Abstract
NOD-like receptor protein 3 (NLRP3) detects microbial infections or endogenous danger signals and activates the NLRP3 inflammasome, which has important functions in host defense and contributes to the pathogenesis of inflammatory diseases, and thereby needs to be tightly controlled. Deubiquitination of NLRP3 is considered a key step in NLRP3 inflammasome activation. However, the mechanisms by which deubiquitination controls NLRP3 inflammasome activation are unclear. Here, we show that the UAF1/USP1 deubiquitinase complex selectively removes K48-linked polyubiquitination of NLRP3 and suppresses its ubiquitination-mediated degradation, enhancing cellular NLRP3 levels, which are indispensable for subsequent NLRP3 inflammasome assembly and activation. In addition, the UAF1/USP12 and UAF1/USP46 complexes promote NF-κB activation, enhance the transcription of NLRP3 and proinflammatory cytokines (including pro-IL-1β, TNF, and IL-6) by inhibiting ubiquitination-mediated degradation of p65. Consequently, Uaf1 deficiency attenuates NLRP3 inflammasome activation and IL-1β secretion both in vitro and in vivo. Our study reveals that the UAF1 deubiquitinase complexes enhance NLRP3 and pro-IL-1β expression by targeting NLRP3 and p65 and licensing NLRP3 inflammasome activation.
Highlights
NOD-like receptor protein 3 (NLRP3) detects microbial infections or endogenous danger signals and activates the NLRP3 inflammasome, which has important functions in host defense and contributes to the pathogenesis of inflammatory diseases, and thereby needs to be tightly controlled
We investigated the physiological relevance of the effects of UAF1 on NLRP3 inflammasome activation in vivo
IL-1β secretion induced by the LPS injection was much lower in the sera of Uaf1CKO mice than in the sera of WT mice, indicating that Uaf[1] deficiency inhibits NLRP3 inflammasome activation in vivo (Fig. 1d)
Summary
NOD-like receptor protein 3 (NLRP3) detects microbial infections or endogenous danger signals and activates the NLRP3 inflammasome, which has important functions in host defense and contributes to the pathogenesis of inflammatory diseases, and thereby needs to be tightly controlled. We show that the UAF1/USP1 deubiquitinase complex selectively removes K48-linked polyubiquitination of NLRP3 and suppresses its ubiquitination-mediated degradation, enhancing cellular NLRP3 levels, which are indispensable for subsequent NLRP3 inflammasome assembly and activation. Our study reveals that the UAF1 deubiquitinase complexes enhance NLRP3 and pro-IL-1β expression by targeting NLRP3 and p65 and licensing NLRP3 inflammasome activation. K48-linked ubiquitination mediates protein degradation of NLRP3 and limits NLRP3 inflammasome activation. Several E3 ubiquitin ligases such as TRIM31, March[7], ARIH2, and FBXL29,12–14 have been reported to attenuate NLRP3 inflammasome activation by mediating NLRP3 protein degradation, the function of K48-linked deubiquitination on NLRP3 inflammasome activity remains largely unclear. Whether any deubiquitinating enzymes exist to remove K48-linked ubiquitination of NLRP3, stabilize its expression, and license NLRP3 inflammasome activation, remains to be investigated. The potential roles of UAF1 deubiquitinase complexes in inflammation are unclear
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