The transcription coactivator YAP plays a vital role in Hippo pathway for organ-size control and tissue homeostasis. Recent studies have demonstrated YAP is closely related to immune disorders and inflammatory diseases, but the underlying mechanisms remain less defined. Here, we find that YAP promotes the activation of NLRP3 inflammasome, an intracellular multi-protein complex that orchestrates host immune responses to infections or sterile injuries. YAP deficiency in myeloid cells significantly attenuates LPS-induced systemic inflammation and monosodium urate (MSU) crystals-induced peritonitis. Mechanistically, YAP physically interacts with NLRP3 and maintains the stability of NLRP3 through blocking the association between NLRP3 and the E3 ligase β-TrCP1, the latter increases the proteasomal degradation of NLRP3 via K27-linked ubiquitination at lys380. Together, these findings establish a role of YAP in the activation of NLRP3 inflammasome, and provide potential therapeutic target to treat the NLRP3 inflammasome-related diseases.
The full activation of NLRP3 inflammasome needs two sequential signals: the fist priming signal and the second assembly signal. Various stimuli including infections and stress signals can provide the assembly signal. However, how NLRP3 detects diverse stimuli and becomes fully activated remain largely unknown. In this study, we found the second signal specially triggers the acetylation of NLRP3, which facilitates the aggregation of NLRP3 and its interaction with ASC and NEK7, thus promoting the assembly of inflammasome. Meanwhile, by employing pharmacological and molecular approaches, we identified KAT5 as a regulator of NLRP3 acetylation and activation.Furthermore, KAT5 specific inhibitor-NU9056 exhibited a robust suppressive effect on NLRP3 inflammasome both in vitro and in vivo. Thus, our study reveals a new mechanism for NLRP3 full activation and suggests targeting NLRP3 acetylation may provide a new approach for treatment of NLRP3 associated diseases.
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