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细胞核因子家族中的一个转录因子，在抗原受体介导的淋巴细胞基因调控中发挥重要作用。NFATc1是以多种异构体合成的，包括独特的高度诱导和有效反式激活的短NFATc1/A。相反，结构性表达的长异构体NFATc1/C跨越一个额外的CT端多肽，我们证明了SUMO1的修饰导致了NFAT靶基因亚群的反式表达。虽然某些效应细胞因子的表达在SUMO化后甚至被增强，但白介素2(IL2)和抗凋亡的Bcl2a1被抑制。从机制上讲，SUMoylated NFATc1/C招募HDAC，导致组蛋白去乙酰化。此外，Sumoylated NFATc1/C与Blimp1相互作用，Blimp1是T细胞中IL2和B细胞中Bcl2a1的已建立的抑制因子。为了阐明体内NFATc1苏莫化的重要性，我们培育了一只复杂的NFATc1突变小鼠。在一只小鼠中，既有NFATc1/C总甲基化缺陷的小鼠，又有额外的C端肽缺陷的小鼠，当与克隆株杂交时，这两种组合使我们能够第一次在体内诱导NFATc1总甲基化的功能作用，第二评估额外的C末端是否仅通过总甲基化发挥作用。最初的实验表明，免疫后体内IL2的产生增加，生发中心B细胞和伴随的免疫球蛋白产生增加。有趣的是，仅NFATc1/C SUMO的缺失就能保护小鼠免受实验性自身免疫性脑脊髓炎的侵袭。