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PLK 4 deubiquitination by Spata2‐CYLD suppresses NEK7‐mediated NLRP3 inflammasome activation at the centrosome
Author(s) -
Yang XiaoDong,
Li Wenguo,
Zhang Shuangyan,
Wu Dandan,
Jiang Xiaoli,
Tan Rong,
Niu Xiaoyin,
Wang Qijun,
Wu Xuefeng,
Liu Zhiduo,
Chen LinFeng,
Qin Jun,
Su Bing
Publication year - 2019
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.15252/embj.2019102201
Subject(s) - biology , centrosome , inflammasome , microbiology and biotechnology , apoptosis , genetics , receptor , cell cycle
The innate immune sensor NLRP 3 assembles an inflammasome complex with NEK 7 and ASC to activate caspase‐1 and drive the maturation of proinflammatory cytokines IL ‐1β and IL ‐18. NLRP 3 inflammasome activity must be tightly controlled, as its over‐activation is involved in the pathogenesis of inflammatory diseases. Here, we show that NLRP 3 inflammasome activation is suppressed by a centrosomal protein Spata2. Spata2 deficiency enhances NLRP 3 inflammasome activity both in the macrophages and in an animal model of peritonitis. Mechanistically, Spata2 recruits the deubiquitinase CYLD to the centrosome for deubiquitination of polo‐like kinase 4 ( PLK 4), the master regulator of centrosome duplication. Deubiquitination of PLK4 facilitates its binding to and phosphorylation of NEK 7 at Ser204. NEK 7 phosphorylation in turn attenuates NEK 7 and NLRP 3 interaction, which is required for NLRP 3 inflammasome activation. Pharmacological or sh RNA ‐mediated inhibition of PLK 4, or mutation of the NEK 7 Ser204 phosphorylation site, augments NEK7 interaction with NLRP 3 and causes increased NLRP 3 inflammasome activation. Our study unravels a novel centrosomal regulatory pathway of inflammasome activation and may provide new therapeutic targets for the treatment of NLRP 3‐associated inflammatory diseases.