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

Abstract Retinoid-related orphan nuclear receptor γt (RORγt) 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 RORγt via Lys-63-linked polyubiquitination. TRAF5 stabilizes the RORγt protein level depending on its RING finger domain. Depletion of TRAF5 in Th17 cells destabilizes RORγt 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 RORγt protein regulation, which may aggravate inflammatory progress and provide new therapeutic drug targets for autoimmune diseases.