RNF13 protects neurons against ischemia-reperfusion injury via stabilizing p62-mediated Nrf2/HO-1 signaling pathway.

Background: Cerebral ischemia/reperfusion injury (CIRI), a common, universal clinical problem that costs a large proportion of the economic and disease burden. Identifying the key regulators of cerebral I/R injury could provide potential strategies for clinically improving the prognosis of stroke. Ring finger protein 13 (RNF13) has been proven to be involved in the inflammatory response. Here, we aimed to identify the role of RNF13 in cerebral I/R injury and further reveal its immanent mechanisms.

Methods: The CRISPR/Cas9 based knockout mice, RNA sequencing, mass spectrometry, co-immunoprecipitation, GST-pull down, immunofluorescent staining, western blot, RT-PCR were used to investigate biodistribution, function and mechanism of RNF13 during cerebral I/R injury.

Results: In the present study, we found that RNF13 was significantly up-regulated in patients, mice and primary neurons after I/R injury. Deficiency of RNF13 aggravated I/R-induced neurological impairment, inflammatory response and apoptosis while overexpression of RNF13 inhibited I/R injury. Mechanistically, this inhibitory effect of RNF13 during I/R injury was confirmed to be dependent on the blocking of TRIM21-mediated autophagy-dependent degradation of p62 and the stabilization of the p62-mediated Nrf2/HO-1 signaling pathway.

Conclusion: RNF13 is a crucial regulator of cerebral I/R injury that plays its role in inhibiting cell apoptosis and inflammatory response by preventing the autophagy-medicated degradation of the p62/Nrf2/HO-1 signaling pathway via blocking the interaction of TRIM21-p62 complex. Therefore, RNF13 represents a potential pharmacological target in acute ischemia stroke therapy.