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 2

Accelerated kinetics of autoimmune diabetes in SUMO-defective c-Maf–transgenic NOD mice.

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Accelerated kinetics of autoimmune diabetes in SUMO-defective c-Maf–tran...
(A) Schematic diagram of distal Lck promoter–driven wild-type c-Maf or K33R c-Maf transgenes. (B) PCR detection of transgenic c-Maf in genomic DNA extracted from control, Tg-WTc, and Tg-KRc mice. Il23 p19 was used as an internal control. (C) Western blot analysis of c-Maf in control, Tg-WTc, and Tg-KRc CD4+ T cells. (D and E) Immunoprecipitation analysis of c-Maf SUMOylation in control, Tg-WTc, and Tg-KRc CD4+ T cells cultured with anti-CD3 and anti-CD28 for 36 hours. (F) Diabetes incidence in Tg-WTc NOD mice and their littermate controls. (G) Diabetes incidence in Tg-KRc NOD mice and their littermate controls. (H) Diabetes incidence in NOD-SCID recipients of splenocytes from 12- to 14-week-old control, Tg-WTc, or Tg-KRc NOD mice. (I and J) CD25–CD4+ plus CD8+ T cells from 12- to 14-week-old indicated NOD mice were transferred into NOD.Rag1–/– mice; all groups were treated simultaneously in 2 independent experiments. The control CD4/control CD8 (white circles) group is presented in both I and J. Diabetic incidences among groups that received control CD8+ T cells plus different CD4+ T cells (I) and diabetic incidences in among groups that received control CD4+ T cells plus different CD8+ T cells (J) were compared with each other by a log-rank test. See complete unedited blots in the supplemental material. For E, data represent the mean ± SEM; n = 3 mice (B and C) or n = 5 mice (D and E) per group; 3 independent experiments (B–E) or 2 independent experiments (H). *P < 0.05; **P < 0.01; 1-way ANOVA with Tukey’s post-test (E) or log-rank test (F–J).