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

Germán Magaña-Ávila; Héctor Carbajal-Contreras; Ramchandra 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 Alessi; Gerardo Gamba; Maria Castañeda-Bueno

doi:10.1126/sciadv.adv2083

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

Germán Magaña-Ávila
, Héctor Carbajal-Contreras
, Ramchandra 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 Alessi
, Gerardo Gamba
, Maria Castañeda-Bueno (Lead / Corresponding author)

MRC PPU

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

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Abstract

The With No lysine (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, impacting various physiological processes.

Original language	English
Article number	eadv2083
Number of pages	18
Journal	Science Advances
Volume	11
Issue number	29
DOIs	https://doi.org/10.1126/sciadv.adv2083
Publication status	Published - 16 Jul 2025

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10.1126/sciadv.adv2083Licence: CC BY

Final Published VersionFinal published version, 4.99 MBLicence: CC BY

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Magaña-Ávila, G., Carbajal-Contreras, H., Amnekar, R., 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., Gamba, G., & Castañeda-Bueno, M. (2025). NRBP1 and TSC22D proteins impact distal convoluted tubule physiology through modulation of the WNK pathway. Science Advances, 11(29), Article eadv2083. https://doi.org/10.1126/sciadv.adv2083

@article{9f1218b1e5484c21b80346d79da67410,

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

abstract = "The With No lysine (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, impacting various physiological processes.",

author = "Germ{\'a}n Maga{\~n}a-{\'A}vila and H{\'e}ctor Carbajal-Contreras and Ramchandra Amnekar 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 Dario Alessi and Gerardo Gamba and Maria Casta{\~n}eda-Bueno",

note = "Copyright: {\textcopyright} 2025 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution License 4.0 (CC BY).",

year = "2025",

month = jul,

day = "16",

doi = "10.1126/sciadv.adv2083",

language = "English",

volume = "11",

journal = "Science Advances",

issn = "2375-2548",

publisher = "American Association for the Advancement of Science",

number = "29",

}

Magaña-Ávila, G, Carbajal-Contreras, H, Amnekar, R, Dite, T, Téllez-Sutterlin, M, García-Ávila, K, Marquina-Castillo, B, Lopez-Saavedra, A, Vazquez, N, Rojas-Ortega, E, Delpire, E, Ellison, DH, Alessi, D, Gamba, G & Castañeda-Bueno, M 2025, 'NRBP1 and TSC22D proteins impact 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 impact distal convoluted tubule physiology through modulation of the WNK pathway

AU - Magaña-Ávila, Germán

AU - Carbajal-Contreras, Héctor

AU - Amnekar, Ramchandra

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

AU - Gamba, Gerardo

AU - Castañeda-Bueno, Maria

N1 - Copyright: © 2025 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution License 4.0 (CC BY).

PY - 2025/7/16

Y1 - 2025/7/16

N2 - The With No lysine (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, impacting various physiological processes.

AB - The With No lysine (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, impacting various physiological processes.

U2 - 10.1126/sciadv.adv2083

DO - 10.1126/sciadv.adv2083

M3 - Article

SN - 2375-2548

VL - 11

JO - Science Advances

JF - Science Advances

IS - 29

M1 - eadv2083

ER -

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

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