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Pyk2 activates the NLRP3 inflammasome by directly phosphorylating ASC and contributes to inflammasome-dependent peritonitis
Scientific Reports
  • I-Che Chung, Chang Gung University
  • Chun-Nan OuYang, Chang Gung University
  • Sheng-Ning Yuan, Chang Gung University
  • Hsin-Pai P. Li, Chang Gung University
  • Jeng-Ting Chen, Chang Gung University
  • Hui-Ru Shieh, Mackay Memorial Hospital
  • Yu-Jen Chen, Mackay Memorial Hospital
  • David M. Ojcius, University of the Pacific
  • Ching-Liang Chu, National Taiwan University
  • Jau-Song Yu, Chang Gung University
  • Yu-Sun Chang, Chang Gung University
  • Lih-Chyang Chen, Mackay Medical College
ORCiD
David M. Ojcius: 0000-0003-1461-4495
Document Type
Article
DOI
10.1038/srep36214
Publication Date
10-31-2016
Abstract
The inflammasome adaptor protein, ASC, contributes to both innate immune responses and inflammatory diseases via self-oligomerization, which leads to the activation of the protease, caspase-1. Here, we report that the cytosolic tyrosine kinases, FAK and Pyk2, are differentially involved in NLRP3 and AIM2 inflammasome activation. The inhibition of FAK and Pyk2 with RNA interference or chemical inhibitors dramatically abolished ASC oligomerization, caspase-1 activation, and IL-1β secretion in response to NLRP3 or AIM2 stimulation. Pyk2 is phosphorylated by the kinase Syk and relocalizes to the ASC specks upon NLRP3 inflammasome activation. Pyk2, but not FAK, could directly phosphorylate ASC at Tyr146, and only the phosphorylated ASC could participate in speck formation and trigger IL-1β secretion. Moreover, the clinical-trial-tested Pyk2/FAK dual inhibitor PF-562271 reduced monosodium urate-mediated peritonitis, a disease model used for studying the consequences of NLRP3 activation. Our results suggest that although Pyk2 and FAK are involved in inflammasome activation, only Pyk2 directly phosphorylates ASC and brings ASC into an oligomerization-competent state by allowing Tyr146 phosphorylation to participate ASC speck formation and subsequent NLRP3 inflammation.
Comments
Article number: 36214
Citation Information
I-Che Chung, Chun-Nan OuYang, Sheng-Ning Yuan, Hsin-Pai P. Li, et al.. "Pyk2 activates the NLRP3 inflammasome by directly phosphorylating ASC and contributes to inflammasome-dependent peritonitis" Scientific Reports Vol. 6 (2016) p. 1 - 13 ISSN: 2045-2322
Available at: http://works.bepress.com/david-ojcius/192/