https://scholars.lib.ntu.edu.tw/handle/123456789/416287
標題: | SUMO-defective c-Maf preferentially transactivates Il21 to exacerbate autoimmune diabetes | 作者: | Hsu, Chao-Yuan Yeh, Li-Tzu Fu, Shin-Huei Chien, Ming-Wei Liu, Yu-Wen SHI-CHUEN MIAW Chang, Deh-Ming Sytwu, Huey-Kang |
關鍵字: | Autoimmunity; Cytokines; Epigenetics; Immunology; T cells | 公開日期: | 31-八月-2018 | 出版社: | AMER SOC CLINICAL INVESTIGATION INC | 卷: | 128 | 期: | 9 | 起(迄)頁: | 3779 | 來源出版物: | The Journal of clinical investigation | 摘要: | 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. |
URI: | https://www.scopus.com/inward/record.uri?eid=2-s2.0-85052596996&doi=10.1172%2fJCI98786&partnerID=40&md5=7f5eee087758b1bb894759a6ee3ae396 https://scholars.lib.ntu.edu.tw/handle/123456789/416287 |
ISSN: | 0021-9738 | DOI: | 10.1172/JCI98786 | SDG/關鍵字: | anacardic 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 Activation |
顯示於: | 免疫學研究所 |
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