TRAF5-mediated Lys-63-linked Polyubiquitination Plays an Essential Role in Positive Regulation of RORγt in Promoting IL-17A Expression

Background: RORt is required for Th17 cell function and differentiation. Results: TRAF5 stabilizes RORt by ubiquitination and augments RORt-mediated transcriptional expression of IL-17A. Conclusion: TRAF5 is a positive regulator for RORt. Significance: TRAF5 could be a novel target for modulating RORt-mediated inflammation and autoimmune diseases, including systemic lupus erythematosus.Retinoid-related orphan nuclear receptor t (RORt) is a key transcription factor for the development and function of Th17 cells. In this study, we show that tumor necrosis factor receptor-associated factor 5 (TRAF5), known as an E3 ubiquitin protein ligase and signal transducer, interacts with and ubiquitinates RORt via Lys-63-linked polyubiquitination. TRAF5 stabilizes the RORt protein level depending on its RING finger domain. Depletion of TRAF5 in Th17 cells destabilizes RORt protein and down-regulates Th17-related genes, including IL-17A, an inflammatory cytokine involved in pathogenic mechanisms of several autoimmune diseases such as systemic lupus erythematosus. Moreover, up-regulation of the TRAF5 mRNA level was found in systemic lupus erythematosus patient CD4(+) T cells. Our findings reveal a direct link between TRAF5-mediated ubiquitination and RORt protein regulation, which may aggravate inflammatory progress and provide new therapeutic drug targets for autoimmune diseases.