E3 ubiquitin ligase RNF5 protects against hepatic ischemia reperfusion injury by mediating PGAM5 ubiquitination

BACKGROUND & AIMS Hepatic ischemia reperfusion (HIR) injury, a common clinical complication of liver transplantation and resection, affects patient prognosis. RNF5 is an E3 ubiquitin ligase that plays important roles in endoplasmic reticulum stress, unfolded protein reactions, and inflammatory responses; however, its role in HIR is unclear. APPROACH & RESULTS RNF5 expression was significantly downregulated during HIR in mice and hepatocytes. Subsequently, RNF5 knockdown and overexpression cell lines were subjected to hypoxia-reoxygenation challenge. The results shown that RNF5 knockdown significantly increased hepatocyte inflammation and apoptosis, while RNF5 overexpression had the opposite effect. Furthermore, hepatocyte-specific RNF5 knockout and transgenic mice were established and subjected to HIR, and RNF5 deficiency markedly aggravated liver damage, cell apoptosis, and activated hepatic inflammatory responses. While hepatic RNF5 transgenic mice had the opposite effect compared with RNF5 knockout mice. Mechanistically, RNF5 interacted with PGAM5 and mediated the degradation of PGAM5 through K48-linked ubiquitination, thereby inhibiting the activation of ASK1 and its downstream JNK/p38. This eventually suppresses the inflammatory response and cell apoptosis in HIR. CONCLUSION We revealed that RNF5 protected against HIR via its interaction with PGAM5 to inhibit the activation of ASK1 and the downstream JNK/p38 signaling cascade. Our findings indicate that the RNF5-PGAM5 axis may be a promising therapeutic target for HIR.