor.authorJin, DY-
dc.date.accessioned2019-08-18T15:04:24Z-
dc.date.available2019-08-18T15:04:24Z-
dc.date.issued2019-
dc.identifier.citationThe FASEB Journal, 2019, v. 33 n. 8, p. 8865-8877-
dc.identifier.issn0892-6638-
dc.identifier.urihttp://hdl.handle.net/10722/274571-
dc.description.abstractSevere acute respiratory syndrome coronavirus (SARS-CoV) is capable of inducing a storm of proinflammatory cytokines. In this study, we show that the SARS-CoV open reading frame 3a (ORF3a) accessory protein activates the NLRP3 inflammasome by promoting TNF receptor-associated factor 3 (TRAF3)–mediated ubiquitination of apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC). SARS-CoV and its ORF3a protein were found to be potent activators of pro–IL-1β gene transcription and protein maturation, the 2 signals required for activation of the NLRP3 inflammasome. ORF3a induced pro–IL-1β transcription through activation of NF-κB, which was mediated by TRAF3-dependent ubiquitination and processing of p105. ORF3a-induced elevation of IL-1β secretion was independent of its ion channel activity or absent in melanoma 2 but required NLRP3, ASC, and TRAF3. ORF3a interacted with TRAF3 and ASC, colocalized with them in discrete punctate structures in the cytoplasm, and facilitated ASC speck formation. TRAF3-dependent K63-linked ubiquitination of ASC was more pronounced in SARS-CoV–infected cells or when ORF3a was expressed. Taken together, our findings reveal a new mechanism by which SARS-CoV ORF3a protein activates NF-κB and the NLRP3 inflammasome by promoting TRAF3-dependent ubiquitination of p105 and ASC.—Siu, K.-L., Yuen, K.-S., Castaño-Rodriguez, C., Ye, Z.-W., Yeung, M.-L., Fung, S.-Y., Yuan, S., Chan, C.-P., Yuen, K.-Y., Enjuanes, L., Jin, D.-Y. Severe acute respiratory syndrome coronavirus ORF3a protein activates the NLRP3 inflammasome by promoting TRAF3-dependent ubiquitination of ASC.-
dc.languageeng-
dc.publisherFederation of American Societies for Experimental Biology. The Journal's web site is located at http://www.fasebj.org/-
dc.relation.ispartofThe FASEB Journal-
dc.subjectSARS coronavirus-
dc.titleSevere acute respiratory syndrome coronavirus ORF3a protein activates the NLRP3 inflammasome by promoting TRAF3-dependent ubiquitination of ASC-
dc.typeArticle-
dc.identifier.emailYeung, ML: pmlyeung@hku.hk-
dc.identifier.emailYuan, S: yuansf@hku.hk-
dc.identifier.emailYuen, KY: kyyuen@hkucc.hku.hk-
dc.identifier.emailJin, DY: dyjin@hku.hk-
dc.identifier.authorityYeung, ML=rp01402-
dc.identifier.authorityYuen, KY=rp00366-
dc.identifier.authorityJin, DY=rp00452-
dc.description.naturelink_to_OA_fulltext-
dc.identifier.doi10.1096/fj.201802418R-
dc.identifier.pmid31034780-
dc.identifier.pmcidPMC6662968-
dc.identifier.scopuseid_2-s2.0-85070788848-
dc.identifier.hkuros301130-
dc.identifier.hkuros301655-
dc.identifier.volume33-
dc.identifier.issue8-
dc.identifier.spage8865-
dc.identifier.epage8877-
dc.publisher.placeUnited States-

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