Control of the Renal WNK Signaling Pathway by Phase Transitions
通过相变控制肾脏 WNK 信号通路
基本信息
- 批准号:10753772
- 负责人:
- 金额:$ 65.63万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2014
- 资助国家:美国
- 起止时间:2014-04-01 至 2027-05-31
- 项目状态:未结题
- 来源:
- 关键词:AmplifiersApicalBehaviorBiologyBypassC-terminalCCL14 geneCationsCell LineCell VolumesCellsChargeChloridesCoupledCrowdingDietDiseaseDistalDistal convoluted renal tubule structureDrosophila genusEnvironmentEnzymesEpithelial CellsEpitheliumFamilyGenesHealthHomeostasisHypertensionHypokalemiaIon TransportIonic StrengthsIonsKidneyKnowledgeLearningLiquid substanceLysineMalpighian TubulesMeasuresMediatingMembraneModelingMolecularMusNephronsPathway interactionsPhasePhase TransitionPhosphorylationPhosphotransferasesPhysical condensationPhysiologicalPhysiologyPotassiumProcessProtein IsoformsProteinsRecoveryRegulationRenal tubular acidosisRenal tubule structureReportingRoleSignal PathwaySignal TransductionSodiumSodium ChlorideStressStructureTestingThinkingTubular formationWorkbiological adaptation to stressblood pressure regulationcell waterchloride-cotransporter potassiumdisease-causing mutationextracellularfallsfamilial hyperkalemic hypertensionhyperkalemiaimaging modalityinnovationlenslive cell imagingmouse modelmutantnovelrenal epitheliumresponsesalt sensitivesalt sensitive hypertensionscaffoldsensorsymporterthiazide
项目摘要
With-No-Lysine (WNK) kinases are ubiquitous regulators of cation chloride cotransport. Disease-causing
mutations of these kinases cause salt-sensitive hypertension, hyperkalemia, and type IV renal tubular acidosis,
indicating their importance in kidney tubular function. Despite advances in our understanding of the WNK
signaling pathway, fundamental questions remain. The most significant knowledge gap concerns the mechanism
by which WNK kinases are activated by cell volume changes. Recently, we reported that the “Long” kinase-
active form of WNK1 (L-WNK1) activates within biomolecular condensates during hypertonic cell shrinkage.
These membraneless liquid-like assemblies form via phase separation, induced by macromolecular crowding.
This process bypasses the inhibitory effects of increased intracellular chloride caused by exosmosis, rapidly
triggering net ion influx and volume recovery. The importance of protein phase behavior in WNK signaling is
further supported by our work in distal convoluted tubule (DCT). In this nephron segment, KS-WNK1, a truncated
WNK1 isoform that likely functions as a scaffold for phase transitions, drives the formation of specialized
biomolecular condensates termed WNK bodies. These structures form in the DCT during hypokalemia, and their
presence correlates with the phosphorylation-dependent activation of the thiazide-sensitive NaCl cotransporter
NCC. This suggests a relationship between extracellular K+ sensing, WNK phase behavior, and distal nephron
salt handling. Here, we will test the hypothesis that WNK kinases undergo phase transitions to respond to their
environment and amplify ion transport. Aim 1 will determine how phosphorylation-dependent charge switching
of the L-WNK1 C-terminus activates ion flux and volume recovery. Aim 2 will investigate how intracellular chloride
and crowding-induced phase separation interact to control WNK activity. Aim 3 will determine if DCT WNK body
condensates are necessary for NCC activation, and whether disrupting WNK bodies reverses Familial
Hyperkalemic Hypertension. This proposal combines the complementary expertise of two leaders in the WNK
signaling field. The MPIs will use a multifaceted and innovative approach that includes mouse models of altered
WNK body function, newly developed live cell imaging methods, and Drosophila Malpighian tubule, a tractable
and genetically malleable model of the nephron. The discovery that WNK kinases function as physiological
crowding sensors marks a conceptual advance that has enabled fresh thinking and logical testable hypotheses,
viewed through the lens of condensate biology. Thus, we expect that the knowledge gained from these studies
will transform our understanding of epithelial cell volume regulation and ion transport, while testing the functional
contributions of biomolecular condensates to kidney physiology and disease.
