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. [email protected].

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