Osmoprotective transcription factor NFAT5/TonEBP modulates nuclear factor-kappaB activity.
Tonicity-responsive binding-protein (TonEBP or NFAT5) is a widely expressed transcription factor whose activity is regulated by extracellular tonicity. TonEBP plays a key role in osmoprotection by binding to osmotic response element/TonE elements of genes that counteract the deleterious effects of cell shrinkage. Here, we show that in addition to this "classical" stimulation, TonEBP protects cells against hypertonicity by enhancing nuclear factor-κB (NF-κB) activity. We show that hypertonicity enhances NF-κB stimulation by lipopolysaccharide but not tumor necrosis factor-α, and we demonstrate overlapping protein kinase B (Akt)-dependent signal transduction pathways elicited by hypertonicity and transforming growth factor-α. Activation of p38 kinase by hypertonicity and downstream activation of Akt play key roles in TonEBP activity, IκBα degradation, and p65 nuclear translocation. TonEBP affects neither of these latter events and is itself insensitive to NF-κB signaling. Rather, we reveal a tonicity-dependent interaction between TonEBP and p65 and show that NF-κB activity is considerably enhanced after binding of NF-κB-TonEBP complexes to κB elements of NF-κB-responsive genes. We demonstrate the key roles of TonEBP and Akt in renal collecting duct epithelial cells and in macrophages. These findings reveal a novel role for TonEBP and Akt in NF-κB activation on the onset of hypertonic challenge.
Roth
Isabelle
I
Department of Cellular Physiology and Metabolism, University of Geneva, Geneva, Switzerland.
Leroy
Valérie
V
Kwon
H Moo
HM
Martin
Pierre-Yves
PY
Féraille
Eric
E
Hasler
Udo
U
D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D056945:Hep G2 Cells; D006801:Humans; D006982:Hypertonic Solutions / Q000494:pharmacology; D020672:I-kappa B Proteins / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology; D008954:Models, Biological; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism*; D009995:Osmosis / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D051996:Transcription Factor RelA / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism*; D016211:Transforming Growth Factor alpha / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D006982:Hypertonic Solutions; D020672:I-kappa B Proteins; D016328:NF-kappa B; C118125:NFAT5 protein, human; C000606204:NFKBIA protein, human; D051996:Transcription Factor RelA; D014157:Transcription Factors; D016211:Transforming Growth Factor alpha; D014409:Tumor Necrosis Factor-alpha; D000072000:NF-KappaB Inhibitor alpha; D051057:Proto-Oncogene Proteins c-akt; D048051:p38 Mitogen-Activated Protein Kinases