与-非赖氨酸(WNK)激酶是阳离子氯化物共转运的普遍调节因子。致病
这些激酶的突变会导致盐敏感型高血压、高钾血症和IV型肾小管性酸中毒,
提示它们在肾小管功能中的重要性。尽管我们对WNK的理解有所进步
信号途径,根本问题仍然存在。最显著的知识差距与机制有关
WNK激酶通过细胞体积变化而被激活。最近,我们报道了“长”的激酶-
活性形式的WNK1(L-WNK1)在高渗细胞收缩过程中在生物分子凝聚体中激活。
这些无膜的类液体集合体是通过大分子拥挤诱导的相分离形成的。
这一过程迅速绕过了外渗引起的细胞内氯化物增加的抑制效应。
触发净离子内流和容量恢复。蛋白质时相行为在WNK信号中的重要性是
我们在远端曲管(DCT)的工作进一步支持了这一点。在这个肾单位节段,KS-WNK1,一个截断的
WNK1亚型可能作为相变的支架,驱动特化的形成
生物分子凝聚体称为WNK小体。这些结构在低钾血症时在DCT中形成,并且它们的
硫氮化物敏感的氯化钠共转运体的磷酸化激活与存在相关
NCC。这表明细胞外K+感觉、WNK时相行为和远端肾单位之间存在联系。
食盐处理。在这里,我们将测试WNK激酶经历相变以响应其
环境和放大离子运输。目标1将确定依赖于磷酸化的电荷转换如何
L-WNK1C-末端的激活离子通量和体积恢复。AIM 2将研究细胞内氯是如何
拥挤诱导的相分离相互作用,控制WNK活性。目标3将确定DCT WNK身体
凝结物是NCC激活所必需的,以及破坏WNK小体是否会逆转家族史
高血钾性高血压。这项建议结合了世界自然资源中心两位领导人的互补专长。
信令字段。MPI将使用一种多方面的创新方法,其中包括更改的鼠标模型
WNK身体功能,新开发的活细胞成像方法,以及果蝇马氏管,一种易于处理的
和遗传上可延展的肾单位模型。WNK激酶的生理功能的发现
拥挤的传感器标志着概念上的进步,使新的思维和逻辑上可测试的假设成为可能,
从凝聚态生物学的角度来看。因此,我们预计从这些研究中获得的知识
将改变我们对上皮细胞体积调节和离子转运的理解,同时测试功能
生物分子缩合物对肾脏生理和疾病的贡献。
项目成果
期刊论文数量(2)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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AYLIN RACHEL RODAN其他文献
AYLIN RACHEL RODAN的其他文献
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{{ truncateString('AYLIN RACHEL RODAN', 18)}}的其他基金
Regulation of WNK signaling by potassium and Mo25: structure, function and physiology
钾和 Mo25 对 WNK 信号传导的调节:结构、功能和生理学
- 批准号:
10474505 - 财政年份:2016
- 资助金额:
$ 65.63万 - 项目类别:
Probing intracellular Cl- in a WNK signaling-dependent transporting epithelium
探测 WNK 信号依赖性转运上皮中的细胞内 Cl-
- 批准号:
9436184 - 财政年份:2016
- 资助金额:
$ 65.63万 - 项目类别:
Molecular mechanisms of WNK-SPAK/OSR1 regulation of transepithelial ion transport in the Drosophila renal tubule
WNK-SPAK/OSR1调节果蝇肾小管跨上皮离子转运的分子机制
- 批准号:
9352322 - 财政年份:2016
- 资助金额:
$ 65.63万 - 项目类别:
Molecular mechanisms of WNK-SPAK/OSR1 regulation of transepithelial ion transport in the Drosophila renal tubule
WNK-SPAK/OSR1调节果蝇肾小管跨上皮离子转运的分子机制
- 批准号:
9480212 - 财政年份:2016
- 资助金额:
$ 65.63万 - 项目类别:
Regulation of WNK signaling by potassium and Mo25: structure, function and physiology
钾和 Mo25 对 WNK 信号传导的调节:结构、功能和生理学
- 批准号:
10677829 - 财政年份:2016
- 资助金额:
$ 65.63万 - 项目类别:
Regulation of WNK signaling by potassium and Mo25: structure, function and physiology
钾和 Mo25 对 WNK 信号传导的调节:结构、功能和生理学
- 批准号:
10298458 - 财政年份:2016
- 资助金额:
$ 65.63万 - 项目类别:
Probing intracellular Cl- in a WNK signaling-dependent transporting epithelium
探测 WNK 信号依赖性转运上皮中的细胞内 Cl-
- 批准号:
8950649 - 财政年份:2015
- 资助金额:
$ 65.63万 - 项目类别:
Using Drosophila to understand WNK and SPAK/OSR1 regulation of SLC12 cotransporte
利用果蝇了解 WNK 和 SPAK/OSR1 对 SLC12 共转运蛋白的调控
- 批准号:
8450886 - 财政年份:2011
- 资助金额:
$ 65.63万 - 项目类别:
Using Drosophila to understand WNK and SPAK/OSR1 regulation of SLC12 cotransporte
利用果蝇了解 WNK 和 SPAK/OSR1 对 SLC12 共转运蛋白的调控
- 批准号:
8088672 - 财政年份:2011
- 资助金额:
$ 65.63万 - 项目类别:
WNK & SPAK/OSR1 regulation of SLC12 cotransporters in Drosophila
温克
- 批准号:
8235050 - 财政年份:2011
- 资助金额:
$ 65.63万 - 项目类别:
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