Sumoylation regulates the transcriptional activity of different human NFAT isoforms in neurons.

In the nervous system, four calcium/calcineurin-regulated members of the nuclear factor of activated T-cells (NFAT) family of transcription factors, NFATc1-c4, are involved in many developmental and functional processes, such as corticogenesis, synaptogenesis, synaptic plasticity and neurotransmission, that all need precise gene regulation. Therefore it is important to understand molecular events that contribute to the regulation of the transcriptional activity of specific NFAT isoforms. Previously, we have shown that there are a number of alternative splice variants of NFAT genes expressed in the brain and that neuronal activity leads to isoform-specific transactivation capacities of different human NFAT proteins. Here we looked at the effect of sumoylation as a possible regulator of the transcriptional activity of different human NFAT isoforms in rat primary cortical and hippocampal neurons in response to membrane depolarization and compared the results to those obtained from non-neuronal HEK293-FT and BHK-21 cells in response to calcium signaling. Our results show that in primary hippocampal neurons, sumoylation represses the transcriptional activity of NFATc1, NFATc2, and NFATc3 isoforms, whereas in cortical neurons, transactivation capacity of only NFATc1 and NFATc2 is repressed by sumoylation. In non-neuronal cells, however, transcriptional activity of all four NFAT isoforms is repressed by sumoylation in HEK293-FT cells, while only NFATc1 and NFATc2 isoforms are affected by sumoylation in BHK-21 cells. Altogether, our results show that sumoylation represses the transcription activation capacities of NFAT isoforms and that the effect is cell type-specific.