Osmoprotective transcription factor NFAT5/TonEBP modulates nuclear factor-kappaB activity.
Osmoprotective transcription factor NFAT5/TonEBP modulates nuclear factor-kappaB activity.
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DOI：
10.1091/mbc.e10-02-0133
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发表时间：
2010-10-01
影响因子：
3.3
通讯作者：
Hasler U
中科院分区：
文献类型：
--
作者：
Roth I;Leroy V;Kwon HM;Martin PY;Féraille E;Hasler U
张力反应结合蛋白（TonEBP）是一种在细胞膜保护中起关键作用的转录因子。在这里，我们证明了在高渗刺激开始时促存活NF-κ B活性的增强，这取决于p38激酶和Akt依赖的p65-TonEBP复合物的形成，该复合物结合NF-κ B反应基因的元件。张力响应结合蛋白（TonEBP或NFAT 5）是一种广泛表达的转录因子，其活性受细胞外张力调节。TonEBP通过与抵消细胞收缩有害影响的基因的渗透反应元件/TonE元件结合，在细胞保护中起关键作用。在这里，我们表明，除了这种“经典”的刺激，TonEBP通过增强核因子-κB（NF-κB）活性保护细胞免受高渗。我们发现高渗可增强脂多糖对NF-κB的刺激作用，但对肿瘤坏死因子-α无此作用，我们还证实了高渗和转化生长因子-α引起的蛋白激酶B（Akt）依赖性信号转导途径的重叠。高渗性激活p38激酶和下游Akt激活在TonEBP活性、IκBα降解和p65核转位中起关键作用。TonEBP不影响后两种事件，并且本身对NF-κB信号传导不敏感。相反，我们揭示了TonEBP和p65之间的张力依赖性相互作用，并表明NF-κB-TonEBP复合物与NF-κ B反应基因的κB元件结合后，NF-κ B B活性显著增强。我们证明了TonEBP和Akt在肾集合管上皮细胞和巨噬细胞中的关键作用。这些发现揭示了TonEBP和Akt在高渗刺激开始时NF-κB活化中的新作用。
Tonicity responsive binding protein (TonEBP) is a transcription factor that plays a key role in osmoprotection. Here, we demonstrate enhanced activity of prosurvival NF-κB—at the onset of hypertonic challenge that depends on p38 kinase—and Akt-dependent formation of p65-TonEBP complexes that bind to elements of NF-κB-responsive genes. 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.