SUMO-defective c-Maf preferentially transactivates Il21 to exacerbate autoimmune diabetes
Chao-Yuan Hsu, … , Deh-Ming Chang, Huey-Kang Sytwu
Chao-Yuan Hsu, … , Deh-Ming Chang, Huey-Kang Sytwu
Published July 30, 2018
Citation Information: J Clin Invest. 2018;128(9):3779-3793. https://doi.org/10.1172/JCI98786.
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Research Article Autoimmunity Immunology

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

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.

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

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Figure 1

c-Maf SUMOylation in CD4+ T cells is inversely correlated with the severity of insulitis and IL-21 production in NOD mice.

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c-Maf SUMOylation in CD4+ T cells is inversely correlated with the sever...
(A) The severity of insulitis was classified and scored on 100 islets from 10 NOD mice per group. Immunoprecipitation analysis of c-Maf SUMOylation in 6- to 8-week-old and 12- to 14-week-old NOD CD4+ cells cultured with anti-CD3 and anti-CD28 for 36 hours. (B and C) Expressions of Sae1, Sae2, Ubc9, and Pias1 mRNA (B) or Il4, Il10, and Il21 mRNA (C) in CD4+ cells cultured for 36 hours as described in A. (D) ELISA of indicated cytokines in supernatants of CD4+ T cells cultured as described in A for 48 hours. (E) ChIP analysis of the interaction of c-Maf with the Il21 promoter (Il21p) in CD4+ cells cultured for 36 hours as described in A. (F) Immunoprecipitation analysis of c-Maf SUMOylation in 6- to 8-week-old NOD CD4+ cells cultured for 36 hours with anti-CD3 and anti-CD28 in the presence of anacardic acid (3 μM) or its solvent (DMSO), which were added after 18 hours of culture. (G) Expressions of indicated cytokine mRNA in CD4+ T cells cultured for 36 hours as described in F. (H) ELISA of indicated cytokines in supernatants of CD4+ cells cultured as described in F for 48 hours. (I) ChIP analysis of the interaction of c-Maf with the Il21 promoter in CD4+ cells cultured for 36 hours as described in F. For E and I, isotype-matched IgG was used as a control. See complete unedited blots in the supplemental material. Data represent the mean ± SEM; n = 5 mice (A and F), n = 3 mice (B–E and G–I) per group; 3 independent experiments. *P < 0.05; **P < 0.01; 2-tailed Student’s t test (A–D and F–H) or 1-way ANOVA with Tukey’s post-test (E and I).