Bridging the NFAT and NF-κB families:: NFAT5 dimerization regulates cytokine gene transcription in response to osmotic stress

The transcription factor NFAT5/TonEBP is evolutionarily the oldest member of the NFAT/Rel family of transcription factors. We show that NFAT5 is uniquely related to NF-KB and is the only member of the Rel/NFAT family to be activated by osmotic stress. Like Rel/NF-kappaB proteins but unlike the calcium-regulated NFAT proteins, NFAT5 is constitutively dimeric, and dimerization is essential for DNA binding and transcriptional activity. Using dominant-negative proteins that inhibit NFAT5 dimerization, we show that NFAT5 regulates expression of the TNF alpha and lymphotoxin-beta genes in osmotically stressed T cells. Chromatin immunoprecipitation experiments confirm that NFAT5 binds to the TNF alpha promoter in vivo. We suggest that NFAT5 participates in specific aspects of host defense by upregulating TNF family genes and other target genes in T cells.