Repression of a potassium channel by nuclear hormone receptor and TGF-β signaling modulates insulin signaling in Caenorhabditis elegans.
Repression of a potassium channel by nuclear hormone receptor and TGF-β signaling modulates insulin signaling in Caenorhabditis elegans.
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DOI：
10.1371/journal.pgen.1002519
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发表时间：
2012
期刊：
影响因子：
4.5
通讯作者：
Riddle DL
中科院分区：
文献类型：
--
作者：
Park D;Jones KL;Lee H;Snutch TP;Taubert S;Riddle DL
转化生长因子 β (TGF-β) 信号通过 Smad 蛋白发挥作用，在细胞增殖、分化、凋亡和代谢中发挥重要作用。受体相关 Smads (R-Smads) 与 DNA 和其他核蛋白相互作用以调节靶基因转录。在这里，我们证明了秀丽隐杆线虫 R-Smad DAF-8 与核激素受体 NHR-69（哺乳动物肝细胞核因子 4α HNF4α 的线虫直系同源物）合作，抑制 exp-2 钾通道基因并增加胰岛素分泌。我们发现 NHR-69 在体内和体外均与 DAF-8 相关。在功能上，daf-8 nhr-69 双突变体表现出神经肽分泌和表型缺陷，与胰岛素信号传导减少一致，例如 sod-3 和 gst-10 基因表达增加和寿命更长。与单一突变体和野生型蠕虫相比，daf-8 nhr-69 突变体中编码电压门控钾通道的 exp-2 基因的表达协同增加。反过来，exp-2 选择性地作用于 ASI 神经元，抑制胰岛素样肽 DAF-28 的分泌。重要的是，exp-2突变缩短了daf-8 nhr-69双突变体的长寿命，这表明exp-2是DAF-8和NHR-69下游所必需的。最后，特别是在分泌 DAF-28 的 ASI 神经元中过度表达 NHR-69 的动物表现出昏睡、低血糖表型，可通过外源葡萄糖来挽救。我们提出了一个模型，其中 DAF-8/R-Smad 和 NHR-69 负向调节 exp-2 的转录，以促进神经元 DAF-28 的分泌，从而证明了秀丽隐杆线虫中 TGF-β 和 HNF4α 样信号传导之间的生理串扰。 NHR-69 和 DAF-8 对 exp-2 和 DAF-28 的依赖调节也提供了一种新的分子机制，有助于先前认识到的线虫中胰岛素和 TGF-β 信号传导之间的联系。所有动物都必须确保代谢稳态；如果他们不这样做，就会出现肥胖和糖尿病等疾病。为了维持葡萄糖平衡，胰岛素在高度调节和协调的过程中在葡萄糖摄入后分泌。先前的研究表明，转化生长因子β（TGF-β）信号通路调节哺乳动物的胰岛素分泌。在遗传上易驯化的线虫中，TGF-β 和胰岛素信号调节幼虫的发育和衰老，尽管胰岛素和 TGF-β 信号之间的分子联系仍知之甚少。在这项研究中，我们发现 TGF-β 信号传导成分 DAF-8 与 NHR-69（一种核激素受体）合作，控制钾通道 exp-2 的表达，进而调节胰岛素样肽的分泌。功能丧失的 exp-2 突变体表现出胰岛素分泌增加和寿命缩短，而功能获得突变体表现出胰岛素分泌减少。我们还发现，一对分泌神经肽的神经元中 nhr-69 的组织特异性表达会导致葡萄糖含量降低、胰岛素样肽水平增加和昏睡表型。由于胰岛素和 TGF-β 信号传导与多种疾病有关，因此我们的数据可能为病理生理变化的机制提供新的见解。
Transforming growth factor β (TGF-β) signaling acts through Smad proteins to play fundamental roles in cell proliferation, differentiation, apoptosis, and metabolism. The Receptor associated Smads (R-Smads) interact with DNA and other nuclear proteins to regulate target gene transcription. Here, we demonstrate that the Caenorhabditis elegans R-Smad DAF-8 partners with the nuclear hormone receptor NHR-69, a C. elegans ortholog of mammalian hepatocyte nuclear factor 4α HNF4α), to repress the exp-2 potassium channel gene and increase insulin secretion. We find that NHR-69 associates with DAF-8 both in vivo and in vitro. Functionally, daf-8 nhr-69 double mutants show defects in neuropeptide secretion and phenotypes consistent with reduced insulin signaling such as increased expression of the sod-3 and gst-10 genes and a longer life span. Expression of the exp-2 gene, encoding a voltage-gated potassium channel, is synergistically increased in daf-8 nhr-69 mutants compared to single mutants and wild-type worms. In turn, exp-2 acts selectively in the ASI neurons to repress the secretion of the insulin-like peptide DAF-28. Importantly, exp-2 mutation shortens the long life span of daf-8 nhr-69 double mutants, demonstrating that exp-2 is required downstream of DAF-8 and NHR-69. Finally, animals over-expressing NHR-69 specifically in DAF-28–secreting ASI neurons exhibit a lethargic, hypoglycemic phenotype that is rescued by exogenous glucose. We propose a model whereby DAF-8/R-Smad and NHR-69 negatively regulate the transcription of exp-2 to promote neuronal DAF-28 secretion, thus demonstrating a physiological crosstalk between TGF-β and HNF4α-like signaling in C. elegans. NHR-69 and DAF-8 dependent regulation of exp-2 and DAF-28 also provides a novel molecular mechanism that contributes to the previously recognized link between insulin and TGF-β signaling in C. elegans. All animals must ensure metabolic homeostasis; if they fail to do so, diseases such as obesity and diabetes can develop. To maintain glucose balance, insulin is secreted upon glucose intake in a highly regulated and coordinated process. Previous studies suggested that the transforming growth factor beta (TGF-β) signaling pathway regulates insulin secretion in mammals. In the genetically tractable roundworm Caenorhabditis elegans, TGF-β and insulin signaling modulate larval development and aging, although the molecular link between insulin and TGF-β signaling remains poorly understood. In this study, we show that the TGF-β signaling component DAF-8 partners with NHR-69, a nuclear hormone receptor, to control the expression of the potassium channel exp-2, which in turn modulates the secretion of an insulin-like peptide. A loss-of-function exp-2 mutant exhibits increased insulin secretion and a shortened life span, whereas a gain-of-function mutant exhibits decreased insulin secretion. We also show that tissue-specific expression of nhr-69 in a pair of neurons that secrete neuropeptides causes reduced glucose content, increased insulin-like peptide levels and a lethargic phenotype. Because insulin and TGF-β signaling are linked to numerous diseases, our data may provide novel insights into the mechanisms contributing to pathophysiological changes.
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影响因子：
9.9
作者：
通讯作者：
--
秀丽隐杆线虫中不饱和脂肪酸组成的遗传调节。
影响因子：
4.5
作者：
Brock, Trisha J.;Browse, John;Watts, Jennifer L.
通讯作者：
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影响因子：
4.5
作者：
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通讯作者：
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影响因子：
5.3
作者：
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通讯作者：
RAOSANADI, D
影响因子：
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作者：
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通讯作者：
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