USP19 Suppresses Th17 Pathogenicity in Autoimmunity

Abstract

Abstract Th17 cells play an essential role in the pathogenesis of murine autoimmune models and human autoimmune diseases. However, Th17 cells exhibit notable plasticity in vivo, adopting pro- or anti-inflammatory effector states in a distinct milieu. The underlying mechanisms that regulate pathogenicity of Th17 cells in health and disease remain unclear. In this study, we investigate the role of the deubiquitinase USP19 in the differentiation and function of Th17 cells. We found that lineage-specific transcription factor RORγt directly binds to ubiquitination-related gene promoters, upregulating the ubiquitination pathway in pathogenic Th17 cells (pTh17). The enhanced ubiquitination activity in pTh17 cells directly correlates with autoimmune disease severity in murine models. The deubiquitinase USP19 suppresses pTh17 differentiation in vitro and Th17-mediated autoimmune disease in vivo. Mechanistically, we found that USP19 removes the K63-linked ubiquitin chain from RORγt lysine 313, resulting in the blocking of the RORγt-SRC3 interaction and ultimately, RORγt activation. Thus, these findings suggest that USP19 selectively suppresses Th17 pathogenicity in murine autoimmune disease. Supported by P30 Award from NIH, National Cancer Institute of Health (P30CA012197) and NIH T32 Training Grant (5T32A1007401-28)