The E3 ubiquitin ligase TRIM31 is involved in cerebral ischemic injury by promoting degradation of TIGAR

Tripartite motif (TRIM) 31 has been implicated in diverse biological and pathological conditions. However, whether TRIM31 plays a role in ischemic stroke progression is not clarified. Here we demonstrated that TRIM31 was significantly downregulated in the ischemic brain and the deficiency of TRIM31 alleviated brain injury induced by middle cerebral artery occlusion by reducing reactive oxygen species production and maintaining mitochondrial homeostasis. Mechanistically, we found that TRIM31 is an E3 ubiquitin ligase for TP53-induced glycolysis and apoptosis regulator (TIGAR), which confers protection against brain ischemia by increasing the pentose phosphate pathway flux and preserving mitochondria function. TRIM31 interacted with TIGAR and promoted the polyubiquitination of TIGAR, consequently facilitated its degradation in a proteasome-dependent pathway. Furthermore, TIGAR knockdown effectively abolished the protective effect of TRIM31 deficiency after cerebral ischemia. In conclusion, we identified that TRIM31 was a novel E3 ubiquitin ligase for TIGAR, played a critical role in regulating its protein level, and subsequently involved in the ischemic brain injury, suggesting TRIM31 as a potential therapeutic target for ischemic stroke. Working model for the role of TRIM31 in ischemic brain injury. TRIM31 in the neurons mediated ubiquitous degradation of TIGAR, resulting in decreasing the pentose phosphate pathway (PPP) flux and mitochondrial dysfunction. Thus, enhanced reactive oxygen species (ROS) production led to cerebral ischemic injury. [Display omitted] •We firstly demonstrated the role of TRIM31 in ischemic stroke both in cellular and animal models.•We identified TRIM31 as the E3 ubiquitin ligase for TIGAR. TRIM31 interacted with TIGAR and promoted its ubiquitination and subsequent proteasomal degradation.•TRIM31 deficiency ameliorated ischemic brain injury by reducing reactive oxygen species and maintaining mitochondrial homeostasis via regulating TIGAR.