High NaCl–induced activation of CDK5 increases phosphorylation of the osmoprotective transcription factor TonEBP/OREBP at threonine 135, which contributes to its rapid nuclear localization

Abstract

When activated by high NaCl, the transcription factor TonEBP/OREBP increases transcription of osmoprotective genes. High NaCl activates CDK5 kinase, which directly phosphorylates TonEBP/OREBP on threonine 135. This contributes to rapid nuclear translocation of TonEBP/OREBP, accelerating transcription of its osmoprotective target genes.

How do kinases contribute to tonicity-dependent regulation of the transcription factor NFAT5?

“…High NaCl increases phosphorylation of NFAT5-Y143, leading to increase of NFAT5 nuclear localization in cell culture [23][24][25] , and phosphorylation of NFAT5-Y143 is increased in the normal rat renal inner medulla and the Brattleboro rat inner medulla treated with vasopressin, known to increase the renal medullary tonicity [25] . The similar Zhou X. Kinases regulate NFAT5 activity phenomena are also observed with NFAT5-T135 [26] . On the other hand, low NaCl increases phosphorylation of NFAT5-S155 and then S158, leading to reduced NFAT5 nuclear accumulation [26,27] .…”

“…The similar Zhou X. Kinases regulate NFAT5 activity phenomena are also observed with NFAT5-T135 [26] . On the other hand, low NaCl increases phosphorylation of NFAT5-S155 and then S158, leading to reduced NFAT5 nuclear accumulation [26,27] . In contrast to the demonstration of regulation of NFAT5 nuclear distribution by direct phosphorylation, how phosphorylation regulates NFAT5 transactivating activity is elusive.…”

“…In HEK293 cells, high NaCl activates CDK5, which directly phosphorylates NFAT5-T135. Phosphorylation of NFAT5-T135 is also increased in the rat renal inner medulla [26] . Inhibition of CDK5 by its siRNA or an inhibitor reduces the increase in NFAT5 transcriptional activity that has occurred by 4 h after NaCl is raised, associated with inhibition of NFAT5 nuclear accumulation at that time, but does not reduce either NFAT5 activity or nuclear NFAT5 after 16 h. This is because high NaCl increases the overall abundance of NFAT5 protein at the later time, which eventually raises its effective level in the nucleus, but the early effect of high NaCl on NFAT5 nuclear localization requires CDK5 [26] .…”

“…The committee members are like different and redundant instrument players in an orchestra in which each one plays his/her instrument, maybe viewed as activation of a signaling molecule, in a coordinated way with other players for a specific music piece signaled by a conductor. This theory explains why each of the identified kinases is necessary for full activation of NFAT5, but none alone, is sufficient [22] , why CDK5 is only required in the early phase of NFAT5 activation [26] , and why over expression of catalytically active PKA only increases NFAT5 activity under isotonicity but not under hypertonicity [35] , because neither a single player nor an over active player can play an orchestra piece. Numerous signaling molecules are required in order to form redundancy in signaling hypertonic stress.…”

“…Instead, its nucleo-cytoplasmic distribution is regulated by phosphorylation of other amino acids in the terminus such as tyrosine 143 [23][24][25] , threonine 135 [26] and serines 155 and 158 [27] . The difference in amino acid composition explains why GSK-3β affects nuclear localization of NFAT5 differently from that of NFAT1-4.…”