ABIN3 Negatively Regulates Necroptosis-induced Intestinal Inflammation Through Recruiting A20 and Restricting the Ubiquitination of RIPK3 in Inflammatory Bowel Disease. (30th June 2020)

• Record Type: Journal Article
• Authors: Zhou, Mingxia; He, Jing; Shi, Yingying; Liu, Xiaoman; Luo, Shangjian; Cheng, Cheng; Ge, Wensong; Qu, Chunying; Du, Peng; Chen, Yingwei
• Is Part Of: Journal of Crohn's and colitis. Volume 15:Number 1(2021)
• Page Start: 99
• Page End: 114
• Publication Date: 2020-06-30
• Subjects: ABIN3 -- A20 -- necroptosis -- inflammation -- intestinal barrier -- RIPK3 -- ubiquitination; Inflammatory bowel diseases -- Periodicals; 616.344005
• DOI: 10.1093/ecco-jcc/jjaa131
• Languages: English
• ISSNs: 1873-9946

Abstract

Abstract: Background and Aims: There is evidence for a disturbed necroptosis function in many inflammatory diseases, but its role in inflammatory bowel diseases [IBD] and the underlying mechanisms are unclear. Here, we studied the functional significance and molecular mechanisms of ABIN3, a ubiquitin-binding protein, in regulating the ubiquitination and activation of necroptosis in IBD. Methods: The expression of necroptosis hallmarks and ABIN3 were assessed in inflamed samples of IBD patients, dextran sodium sulphate [DSS]-induced colitis models, and azoxymethane [AOM]/DSS models in mice. ABIN3 was overexpressed and silenced to explore its function in regulating necroptosis, inflammation, and intestinal barrier function. Immuoprecipitiation [IP] and co-IP assays were performed to investigate the cross-talk between ABIN3 and deubiquitinating enzyme A20, and the mechanisms of coordinating ubiquitination modification to regulate necroptosis. Results: Excessive necroptosis is an important contributory factor towards the uncontrolled inflammation and intestinal barrier defects in IBD and experimental colitis. Blocking necroptosis by Nec-1s or GSK'872 significantly prevented cell death and alleviated DSS-induced colitis in vivo, whereas in the AOM/DSS model, necroptosis inhibitors aggravated the severity of colitis-associated colon carcinogenesis [CAC]. Mechanistically, ABIN3 is rapidly recruited to the TNF-RSC complex, which interacts and coordinates with deubiquitinating enzyme A20 to control the K63 deubiquitination modification and subsequent activation of the critical necroptosis kinase, RIPK3, to suppress necroptosis. Conclusions: ABIN3 regulates inflammatory response and intestinal barrier function by interacting with A20 and coordinating the K63 deubiquitination modification of necroptosis in IBD.