PLK 4 deubiquitination by Spata2‐CYLD suppresses NEK7‐mediated NLRP3 inflammasome activation at the centrosome

Abstract

The innate immune sensor NLRP3 assembles an inflammasome complex with NEK7 and ASC to activate caspase-1 and drive the maturation of proinflammatory cytokines IL-1b and IL-18. NLRP3 inflammasome activity must be tightly controlled, as its overactivation is involved in the pathogenesis of inflammatory diseases. Here, we show that NLRP3 inflammasome activation is suppressed by a centrosomal protein Spata2. Spata2 deficiency enhances NLRP3 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 (PLK4), the master regulator of centrosome duplication. Deubiquitination of PLK4 facilitates its binding to and phosphorylation of NEK7 at Ser204. NEK7 phosphorylation in turn attenuates NEK7 and NLRP3 interaction, which is required for NLRP3 inflammasome activation. Pharmacological or shRNA-mediated inhibition of PLK4, or mutation of the NEK7 Ser204 phosphorylation site, augments NEK7 interaction with NLRP3 and causes increased NLRP3 inflammasome activation. Our study unravels a novel centrosomal regulatory pathway of inflammasome activation and may provide new therapeutic targets for the treatment of NLRP3-associated inflammatory diseases.

Polo-Like Kinase 4’s Critical Role in Cancer Development and Strategies for Plk4-Targeted Therapy

“…Subsequently, the deubiquitinated Plk4 binds to and phosphorylates NEK7 at Ser204, which results in a weakening of the interaction between NEK7 and NLRP3. This process is necessary for NLRP3 inflammasome activation (102). Additionally, ubiquitin ligase was also recognized as an important partner in the modification of Plk4.…”

Physiological and Pathological Roles of Mammalian NEK7

“…However, a subsequent study found a novel complicated post-translation modification of NEK7. Specific centrosome-localized spata2 recruits CYLD for the deubiquitination of polo-like kinase 4 (PLK4), which further binds to and phosphorylates NEK7 at Ser204 ( Yang et al, 2019 ). Thereby, this phosphorylation modification of NEK7 suppressed its binding with NLRP3 and inhibited NLRP3 inflammasome activation ( Yang et al, 2019 ).…”

“…Specific centrosome-localized spata2 recruits CYLD for the deubiquitination of polo-like kinase 4 (PLK4), which further binds to and phosphorylates NEK7 at Ser204 ( Yang et al, 2019 ). Thereby, this phosphorylation modification of NEK7 suppressed its binding with NLRP3 and inhibited NLRP3 inflammasome activation ( Yang et al, 2019 ). In addition, HDAC6-mediated MTOC localization of NLRP3 may ensure the engagement of centrosomal kinase NEK7 ( Magupalli et al, 2020 ).…”

“…These studies suggest the important role of NEK7 in NLRP3 inflammasome activation. However, the mechanism by which NEK7 switches from a cell cycle regulator to an inflammasome regulator remains unclear ( Yang et al, 2019 ). In conclusion, it is imperative to characterize the precise regulation of NEK7 involved in NLRP3 inflammasome activation for finding more refined therapeutic targets for related diseases.…”

NLRP3 inflammasome priming: A riddle wrapped in a mystery inside an enigma

“…3), with glutathione S‐transferase omega‐1 (GSTO1‐1) mediating deglutathionylation of NEK7 to promote NLRP3 activation 81 . NEK7 is also phosphorylated by polo‐like kinase 4 (PLK4) at Ser204 that attenuates NEK7‐NLRP3 interaction, therefore suppressing inflammasome activation 82 …”