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- Title
SUMO-defective c-Maf preferentially transactivates Il21 to exacerbate autoimmune diabetes.
- Authors
Chao-Yuan Hsu; Li-Tzu Yeh; Shin-Huei Fu; Ming-Wei Chien; Yu-Wen Liu; Shi-Chuen Miaw; Deh-Ming Chang; Huey-Kang Sytwu; Hsu, Chao-Yuan; Yeh, Li-Tzu; Fu, Shin-Huei; Chien, Ming-Wei; Liu, Yu-Wen; Miaw, Shi-Chuen; Chang, Deh-Ming; Sytwu, Huey-Kang
- Abstract
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.
- Subjects
AUTOIMMUNE diseases; DIABETES; MYC proteins; T cell receptors; CARRIER proteins; IMMUNOLOGY
- Publication
Journal of Clinical Investigation, 2018, Vol 128, Issue 9, p3779
- ISSN
0021-9738
- Publication type
journal article
- DOI
10.1172/JCI98786