YAP inactivated by NF-κB p65, can protect against colonic epithelial cell pyroptosis in ulcerative colitis via...

The aberrant activation of the intestinal mucosal immune system is a critical driver of inflammatory injury in ulcerative colitis. Emerging evidence implicates pyroptosis, a pro-inflammatory programmed cell death, plays important role in UC pathogenesis. YAP, a core component of the Hippo pathway, closely associates with tissue regeneration and inflammatory regulation. In this study, we explored the role of YAP and pyroptosis in UC, and investigated their internal regulatory mechanism.

Pyroptosis cell models was established by using LPS + ATP-treated FHC cells, Colitis mouse models were established using DSS-induced WT and GSDMD knockout mice. YAP over expression lentiviral was intraperitoneal injection in mice and used in FHC cells to establish YAP-overexpressed model, the molecular mechanism of YAP regulate pyroptosis were used nucleoplasmic separation and chromatin immunoprecipitation.

We found that GSDMD related pyroptosis were elevated in both UC patients and DSS-induced colitis mice, and overexpressed YAP inhibited pyroptosis in FHC cells. Mechanistically, YAP could bind to transcriptional promoter of NLRP3 to repress pyroptosis. Moreover, NF-κB p65 was elevated in pyroptosis, which promoted YAP phosphorylation via LATS1, resulting in decreased YAP expression. Importantly, genetic ablation of GSDMD dramatically attenuated DSS induced colitis in mice, while overexpressed YAP in GSDMD-KO mice didn't further improve the colonic inflammation.

This study reveals that NF-κB p65 is activated in inflamed colonic epithelial cells and phosphorylates YAP through upregulating LATS1, which inhibiting nuclear translocation and expression of YAP. Consequently, this inactive YAP reduces transcriptional repression of NLRP3, causing enhanced pyroptosis and initiate UC.