TRIM26 aggravates cerebral ischemia-reperfusion injury via promoting TAK1-mediated JNK/P38 MAPK pathway

Stroke is the second leading cause of death worldwide, with ischemic stroke accounting for the majority. During ischemic stroke, timely intervention of blood flow is life-critical, but cerebral injury after reperfusion is most related to patient prognosis. A thorough understanding of regulatory mechanisms would be helpful in exploring effective drugs for cerebral ischemia/reperfusion (I/R) injury. As an E3 ubiquitin ligase, TRIM26 has been demonstrated to play a significant regulatory role in viral infections as well as in various types of cancers. In this study, we found that the protein level of TRIM26 was increased in both in vivo and in vitro models of cerebral I/R injury. In mice, Trim26 knockout alleviated cerebral infarcted area, reduced inflammatory cytokine expressions and the activation of NF-κB signaling pathway, and decreased apoptosis. Likewise, knocking down Trim26 reduced cell inflammatory responses and apoptosis in primary neurons. However, overexpressing Trim26 produced opposite effects. The expressions of activated TAK1, JNK and P38 were found positively correlated with the expression of TRIM26. Inhibiting the activity of TAK1 abolished the regulatory effect of TRIM26 overexpression on inflammatory responses and apoptosis in primary neurons. TRIM26 exerted detrimental roles in the regulation of cerebral I/R injury depending on the activation of TAK1. TRIM26-TAK1 axis would shed light on new therapeutic strategy development for ischemic stroke.