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Nat Commun. 2019 May 2;10(1):2024. doi: 10.1038/s41467-019-10045-y.

TMEM33 regulates intracellular calcium homeostasis in renal tubular epithelial cells.

Author information

1
Université Côte d'Azur, Centre National de la Recherche Scientifique, Institut national de la santé et de la recherche médicale, Institut de Pharmacologie Moléculaire et Cellulaire, Labex ICST, Valbonne, 06560, France.
2
Department of Pharmacology, University of Minnesota, Minneapolis, MN, 55455, USA.
3
Cell and Molecular Physiology Stritch School of Medicine Loyola University Chicago, Maywood, IL, 60153, USA.
4
The State Key Laboratory of Pharmaceutical Biotechnology, Department of Pharmacology and Pharmacy, The University of Hong Kong, Hong Kong SAR, China.
5
Laboratory of Tissue Biology and Therapeutic Engineering, UMR 5305 CNRS, University Lyon 1, Lyon, 69367, France.
6
Université Côte d'Azur, LP2M CNRS-UMR7370, Labex ICST, Medical Faculty, Nice, 06108, France.
7
CCMA UFR Sciences, Université Côte d'Azur, Nice, 06108, France.
8
Department of Pharmacology, School of Medicine, Yale University, New Haven, CT, 06520-8066, USA.
9
Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, WI, 53226, USA.
10
Department of Infection, Immunity and Cardiovascular Disease, Medical School, University of Sheffield, Sheffield, S102TN, UK.
11
The Bateson Centre, University of Sheffield, Sheffield, S102TN, UK.
12
Department of Biomedical Science, University of Sheffield, Sheffield, S102TN, UK.
13
Université Côte d'Azur, Centre National de la Recherche Scientifique, Institut national de la santé et de la recherche médicale, Institut de Pharmacologie Moléculaire et Cellulaire, Labex ICST, Valbonne, 06560, France. honore@ipmc.cnrs.fr.

Abstract

Mutations in the polycystins cause autosomal dominant polycystic kidney disease (ADPKD). Here we show that transmembrane protein 33 (TMEM33) interacts with the ion channel polycystin-2 (PC2) at the endoplasmic reticulum (ER) membrane, enhancing its opening over the whole physiological calcium range in ER liposomes fused to planar bilayers. Consequently, TMEM33 reduces intracellular calcium content in a PC2-dependent manner, impairs lysosomal calcium refilling, causes cathepsins translocation, inhibition of autophagic flux upon ER stress, as well as sensitization to apoptosis. Invalidation of TMEM33 in the mouse exerts a potent protection against renal ER stress. By contrast, TMEM33 does not influence pkd2-dependent renal cystogenesis in the zebrafish. Together, our results identify a key role for TMEM33 in the regulation of intracellular calcium homeostasis of renal proximal convoluted tubule cells and establish a causal link between TMEM33 and acute kidney injury.

PMID:
31048699
PMCID:
PMC6497644
DOI:
10.1038/s41467-019-10045-y
[Indexed for MEDLINE]
Free PMC Article

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