Hsu, Chao-YuanChao-YuanHsuYeh, Li-TzuLi-TzuYehFu, Shin-HueiShin-HueiFuChien, Ming-WeiMing-WeiChienLiu, Yu-WenYu-WenLiuSHI-CHUEN MIAWChang, Deh-MingDeh-MingChangSytwu, Huey-KangHuey-KangSytwu2019-08-062019-08-062018-08-310021-9738https://www.scopus.com/inward/record.uri?eid=2-s2.0-85052596996&doi=10.1172%2fJCI98786&partnerID=40&md5=7f5eee087758b1bb894759a6ee3ae396https://scholars.lib.ntu.edu.tw/handle/123456789/416287SUMOylation 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.enAutoimmunity; Cytokines; Epigenetics; Immunology; T cells[SDGs]SDG3anacardic acid; CD4 antigen; CD8 antigen; chemokine receptor CXCR5; cyclic AMP responsive element binding protein binding protein; Daxx protein; E1A associated p300 protein; gamma interferon; granzyme B; histone deacetylase 2; interleukin 10; interleukin 21; interleukin 4; transcription factor c Maf; benzimidazole derivative; CBP30 compound; histone acetyltransferase PCAF; interleukin 21; interleukin derivative; isoxazole derivative; Maf protein, mouse; mutant protein; transcription factor c Maf; animal experiment; Article; autoimmune disease; CD4+ T lymphocyte; CD8+ T lymphocyte; cell differentiation; controlled study; correlational study; diabetes mellitus; diabetogenesis; disease severity; embryo; helper cell; histone acetylation; immunoprecipitation; mouse; nonhuman; phenotype; priority journal; promoter region; sumoylation; transactivation; amino acid substitution; animal; Bagg albino mouse; binding site; biological model; biosynthesis; C57BL mouse; chemistry; genetic epigenesis; genetics; immunology; insulin dependent diabetes mellitus; knockout mouse; metabolism; nonobese diabetic mouse; SCID mouse; transcription initiation; transgenic mouse; Amino Acid Substitution; Animals; Benzimidazoles; Binding Sites; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Diabetes Mellitus, Type 1; Epigenesis, Genetic; Interleukins; Isoxazoles; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Inbred NOD; Mice, Knockout; Mice, SCID; Mice, Transgenic; Models, Biological; Mutant Proteins; p300-CBP Transcription Factors; Promoter Regions, Genetic; Proto-Oncogene Proteins c-maf; Sumoylation; Transcriptional Activationjournal article10.1172/JCI98786300590182-s2.0-85052596996WOS:000443283400020https://api.elsevier.com/content/abstract/scopus_id/85052596996