SUMO-specific protease 2 restrains the differentiation of Th17 cells

Abstract

Abstract Accumulating evidence suggests that posttranslational modifications (PTMs) play a critical role in the regulation of cellular functions and disease progression. Several reports indicated that SUMOylation, a type of PTMs, contributes to diseases through modulation of cell signaling and functions. The process of SUMOylation is dynamic and can be reversibly removed by the sentrin-specific protease (SENP) family. Smad4 has been shown to suppress the differentiation of pathogenic Th17 cells and can be deSUMOylated by SENP2. Here, we would like to study whether SUMOylation may affect T cell development and differentiation, and T cell-mediated diseases. To study the roles of Senp2 in T cell lineage, we generated Senp2f/f×Lck-cre (CKO) mice. We found that there were more Th1 and Th17 cells in CKO mice in the steady state, as compared with those in littermate controls (wild type, WT) mice. Besides, Senp2-deficiency in T cells also promotes the progression of dextran sodium sulfate (DSS)-induced colitis in mice. The levels of IFNg and IL-17 produced by in vitro differentiated Th1 and Th17 cells, respectively, were higher when Senp2 is deleted. The enzymatic activity of Senp2 is required for the inhibition of Th17 differentiation; as compared with the effects of lentiviral vector expressing wild type Senp2, transduction of differentiating CKO Th17 cells with a lentiviral vector expressing a catalytic domain mutant Senp2 failed to suppress the frequency of Th17 cells. We are examining if SUMOylation affects the function of Smad4 in Th17 cells. Results from this study may provide insights into the new therapeutic strategy for the control of Th17-mediated diseases.