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

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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.