2. Academic Validation
  3. TRIM2 inhibits apoptosis by ubiquitinating BNIP3 to protect the intestine against ischemia-reperfusion injury in mice

TRIM2 inhibits apoptosis by ubiquitinating BNIP3 to protect the intestine against ischemia-reperfusion injury in mice

  • Commun Biol. 2025 Aug 29;8(1):1308. doi: 10.1038/s42003-025-08708-2.
Jinping Nie # 1,  Chao Mei # 1 2,  Aiping Wei 1,  Yingjie Wang 1,  Chenlu Fan 1,  Yingjie Huang 1,  Ming Jiang 1,  Han Che 1,  Tao Chen 1,  Juan Tian 1,  Yong Li 3,  Xuan Huang 4,  Xuekang Zhang 5
Affiliations

Affiliations

  • 1 Department of Anesthesiology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330006, China.
  • 2 Department of Surgery and Anesthesia, Ganjiang New Area Hospital of The First Affiliated Hospital of Nanchang University, Ganjiang New Area People's Hospital, Nanchang, 330029, China.
  • 3 Department of Anesthesiology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330006, China. liyong@ncu.edu.cn.
  • 4 The National Engineering Research Center for Bioengineering Drugs and the Technologies, Jiangxi Provincial Key Laboratory of Bioengineering Drugs, Institute of Translational Medicine, Jiangxi Medical College, Nanchang University, Nanchang, 330031, China. huangxuan@ncu.edu.cn.
  • 5 Department of Anesthesiology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330006, China. ndyfy00768@ncu.edu.cn.
  • # Contributed equally.
PMID: 40883557 DOI: 10.1038/s42003-025-08708-2
Abstract

Intestinal damage following interrupted blood flow and its return (intestinal ischemia/reperfusion injury) is a serious medical problem occurring in various clinical situations. While the death of intestinal epithelial cells is a key factor, the precise reasons behind this cell death are not fully known. In this study, we identified significant downregulation of an E3 ubiquitin Ligase TRIM2 in mouse models of this injury and in cells mimicking the condition. Genetic deletion of TRIM2 promotes intestinal Apoptosis and worsens injury severity in studies using only male mice. We discovered that TRIM2 directly interacts with the pro-apoptotic protein Bcl2-interacting protein 3 (BNIP3) and mediates K48-linked polyubiquitination of BNIP3 at lysine 130 (K130), leading to its proteasomal degradation. Mutation of BNIP3 at K130 to arginine (K130R) abolished TRIM2-mediated ubiquitination, increased BNIP3 stability, and led to increased cell death after oxygen deprivation and restoration (hypoxia/reoxygenation). Increasing BNIP3 levels counteract the protective effect of boosting TRIM2 in intestinal epithelial cells, while lowering BNIP3 mimics the protection seen with more TRIM2. Therefore, TRIM2 protects against intestinal injury by inhibiting Apoptosis through the ubiquitination and degradation of BNIP3. Targeting this TRIM2-BNIP3 axis offers possibilities for developing future treatments for intestinal ischemia/reperfusion injury.

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