USP15 regulates p66Shc stability associated with Drp1 activation in liver ischemia/reperfusion

作者：Xinyao Tian, Yan Zhao, Zhe Yang, Qianrang Lu, Lin Zhou, Shusen Zheng · 发表于：Cell Death and Disease · 年份：2022 · DOI：10.1038/s41419-022-05277-8 · 被引用次数：20 · 研究领域：Mitochondrial Function and Pathology、Ubiquitin and proteasome pathways、Autophagy in Disease and Therapy

Liver ischemia/reperfusion (I/R) injury is a major clinical concern of liver transplantation, which accounts for organ rejection and liver dysfunction. The adaptor protein p66Shc acts as a crucial redox enzyme and is implicated in liver I/R. Elevated p66Shc expression is associated with hepatocellular apoptosis in liver I/R, but the molecular mechanisms of p66Shc responsible for its aberrant expression and function remain unknown. In the present study, hepatocyte-specific p66Shc-knockdown mice exhibited clear inhibition in hepatocellular apoptosis and oxidative stress under liver I/R, while hepatocyte-specific p66Shc overexpression mice displayed the deteriorative impairment. Mechanistically, p66Shc-triggered mitochondrial fission and apoptosis in liver I/R by mediating ROS-driven Drp1 activation. Furthermore, a screening for p66Shc-interacting proteins identified ubiquitin-specific protease 15 (USP15) as a mediator critical for abnormal p66Shc expression. Specifically, USP15 interacted with the SH2 domain of p66Shc and maintained its stabilization by removing ubiquitin. In vivo, p66Shc knockdown abrogated USP15-driven hepatocellular apoptosis, whereas p66Shc overexpression counteracted the antiapoptotic effect of USP15 silencing in response to liver I/R. There was clinical evidence for the positive association between p66Shc and USP15 in patients undergoing liver transplantation. In summary, p66Shc contributes to mitochondrial fission and apoptosis associated with Drp1 activ...