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NRBP1和TSC22D蛋白通过调节WNK信号通路影响远曲小管生理功能。

NRBP1 and TSC22D proteins affect distal convoluted tubule physiology through modulation of the WNK pathway.

作者信息

Magaña-Ávila Germán, Carbajal-Contreras Héctor, Amnekar Ramchandra V, Dite Toby, Téllez-Sutterlin Michelle, García-Ávila Kevin, Marquina-Castillo Brenda, Lopez-Saavedra Alejandro, Vazquez Norma, Rojas-Ortega Eréndira, Delpire Eric, Ellison David H, Alessi Dario R, Gamba Gerardo, Castañeda-Bueno María

机构信息

Department of Nephrology and Mineral Metabolism, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Tlalpan, Mexico City, Mexico.

Facultad de Medicina, Universidad Nacional Autónoma de México, Coyoacan, Mexico City, Mexico.

出版信息

Sci Adv. 2025 Jul 18;11(29):eadv2083. doi: 10.1126/sciadv.adv2083. Epub 2025 Jul 16.

DOI:10.1126/sciadv.adv2083
PMID:40668923
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12266109/
Abstract

The with-no-lysine (K) (WNK) kinases regulate processes such as cell volume and epithelial ion transport through the modulation of cation chloride cotransporters such as the NaCl cotransporter (NCC) present in the distal convoluted tubule (DCT) of the kidney. Recently, the interaction of WNKs with nuclear receptor binding protein 1 (NRBP1) and transforming growth factor-β-stimulated clone 22 domain (TSC22D) proteins was reported. Here, we explored the effect of NRBP1 and TSC22Ds on WNK signaling in vitro and in the DCT. TSC22D1.1, TSC22D2, and NRBP1 are localized in DCT WNK bodies, which are cytoplasmic biomolecular condensates associated with WNK activation. In HEK293 cells, long TSC22D isoforms and NRBP1 increase WNK4 activity. DCT-specific NRBP1-knockout mice have reduced NCC phosphorylation and activate a compensatory response. Thus, NRBP1 and long TSC22D proteins are positive modulators of WNK signaling and modulate Na reabsorption in the kidney. NRBP1 and TSC22Ds likely influence WNK signaling in other tissues, affecting various physiological processes.

摘要

无赖氨酸（K）（WNK）激酶通过调节阳离子氯化物共转运蛋白，如存在于肾远曲小管（DCT）中的氯化钠共转运蛋白（NCC），来调控细胞体积和上皮离子转运等过程。最近，有报道称WNK与核受体结合蛋白1（NRBP1）和转化生长因子-β刺激克隆22结构域（TSC22D）蛋白之间存在相互作用。在此，我们在体外和DCT中探究了NRBP1和TSC22D对WNK信号传导的影响。TSC22D1.1、TSC22D2和NRBP1定位于DCT的WNK小体中，WNK小体是与WNK激活相关的细胞质生物分子凝聚物。在HEK293细胞中，长链TSC22D异构体和NRBP1可增加WNK4的活性。DCT特异性NRBP1基因敲除小鼠的NCC磷酸化水平降低，并激活了一种代偿反应。因此，NRBP1和长链TSC22D蛋白是WNK信号传导的正向调节因子，并调节肾脏中的钠重吸收。NRBP1和TSC22D可能会影响其他组织中的WNK信号传导，从而影响各种生理过程。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/86f7/12266109/42a455483cff/sciadv.adv2083-f10.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/86f7/12266109/6f044e492493/sciadv.adv2083-f9.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/86f7/12266109/42a455483cff/sciadv.adv2083-f10.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/86f7/12266109/d33d5990f880/sciadv.adv2083-f7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/86f7/12266109/c773d05a12b8/sciadv.adv2083-f8.jpg
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Elife. 2024 Nov 25;12:RP88224. doi: 10.7554/eLife.88224.
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The TSC22D, WNK, and NRBP gene families exhibit functional buffering and evolved with Metazoa for cell volume regulation.TSC22D、WNK 和 NRBP 基因家族表现出功能缓冲作用，并与后生动物一起进化以调节细胞体积。
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Kinase Scaffold Cab39 Is Necessary for Phospho-Activation of the Thiazide-Sensitive NCC.
激酶支架蛋白 Cab39 对于噻嗪类敏感的 NCC 的磷酸化激活是必需的。
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Arginine vasopressin regulates the renal Na-Cl and Na-K-Cl cotransporters through with-no-lysine kinase 4 and inhibitor 1 phosphorylation.精氨酸血管加压素通过无赖氨酸激酶 4 和抑制剂 1 磷酸化调节肾脏钠-氯和钠-钾-氯共转运蛋白。
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Systematic transcriptional analysis of human cell lines for gene expression landscape and tumor representation.系统转录分析人类细胞系的基因表达图谱和肿瘤代表性。
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