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Severe acute respiratory syndrome Coronavirus ORF3a protein activates the NLRP3 inflammasome by promoting TRAF3‐dependent ubiquitination of ASC
Open accessAbstract
Severe 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., Castano‐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. FASEB J. 33, 8865–8877 (2019). www.fasebj.org
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Metadata
- Authors
- Siu, K., Yuen, K., Castano‐Rodriguez, C., Ye, Z., Yeung, M., Fung, S., Yuan, S., Chan, C., Yuen, K., Enjuanes, L., & Jin, D.
- Venue
- The FASEB Journal
- Publisher
- Wiley
- Published
- 2019-04-29
- Volume
- 33
- Issue
- 8
- Pages
- 8865-8877
- ISSN
- 0892-6638 (ISSN-L)
- 1530-6860
- OpenAlex
- W2943109925
- Cited by
- 502
- References
- 66
- FWCI
- 27.28
- Type
- journal article
- Language
- en
- Open access
- green
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