Abstract
The cellular NLRP3 protein level is crucial for assembly and activation of the NLRP3 inflammasome. Various posttranslational modifications (PTMs), including phosphorylation and ubiquitination, control NLRP3 protein degradation and inflammasome activation; however, the function of small ubiquitin-like modifier (SUMO) modification (called SUMOylation) in controlling NLRP3 stability and subsequent inflammasome activation is unclear. Here, we show that the E3 SUMO ligase tripartite motif-containing protein 28 (TRIM28) is an enhancer of NLRP3 inflammasome activation by facilitating NLRP3 expression. TRIM28 binds NLRP3, promotes SUMO1, SUMO2 and SUMO3 modification of NLRP3, and thereby inhibits NLRP3 ubiquitination and proteasomal degradation. Concordantly, Trim28 deficiency attenuates NLRP3 inflammasome activation both in vitro and in vivo. These data identify a mechanism by which SUMOylation controls the cellular NLRP3 level and inflammasome activation, and reveal correlations and interactions of NLRP3 SUMOylation and ubiquitination during inflammasome activation.
Highlights
The cellular NLRP3 protein level is crucial for assembly and activation of the NLRP3 inflammasome
NLRP3 is subjected to multiple posttranslational modifications (PTMs), including phosphorylation, ubiquitination, alkylation, S-nitrosylation, and SUMOylation, to tightly control optimal activation of NLRP3 inflammasome
SUMO1 modification of NLRP3 may block the conjugation of ubiquitin by competing with the same K sites of NLRP3 and inhibits ubiquitous degradation of NLRP3 and facilitates inflammasome activation
Summary
The cellular NLRP3 protein level is crucial for assembly and activation of the NLRP3 inflammasome. We show that the E3 SUMO ligase tripartite motif-containing protein 28 (TRIM28) is an enhancer of NLRP3 inflammasome activation by facilitating NLRP3 expression. Various posttranslational modifications (PTMs) of NLRP3, including phosphorylation, ubiquitination, and SUMOylation, play crucial roles in controlling inflammasome activation[1]. The ubiquitin-specific peptidase 1 (USP1)-associated factor 1 (UAF1) /USP1 deubiquitinase complex selectively inhibits K48-linked ubiquitination and protein degradation of NLRP3 enhances cellular NLRP3 levels[12], which are indispensable for subsequent NLRP3 inflammasome assembly and activation. Small ubiquitin-like modifier (SUMO) protein-conjugated modifications, which are termed as SUMOylation, were identified in NLRP3 during inflammasome activation[13,14]. SUMO1 modification of NLRP3 is required for inflammasome activation, both the mechanism details and the E3 SUMO ligase that mediates SUMO1-catalyzed SUMOylation of NLRP3 are unclear
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