[HTML][HTML] SUMO-defective c-Maf preferentially transactivates Il21 to exacerbate autoimmune diabetes

CY Hsu, LT Yeh, SH Fu, MW Chien… - The Journal of …, 2018 - Am Soc Clin Investig
CY Hsu, LT Yeh, SH Fu, MW Chien, YW Liu, SC Miaw, DM Chang, HK Sytwu
The Journal of clinical investigation, 2018Am Soc Clin Investig
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–mediated
diabetogenesis in NOD mice. Using 2 strains of T cell–specific transgenic NOD mice
overexpressing wild-type c-Maf (Tg-WTc) or SUMOylation site–mutated c-Maf (Tg-KRc), we …
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–mediated diabetogenesis in NOD mice. Using 2 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 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 histone acetylation mediated by CREB-binding protein (CBP) and p300. Using pharmacological interference with CBP/p300, we illustrated that CBP30 treatment ameliorated c-Maf–mediated/IL-21–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–restricted manner and on the basis of a single transcription factor.
The Journal of Clinical Investigation