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

NFATc 1是“活化T细胞核因子”家族的转录因子，其在淋巴细胞中抗原受体介导的基因调控中起重要作用。NFATc 1以多种同种型合成，包括独特的高度诱导型和强效反式激活短NFATc 1/A。相反，组成型表达的长亚型NFATc 1/C跨越一个额外的C末端肽，我们证明了SUMO 1的修饰引起NFAT靶基因亚组的反式阻遏。虽然一些效应细胞因子的表达甚至在类小泛素化后增强，但白细胞介素-2（IL 2）和抗凋亡Bcl 2a 1被抑制。在机制上，类小泛素化的NFATc 1/C募集HDAC，导致组蛋白的脱乙酰化。此外，类小泛素化的NFATc 1/C与Blimp 1相互作用，Blimp 1是T细胞中IL 2和B细胞中Bcl 2a 1的既定阻遏物。为了阐明NFATc 1类小泛素化在体内的重要性，我们产生了一个复杂的NFATc 1突变的小鼠。在单个小鼠中，小泛素化缺陷型NFATc 1/C和-在与cre-deleter菌株杂交后-额外的C-末端肽缺陷型小鼠的组合使我们能够首先在体内引发NFATc 1小泛素化的功能作用，然后评估额外的C-末端是否仅通过小泛素化发挥功能。第一个实验揭示了增强的IL 2在体内的生产，增加生殖中心B细胞和伴随的免疫球蛋白的生产后免疫。有趣的是，仅仅是NFATc 1/C类小泛素化的缺乏保护小鼠免受实验性自身免疫性脑脊髓炎。

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.