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

Abstract

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.

TIGAR alleviates oxidative stress in brain with extended ischemia via a pentose phosphate pathway-independent manner

“…After 2 h of MCAO, TIGAR reached approximately 2.29-fold ( p < 0.05) of that in sham mice. These results were in line with previous findings that TIGAR undergoes significant upregulation after cerebral ischemia [ 6 , 12 ]. Notably, NADPH, the product from glucose metabolism via the PPP, declined as the ischemia duration increased, suggesting TIGAR failed to further activate PPP to meet the demand under sustained ischemic condition ( Fig.…”

“…In addition, glucose is predominantly metabolized by glycolysis, rather than the PPP, upon reperfusion [ 11 ]. Paradoxically, neuronal TIGAR shows a four-fold upregulation after 2 h of ischemia [ 6 ], which can be sustained as long as 24 h after ischemia in mice [ 12 ]. It remains largely unexplored whether TIGAR-NADPH may play a role in counteracting oxidation caused by prolonged cerebral ischemia.…”

Abrogation of graft ischemia‐reperfusion injury in ischemia‐free liver transplantation

“… 26 , 27 Furthermore, the PPP is the key to maintaining mitochondrial function. 28 Impaired mitochondrial function plays an essential role in allograft IRI. 29 In this study, transcriptome, proteome, and metabolome network analysis confirmed that PPP activity was stable throughout IFLT, while it was suppressed during preservation but enhanced postrevascularization in CLT.…”

“…Studies have shown that its rate‐limiting enzyme, glucose‐6‐phosphate dehydrogenase (G6PDH), can protect the brain and heart from IRI 26,27 . Furthermore, the PPP is the key to maintaining mitochondrial function 28 . Impaired mitochondrial function plays an essential role in allograft IRI 29 .…”

TRIM7 modulates NCOA4-mediated ferritinophagy and ferroptosis in glioblastoma cells

“…Tripartite motif-containing proteins (TRIMs) are a family of E3 ubiquitin ligases and mediate endogenous proteins for degradation by the ubiquitin-proteasome system [ 23 , 24 ]. TRIMs are implicated in the pathogenesis of various human tumors, including the glioblastoma.…”