USP19 Suppresses Th17-Driven Pathogenesis in Autoimmunity

Th17 cells have emerged as a chief pathogenic cell type in murine models of autoimmunity and human autoimmune diseases. Th17 cells are markedly plastic in their pathogenic potential, as they can adopt pro- or anti-inflammatory programming under distinct conditions. The specific mechanism underlying the plasticity of Th17 pathogenesis remains elusive. In this study, we found that Th17 lineage-specific transcription factor ROR gamma t directly bound to the promoters of genes engaged in the ubiquitination pathway and thus upregulated their expression in pathogenic Th17 cells. We observed that ubiquitination activity correlated with Th17-related pathology in the context of autoimmunity. Consistent with this finding, the deubiquitinase USP19 was shown to suppress pathogenic Th17 differentiation in vitro and Th17-mediated pathogenesis in vivo. Mechanistically, USP19 removed the K63-linked ubiquitin chain from ROR gamma t lysine 313, which is essential for recruiting the coactivator SRC3. Collectively, our findings indicate that USP19 selectively suppresses the pathogenic potential of Th17 cells and offer novel strategies for treating autoimmune diseases.

Automated summary

Th17 cells play an important role in autoimmune pathology and exhibit plasticity in their pathogenic potential. Research has identified that ROR gamma t and the ubiquitination pathway play key roles in the pathogenesis of Th17 cells. USP19 suppresses the pathogenicity of Th17 cells by regulating the ubiquitin chain of ROR gamma t.