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

• Published in: Nature communications 2021-05, Vol.12 (1), p.2674-2674, Article 2674
• Main Authors: Wang, Dan, Zhang, Yening, Xu, Xueming, Wu, Jianfeng, Peng, Yue, Li, Jing, Luo, Ruiheng, Huang, Lingmin, Liu, Liping, Yu, Songlin, Zhang, Ningjie, Lu, Ben, Zhao, Kai
• Format: Article
• Language: English
• Subjects: 38/88; 38/89; 42/109; 42/44; 42/70; 45/88; 59; 631/250; 631/80; 64/60; 82/1; Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - metabolism; Animals; Atherosclerosis; beta-Transducin Repeat-Containing Proteins - genetics; beta-Transducin Repeat-Containing Proteins - metabolism; Cells, Cultured; Crystals; HEK293 Cells; Homeostasis; Hospitals; Humanities and Social Sciences; Humans; Immune response; Inflammasomes; Inflammasomes - genetics; Inflammasomes - metabolism; Inflammation; Inflammatory diseases; Laboratories; Lipopolysaccharides; Lysine - metabolism; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; multidisciplinary; Myeloid cells; NLR Family, Pyrin Domain-Containing 3 Protein - genetics; NLR Family, Pyrin Domain-Containing 3 Protein - metabolism; Peritonitis; Polyubiquitin - metabolism; Proteasomes; Proteins; Rheumatism; RNA Interference; Science; Science (multidisciplinary); Sepsis; Signal transduction; Therapeutic targets; Transcription; Tumor necrosis factor-TNF; Ubiquitin-protein ligase; Ubiquitin-Protein Ligases - genetics; Ubiquitin-Protein Ligases - metabolism; Ubiquitination; Uric acid; YAP-Signaling Proteins; Yes-associated protein
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-021-22987-3

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. YAP is known to play a role both in organ size via the Hippo signalling pathway and in inflammation, though the precise mechanism are unclear. Here, the authors report that YAP promotes activation of the NLRP3 inflammosome through binding interactions.