YAP promotes the activation of NLRP3 inflammasome via blocking K27-linked polyubiquitination of NLRP3

Dan Wang, Yening Zhang, Xueming Xu, Jianfeng Wu, Yue Peng, Jing Li, Ruiheng Luo, Lingmin Huang, Liping Liu, Songlin Yu, Ningjie Zhang, Ben Lu () and Kai Zhao ()
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Dan Wang: Central South University
Yening Zhang: Central South University
Xueming Xu: Central South University
Jianfeng Wu: Xiamen University
Yue Peng: Central South University
Jing Li: Central South University
Ruiheng Luo: Central South University
Lingmin Huang: Central South University
Liping Liu: Central South University
Songlin Yu: Central South University
Ningjie Zhang: Central South University
Ben Lu: Central South University
Kai Zhao: Central South University

Nature Communications, 2021, vol. 12, issue 1, 1-14

Abstract: Abstract 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.

Date: 2021
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DOI: 10.1038/s41467-021-22987-3

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