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 7

A CBP/p300 inhibitor attenuates SUMO-defective c-Maf–mediated transactivation of Il21 and ameliorates autoimmune diabetes in NOD mice.

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A CBP/p300 inhibitor attenuates SUMO-defective c-Maf–mediated transactiv...
(A) Expression of Il21 mRNA in naive control, Tg-WTc, and Tg-KRc CD4+ T cells cultured for 36 hours with anti-CD3 and anti-CD28 in the presence of CBP30 (2 μM) or its solvent (DMF), which were added after 18 hours of culture. (B–D) ChIP analysis of the interaction of c-Maf (B), CBP (C), and p300 (D) with the c-Maf–binding site in the Il21p in naive CD4+ T cells cultured for 36 hours as in A. (E and F) ChIP analysis of the abundance of H3ac (E) and H4ac (F) in the c-Maf–binding site of the Il21p in naive CD4+ T cells cultured for 36 hours as in A. Isotype-matched IgG was used as a control. (G) Diabetic incidence in NOD.Rag1–/– recipients injected with effector Tg-WTc and Tg-KRc CD4+ T cells (CD4+CD25–) plus control CD8+ T cells on day 0, and then injected with 2 mg/kg CBP30 or its solvent (DMF) every 2 days from day 1 to day 13. (H) On day 14, RT-qPCR analysis of Il21 mRNA expression in CD4+ T cells and Gzmb mRNA expression in CD8+ T cells from NOD.Rag1–/– recipients reconstituted as in G. Data represent the mean ± SEM; n = 3 mice (A and H), n = 5 mice (B–F), n = 5–6 mice (G) per group; 3 independent experiments (A–F) or 2 independent experiments (G and H). *P < 0.05; **P < 0.01; 2-tailed Student’s t test (A–F), log-rank test (G), or 1-way ANOVA with Tukey’s post-test (H).