Scribble deficiency promotes colon inflammation by inhibiting autophagy-dependent oxidative stress elimination

Abstract

Abstract Background：Scribble, a master scaffold in apical-basal polarity, proliferation and epithelial integrity. Current knowledge about the biological function of Scribble in the colonic epithelial plasticity/regeneration during intestinal inflammation is limited. Here, we explore the unexpected role of Scribble in IBD. Results：We showed that Scribble level are decreased in IBD patients and mice with DSS-induced colitis. Our study suggested that ScribΔIEC mice develops severe acute colitis by disrupting epithelial barrier integrity and impairing the function of crypt stem cells. Here, we confirmed that Scribble KO may contribute to the dysregulated autophagy level due to the deletion of Atg16L1, and led to an accumulation of mitochondrial ROS both in intestinal stem cells and epithelial cells. Mechanistically, Scribble suppressed the process of autophagy by modulating the stability of caspase-dependent degradation of Atg16L1 by directly interacting with Atg16L1 in a LRR domain-dependent manner in IECs. Moreover, when ScribΔIEC organoids were treated with autophagy activator Rapa, the ROS signal in the organoids was significantly reduced, which indicates that the specific association of Scribble and Atg16L1 are crucial signaling molecules in oxidative stress response of intestinal inflammation. In addition, further study indicates that dietary sphingomyelin alleviates DSS-induced colitis by increase the expression of Scribble, which suggests that Scribble may be the critical marker of IBD. Conclusions：Our study firstly shows that Scribble deficiency maybe associated with the dysregulated autophagy and impaired maintenance of colonic stemness, and it may be a target for diagnosis and treatment of inflammatory bowel disease.