Functional consequences of NFATc1 sumoylation on lymphocyte activation, differentiation and tolerance

NFATc1 sumoylation 对淋巴细胞活化、分化和耐受性的功能影响

• 批准号: 71924695
• 负责人: Professorin Dr. Friederike Berberich-Siebelt
• 金额: --
• 依托单位: Pathologisches Institut
• 依托单位国家: 德国
• 项目类别: Priority Programmes
• 财政年份: 2008
• 资助国家: 德国
• 起止时间: 2007-12-31 至 2014-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/71924695?language=en
• 关键词: Functional; consequences; NFATc1; sumoylation; lymphocyte

NFATc1 is a transcription factor of the family of “Nuclear Factors of Activated T cells” which plays an essential role in antigen receptor-mediated gene regulation in lymphoid cells. NFATc1 is synthesised in multiple isoforms including the distinguished highly inducible and potently transactivating short NFATc1/A. On the contrary, the constitutively expressed long isoform NFATc1/C spans an extra Cterminal peptide, for which we demonstrated modification by SUMO1 causing transrepression on a subgroup of NFAT target genes. While expression of some effector cytokines is even enhanced upon sumoylation, interleukin-2 (Il2) and the antiapoptotic Bcl2a1 are repressed. Mechanistically, sumoylated NFATc1/C recruits HDACs leading to deacetylation of histones. Moreover, sumoylated NFATc1/C interacts with Blimp1, an established repressor for Il2 in T cells and Bcl2a1 in B cells. To elucidate the importance of NFATc1 sumoylation in vivo, we generated a sophisticated NFATc1-mutated mouse. The combination, in a single mouse, of both a sumoylation-deficient NFATc1/C and - upon crossing with a cre-deleter strain - an extra C-terminal peptide-deficient mouse puts us in the position to 1st elicit the functional role of NFATc1 sumoylation in vivo and 2nd evaluate if the extra C-terminus functions solely through sumoylation. First experiments revealed enhanced Il2 production in vivo, an increase in germinal centre B cells and concomitant immunoglobulin production upon immunization. Intriguingly, solely the absence of NFATc1/C sumoylation protects mice from Experimental Autoimmune Encephalomyelitis.

NFATC1是“活化T细胞的核因子”的转录家族，在淋巴样细胞中起着至关重要的作用独特的作用。 NFAT靶基因。为了阐明NFATC1的重要性，使nfatc1杂化的小鼠降低了。 NFATC1在体内的作用并评估脚趾的脚趾脚趾脚趾通过Sumoylation的脚趾脚趾的作用。