%0 Journal Article
%T SUMO-defective c-Maf preferentially transactivates Il21 to exacerbate autoimmune diabetes
%A Chao-Yuan Hsu
%A Deh-Ming Chang
%A Huey-Kang Sytwu
%A Li-Tzu Yeh
%A Ming-Wei Chien
%A Shi-Chuen Miaw
%A Shin-Huei Fu
%A Yu-Wen Liu
%J The Journal of Clinical Investigation
%D 2018
%R 10.1172/JCI98786
%X SUMOylation is involved in the development of several inflammatory diseases, but the physiological significance of SUMO-modulated 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每mediated diabetogenesis in NOD mice. Using 2 strains of T cell每specific transgenic NOD mice overexpressing wild-type c-Maf (Tg-WTc) or SUMOylation site每mutated c-Maf (Tg-KRc), we demonstrated that Tg-KRc mice developed diabetes more rapidly than Tg-WTc mice in a CD4+ T cell每autonomous manner. Moreover, SUMO-defective c-Maf preferentially transactivated Il21 to promote the development of CD4+ T cells with an extrafollicular helper T cell phenotype and expand the numbers of granzyme B每producing effector/memory CD8+ T cells. Furthermore, SUMO-defective c-Maf selectively inhibited recruitment of Daxx/HDAC2 to the Il21 promoter and enhanced histone acetylation mediated by CREB-binding protein (CBP) and p300. Using pharmacological interference with CBP/p300, we illustrated that CBP30 treatment ameliorated c-Maf每mediated/IL-21每based diabetogenesis. Taken together, our results show that the SUMOylation status of c-Maf has a stronger regulatory effect on IL-21 than the level of c-Maf expression, through an epigenetic mechanism. These findings provide new insights into how SUMOylation modulates the pathogenesis of autoimmune diabetes in a T cell每restricted manner and on the basis of a single transcription factor
%U https://www.jci.org/articles/view/98786