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

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

doi:10.1126/sciadv.adv2083

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

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

MRC PPU

Research output: Contribution to journal › Article › peer-review

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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.

Original language	English
Article number	eadv2083
Number of pages	17
Journal	Science Advances
Volume	11
Issue number	29
DOIs	https://doi.org/10.1126/sciadv.adv2083
Publication status	Published - 18 Jul 2025

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Magaña-Ávila, G., Carbajal-Contreras, H., Amnekar, R. V., Dite, T., Téllez-Sutterlin, M., García-Ávila, K., Marquina-Castillo, B., Lopez-Saavedra, A., Vazquez, N., Rojas-Ortega, E., Delpire, E., Ellison, D. H., Alessi, D. R., Gamba, G., & Castañeda-Bueno, M. (2025). NRBP1 and TSC22D proteins affect distal convoluted tubule physiology through modulation of the WNK pathway. Science Advances, 11(29), Article eadv2083. https://doi.org/10.1126/sciadv.adv2083

@article{b53c3a5e73174435bebf4c6795362325,

title = "NRBP1 and TSC22D proteins affect distal convoluted tubule physiology through modulation of the WNK pathway",

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.",

author = "Germ{\'a}n Maga{\~n}a-{\'A}vila and H{\'e}ctor Carbajal-Contreras and Amnekar, \{Ramchandra V.\} and Toby Dite and Michelle T{\'e}llez-Sutterlin and Kevin Garc{\'i}a-{\'A}vila and Brenda Marquina-Castillo and Alejandro Lopez-Saavedra and Norma Vazquez and Er{\'e}ndira Rojas-Ortega and Eric Delpire and Ellison, \{David H.\} and Alessi, \{Dario R.\} and Gerardo Gamba and Mar{\'i}a Casta{\~n}eda-Bueno",

note = "Publisher Copyright: Copyright {\textcopyright} 2025 The Authors, some rights reserved;",

year = "2025",

month = jul,

day = "18",

doi = "10.1126/sciadv.adv2083",

language = "English",

volume = "11",

journal = "Science Advances",

issn = "2375-2548",

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Magaña-Ávila, G, Carbajal-Contreras, H, Amnekar, RV, Dite, T, Téllez-Sutterlin, M, García-Ávila, K, Marquina-Castillo, B, Lopez-Saavedra, A, Vazquez, N, Rojas-Ortega, E, Delpire, E, Ellison, DH, Alessi, DR, Gamba, G & Castañeda-Bueno, M 2025, 'NRBP1 and TSC22D proteins affect distal convoluted tubule physiology through modulation of the WNK pathway', Science Advances, vol. 11, no. 29, eadv2083. https://doi.org/10.1126/sciadv.adv2083

TY - JOUR

T1 - NRBP1 and TSC22D proteins affect distal convoluted tubule physiology through modulation of the WNK pathway

AU - Magaña-Ávila, Germán

AU - Carbajal-Contreras, Héctor

AU - Amnekar, Ramchandra V.

AU - Dite, Toby

AU - Téllez-Sutterlin, Michelle

AU - García-Ávila, Kevin

AU - Marquina-Castillo, Brenda

AU - Lopez-Saavedra, Alejandro

AU - Vazquez, Norma

AU - Rojas-Ortega, Eréndira

AU - Delpire, Eric

AU - Ellison, David H.

AU - Alessi, Dario R.

AU - Gamba, Gerardo

AU - Castañeda-Bueno, María

PY - 2025/7/18

Y1 - 2025/7/18

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/105011883641

U2 - 10.1126/sciadv.adv2083

DO - 10.1126/sciadv.adv2083

M3 - Article

C2 - 40668923

AN - SCOPUS:105011883641

SN - 2375-2548

VL - 11

JO - Science Advances

JF - Science Advances

IS - 29

M1 - eadv2083

ER -

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

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