SEC22B modulates ClC-5/TMEM9 trafficking and serves as a urinary marker for Dent’s Disease
5 affiliations
- 1Renal Physiopathology Group, Vall d’Hebron Research Institute (VHIR), Barcelona, Spain
- 2Proteomics Core Facility, EMBL Heidelberg, Heidelberg, Germany
- 3Pediatric Nephrology Department, Vall d’Hebron University Hospital (HUVH), Barcelona, Spain
- 4Pediatrics Department, School of Medicine, Autonomous University of Barcelona (UAB), Bellaterra, Spain
- 5Biochemistry and Molecular Biology Department, School of Medicine, Autonomous University of Barcelona (UAB), Bellaterra, Spain
Abstract
Background: The Cl−/H+ antiporter ClC-5 is a key regulator of renal proximal tubule function, primarily by controlling endosomal acidification. Loss-of-function mutations in ClC-5 cause Dent’s Disease type 1 (DD1), a rare renal tubulopathy that progresses to kidney failure with significant phenotypic heterogeneity. The molecular mechanisms linking specific ClC-5 variants to this clinical variability, however, remain incompletely understood.
Methods: We investigated three ClC-5 pathogenic variants (I524K, E527D and V523∆) using renal proximal tubule epithelial cells (RPTEC/TERT1). An interactome analysis was performed to identify novel ClC-5 protein partners. The functional role of the identified interactor, SEC22B, was evaluated in RPTEC cells depleted of this protein, focusing on its impact on ClC-5 trafficking, endolysosomal pH, and epithelial differentiation. Finally, SEC22B levels were quantified in urinary extracellular vesicles (uEVs) from a DD1 patients’ cohort.
Results: ClC-5 mutants exhibited distinct intracellular retention patterns, all of which resulted in altered endolysosomal pH and disrupted secretory pathway organization. We identified the R-SNARE SEC22B as a novel partner that specifically interacts with wild-type ClC-5, but not DD1 mutants. SEC22B deletion impaired ClC-5 trafficking, leading to its retention at the Golgi and endosomes. This loss of SEC22B recapitulated key DD1 cellular hallmarks, including defective endocytosis, epithelial dedifferentiation, and altered secretory pathway. Intriguingly, SEC22B depletion paradoxically enhanced endosomal acidification. We resolve this mechanism by showing that SEC22B also regulates the trafficking of TMEM9, a known ClC-5 inhibitor that associates with both wild-type and mutant ClC-5 forms. Thus, our findings strongly suggest that SEC22B is essential for the proper sorting of the ClC-5/TMEM9 complex. Clinically, we observed elevated SEC22B levels in urinary extracellular vesicles from DD1 patients.
Conclusions: Our findings establish SEC22B as a critical modifier of DD1 pathophysiology and a promising non-invasive biomarker for monitoring the disease.
Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1186/s12967-026-08760-4.
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BibTeX
@article{duran2026sec22b,
title = {{SEC22B modulates ClC-5/TMEM9 trafficking and serves as a urinary marker for Dent’s Disease}},
author = {M. Durán and A. Casal-Pardo and E. Sarró and F. Stein and S. Cases-Palau and C. Garcia and G. Ariceta and A. Meseguer and G. Cantero-Recasens},
journal = {Journal of Translational Medicine},
year = {2026},
month = aug,
doi = {10.1186/s12967-026-08760-4},
url = {https://doi.org/10.1186/s12967-026-08760-4},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - SEC22B modulates ClC-5/TMEM9 trafficking and serves as a urinary marker for Dent’s Disease
AU - M. Durán
AU - A. Casal-Pardo
AU - E. Sarró
AU - F. Stein
AU - S. Cases-Palau
AU - C. Garcia
AU - G. Ariceta
AU - A. Meseguer
AU - G. Cantero-Recasens
PY - 2026
DA - 2026/08/07
JO - Journal of Translational Medicine
DO - 10.1186/s12967-026-08760-4
UR - https://doi.org/10.1186/s12967-026-08760-4
AB - Background: The Cl−/H+ antiporter ClC-5 is a key regulator of renal proximal tubule function, primarily by controlling endosomal acidification. Loss-of-function mutations in ClC-5 cause Dent’s Disease type 1 (DD1), a rare renal tubulopathy that progresses to kidney failure with significant phenotypic heterogeneity. The molecular mechanisms linking specific ClC-5 variants to this clinical variability, however, remain incompletely understood. Methods: We investigated three ClC-5 pathogenic variants (I524K, E527D and V523∆) using renal proximal tubule epithelial cells (RPTEC/TERT1). An interactome analysis was performed to identify novel ClC-5 protein partners. The functional role of the identified interactor, SEC22B, was evaluated in RPTEC cells depleted of this protein, focusing on its impact on ClC-5 trafficking, endolysosomal pH, and epithelial differentiation. Finally, SEC22B levels were quantified in urinary extracellular vesicles (uEVs) from a DD1 patients’ cohort. Results: ClC-5 mutants exhibited distinct intracellular retention patterns, all of which resulted in altered endolysosomal pH and disrupted secretory pathway organization. We identified the R-SNARE SEC22B as a novel partner that specifically interacts with wild-type ClC-5, but not DD1 mutants. SEC22B deletion impaired ClC-5 trafficking, leading to its retention at the Golgi and endosomes. This loss of SEC22B recapitulated key DD1 cellular hallmarks, including defective endocytosis, epithelial dedifferentiation, and altered secretory pathway. Intriguingly, SEC22B depletion paradoxically enhanced endosomal acidification. We resolve this mechanism by showing that SEC22B also regulates the trafficking of TMEM9, a known ClC-5 inhibitor that associates with both wild-type and mutant ClC-5 forms. Thus, our findings strongly suggest that SEC22B is essential for the proper sorting of the ClC-5/TMEM9 complex. Clinically, we observed elevated SEC22B levels in urinary extracellular vesicles from DD1 patients. Conclusions: Our findings establish SEC22B as a critical modifier of DD1 pathophysiology and a promising non-invasive biomarker for monitoring the disease. Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1186/s12967-026-08760-4.
SN - 1479-5876
ER -