NFAT5 moves to Fat City

Abstract

Fat City, a term of endearment for the land of milk-and-honey, is a 1972 American neo-noir boxing drama film directed by the legendary John Huston. Susan Tyrrell received a Best Supporting Actress Oscar nomination as the alcoholic, world-weary Oma. So it is for the Nuclear Factor of Activated T Cells-5 (NFAT5), the world-weary transcription factor that has something for nearly everybody.NFAT5, also known as tonicity-responsive enhancer binding protein (TonEBP), is a member of the nuclear-factoractivated T-cell transcription-factor family [1]. NFAT5 was initially identified in the hypertonic renal inner medulla, where the protein orchestrates a genetic program to maintain cellular homeostasis [2]. However, NFAT5 plays a more diverse functional role, including a hardly appreciated function in blood pressure regulation and in the development of autoimmune diseases. Despite the growing significance of NFAT5 in physiology and diseases, our understanding of how NFAT5 is regulated is limited. Furthermore, how changes in tonicity are converted into functional outputs via NFAT5 remains elusive. More than a dozen protein kinases have been identified that contribute to tonicity-dependent regulation of NFAT5 [3]. Hypertonicity activates NFAT5 by increasing its nuclear localization and by transactivating its activity in the early phase and protein abundance in the late phase of activation. The inhibition of NFAT5 by hypotonicity features a decrease in nuclear NFAT5 expression.Recent evidence indicates that NFAT5 is not solely regulated by tonicity, but instead that NFAT5 can be stimulated by various tonicity-independent mechanisms in both hypertonic and isotonic tissues [4]. Cytokines, growth factors, receptor and integrin activation, contractile agonists, ions, and reactive oxygen species have all been implicated in the positive regulation of NFAT5 expression and activity in diverse cell types, notably immune cells [5]. These data demonstrate that tonicity-independent stimulation of NFAT5 is important for various tissue-specific functions, such as enhanced cell survival, migration, proliferation, vascular remodeling, invasion, and angiogenesis.In this issue of J Mol Med, Li et al. demonstrate that NFAT5 can bind to a TGGAAGCGTTC consensus sequence in the gene (CACNA1C) encoding the calcium channel, voltage-dependent, L type, alpha 1C subunit and activates the transcription of the L-type calcium channel (LTCC) [6]. The investigators performed a comparative genomic study on 5-kb promoter regions of the CACNA1C gene across eight vertebrate species, and showed that six factors were developmentally regulated with the expression of cacna1c in a mouse P19cl6 i n v i t r o c a r d i o m y o c y t e d i ff e r e n t i a t i o n m o d e l . Furthermore, they demonstrated the conserved nature of this interaction by using a morpholino-mediated knockdown of nfat5 in zebrafish. The knockdown prohibited the expression of cacna1c in the fish embryos and resulted in a non-contractile ventricle, while over-expression of either cacna1c or nfa...