TMEM33 regulates intracellular calcium homeostasis in renal tubular epithelial cells

Malika Arhatte; Gihan S Gunaratne; Charbel El Boustany; Ivana Y Kuo; Céline Moro; Fabrice Duprat; Magali Plaisant; Hélène Duval; Dahui Li; Nicolas Picard; Anais Couvreux; Christophe Duranton; Isabelle Rubera; Sophie Pagnotta; Sandra Lacas-Gervais; Barbara E Ehrlich; Jonathan S Marchant; Aaron M Savage; Fredericus J M van Eeden; Robert N Wilkinson; Sophie Demolombe; Eric Honoré; Amanda Patel

doi:10.1038/s41467-019-10045-y

TMEM33 regulates intracellular calcium homeostasis in renal tubular epithelial cells

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

Authors

Malika Arhatte¹, Gihan S Gunaratne², Charbel El Boustany¹, Ivana Y Kuo³, Céline Moro¹, Fabrice Duprat¹, Magali Plaisant¹, Hélène Duval¹, Dahui Li⁴, Nicolas Picard⁵, Anais Couvreux¹, Christophe Duranton⁶, Isabelle Rubera⁶, Sophie Pagnotta⁷, Sandra Lacas-Gervais⁷, Barbara E Ehrlich⁸, Jonathan S Marchant⁹, Aaron M Savage^{10

11}, Fredericus J M van Eeden^{11

12}, Robert N Wilkinson^{10

11}, Sophie Demolombe¹, Eric Honoré¹³, Amanda Patel¹

Affiliations

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Acute Kidney Injury / genetics
Acute Kidney Injury / pathology*
Animals
Calcium / metabolism*
Cell Membrane / metabolism
Disease Models, Animal
Embryo, Nonmammalian
Endoplasmic Reticulum / metabolism
Endoplasmic Reticulum Stress
Epithelial Cells / cytology
Epithelial Cells / metabolism
Gene Knockdown Techniques
HeLa Cells
Humans
Kidney Tubules, Proximal / cytology
Kidney Tubules, Proximal / metabolism*
Lysosomes / metabolism
Membrane Proteins / genetics
Membrane Proteins / metabolism*
Membrane Proteins / physiology
Mice
Mice, Knockout
Mutation
Polycystic Kidney, Autosomal Dominant / genetics
Polycystic Kidney, Autosomal Dominant / pathology
RNA, Small Interfering / metabolism
TRPP Cation Channels / genetics
TRPP Cation Channels / metabolism*
TRPP Cation Channels / physiology
Zebrafish
Zebrafish Proteins / metabolism*
Zebrafish Proteins / physiology

Substances

Membrane Proteins
PKD2 protein, zebrafish
RNA, Small Interfering
TRPP Cation Channels
Tmem33 protein, mouse
Zebrafish Proteins
polycystic kidney disease 2 protein
tmem33 protein, zebrafish
Calcium

Abstract

Publication types

MeSH terms

Substances

Grants and funding