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”家族的转录因子，在淋巴样细胞中抗原受体介导的基因调节中起着至关重要的作用。 NFATC1在多种同工型中合成，包括高度诱导和潜在反式激活的短NFATC1/A。相反，始终表达的长同工型NFATC1/C跨越了额外的C端胡椒粉，为此我们通过SUMO1通过在NFAT靶基因的亚组上引起反抑制来证明它的修饰。虽然在sumoylation时甚至可以增强某些效应子细胞因子的表达，但重复了白介素-2（IL2）和抗凋亡BCL2A1。从机械上讲，sumoy的NFATC1/C募集了导致组蛋白脱乙酰基化的HDAC。此外，sumoy的NFATC1/C与Blimp1相互作用，Blimp1是T细胞中IL2的已建立副本，而B细胞中的BCl2a1相互作用。为了阐明体内NFATC1 sumoylation的重要性，我们生成了一个复杂的NFATC1突变小鼠。单一小鼠中的组合均与sumoylation缺陷NFATC1/c和 - 在与CRE-DELETER菌株交叉时 - 额外的C末端胡椒缺陷鼠标使我们能够首先通过Vivo In Vivo和2ND评估的NFATC1 Sumoylation的功能，并通过额外的C- termientions functions Insupy sumperions insumions insumions ysumions insume sumperions。第一个实验表明，体内IL2产生增强，生成中心B细胞的增加以及免疫免疫后的免疫球蛋白产生。有趣的是，仅缺乏NFATC1/c Sumoylation会保护小鼠免受实验性自身免疫性脑脊髓炎的侵害。