Format

Send to

Choose Destination

See 1 citation found by title matching your search:

Sci Rep. 2016 Oct 31;6:36214. doi: 10.1038/srep36214.

Pyk2 activates the NLRP3 inflammasome by directly phosphorylating ASC and contributes to inflammasome-dependent peritonitis.

Author information

1
Molecular Medicine Research Center, Chang Gung University, 333 Taoyuan, Taiwan.
2
Department of Microbiology and Immunology, Chang Gung University, 333 Taoyuan, Taiwan.
3
Graduate Institute of Biomedical Sciences, Chang Gung University, 333 Taoyuan, Taiwan.
4
Division of Hematology-Oncology, Chang Gung Memorial Hospital at Lin-Kuo, 333 Taoyuan, Taiwan.
5
Department of Medical Research Mackay Memorial Hospital, 251 New Taipei City, Taiwan.
6
Department of Radiation Oncology, Mackay Memorial Hospital, 251 New Taipei City, Taiwan.
7
Department of Biomedical Sciences, University of the Pacific Arthur A. Dugoni School of Dentistry, San Francisco, CA 94103, USA.
8
Graduate Institute of Immunology, College of Medicine, National Taiwan University, 100 Taipei, Taiwan.
9
Proteomics Core Laboratory, Chang Gung University, 333 Taoyuan, Taiwan.
10
Liver Research Center, Chang Gung Memorial Hospital at Lin-Kou, 333 Taoyuan, Taiwan.
11
Department of Otolaryngology, Chang Gung Memorial Hospital at Lin-Kuo, 333 Taoyuan, Taiwan.
12
Department of Medicine, Mackay Medical College, 252 New Taipei City, Taiwan.

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.

PMID:
27796369
PMCID:
PMC5087076
DOI:
10.1038/srep36214
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center