Ubiquitin-Conjugating Enzyme E2O Primes Hepatocytes to Restore Immune Tolerance in Autoimmune Hepatitis via Inhibiting Y-Box Binding Protein 1/Interleukin-6 Axis

BACKGROUND & AIMS: Autoimmune hepatitis (AIH) is a chronic progressive inflammatory liver disease, with its incidence increasing continuously worldwide. The mechanisms underlying the regulation of immune tolerance in AIH remain largely unknown. This study investigated a novel regulatory pathway of regulatory T cell/T helper 17 (Treg/Th17) balance involving the ubiquitin-conjugating enzyme E2O (UBE2O) and underlying mechanisms. METHODS: T differentiation induction assays were used to investigate the exact role of UBE2O in AIH. Liver samples were assessed by histology, immunochemistry, immunoblot, flow cytometry, and enzyme-linked immunosorbant assays. Mass spectrometry, co-immunoprecipitation, cytokine microarray, and site-specific mutation experiments were utilized to elucidate underlying molecular mechanisms. RESULTS: T cells differentiation into Tregs. Furthermore, YBX1 partially reversed the protective effects of UBE2O overexpression in AIH. CONCLUSIONS: Our study revealed a previously unrecognized hepatocellular UBE2O/YBX1/interleukin-6 axis in AIH that primes hepatocytes to restore immune tolerance. Targeting UBE2O might provide a promising therapeutic target for AIH by linking posttranslational modification and hepatic immune tolerance.