The conjugation of small ubiquitin-like modifier (SUMO) to specific lysine residues of cellular proteins (SUMOylation) is a dynamic and reversible posttranslational modification and is involved in the development of several inflammatory diseases, but the physiological significance of SUMO-modulated transcription factor c-Maf in autoimmune diabetes is not completely understood. Here, we report that an age-dependent attenuation of c-Maf SUMOylation in CD4 + T cells is positively correlated with the IL-21-mediated diabetogenic process in NOD mice. Using two strains of T cell-specific transgenic NOD mice overexpressing wild-type c-Maf (Tg-WTc) or SUMOylation site-mutated c-Maf (Tg-KRc), we demonstrated that Tg-KRc mice developed diabetes more rapidly than Tg-WTc mice in a CD4 + T cell-autonomous manner. Moreover, SUMO-defective c-Maf preferentially transactivated Il21 to promote the development of CD4 + T cells with an extrafollicular helper T (Tefh) cell phenotype and expand the numbers of granzyme B-producing effector/memory CD8 + T cells. Furthermore, SUMO-defective c-Maf selectively inhibited recruitment of Daxx/HDAC2 to the Il21 promoter and enhanced CREB-binding protein (CBP)/p300-mediated histone acetylation. Using pharmacological interference with CBP/p300 as a therapeutic strategy, we illustrated that CBP30 treatment ameliorated c-Maf-mediated/IL-21-based pathogenesis in autoimmune diabetes. Taken together, our results show that the SUMOylation status of c-Maf has a stronger regulatory effect on IL-21 than the c-Maf level of expression through an epigenetic mechanism. These findings provide new insights into how SUMOylation modulates the pathogenesis of autoimmune diabetes in a T cell-restricted and single transcription factor-based manner.
Date:
2019-10
Relation:
European Journal of Immunology. 2019 Oct;49(S3):761.
