TRIM32 promotes neuronal ferroptosis by enhancing K63-linked ubiquitination and subsequent p62-selective autophagic degradation of GPX4
Xin Zhou, Yuqing Zhao, Shixue Huang, Haoming Shu, Yinuo Zhang, Haiyuan Yang, Yilong Ren, Xuhui Zhou, Wei Liu, Tengfei Song, Jianquan Zhao, Jun Ma
Abstract
showed aggravated neuronal loss and poor behavioral function, which could be attenuated by ferroptosis inhibitor Liproxstatin-1. Mechanistically, TRIM32 interacted with GPX4, promoted K63-linked ubiquitination modification of GPX4 at K107, thus enhanced p62-dependent autophagic degradation of GPX4. Moreover, ROS-ATM-Chk2 signaling pathway phosphorylates TRIM32 at S55, further contributing to GPX4 ubiquitination and degradation and subsequent neuronal ferroptosis after SCI, suggesting a positive feedback loop between ROS and TRIM32. Clinically, lipid peroxidation was significantly promoted in patients with SCI. These findings reveal that TRIM32 functions as a neuronal ferroptosis enhancer which is detrimental to neuronal survival and locomotor functional recovery in mice after SCI by promoting K63-linked ubiquitination and subsequent p62-dependent autophagic degradation of GPX4, suggesting a promising therapeutic target for SCI.