TMEM33 regulates intracellular calcium homeostasis in renal tubular epithelial cells

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...

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Published in:	Nature communications Vol. 10; no. 1; p. 2024
Main Authors:	Arhatte, Malika, Gunaratne, Gihan S., El Boustany, Charbel, Kuo, Ivana Y., Moro, Céline, Duprat, Fabrice, Plaisant, Magali, Duval, Hélène, Li, Dahui, Picard, Nicolas, Couvreux, Anais, Duranton, Christophe, Rubera, Isabelle, Pagnotta, Sophie, Lacas-Gervais, Sandra, Ehrlich, Barbara E., Marchant, Jonathan S., Savage, Aaron M., van Eeden, Fredericus J. M., Wilkinson, Robert N., Demolombe, Sophie, Honoré, Eric, Patel, Amanda
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 02-05-2019 Nature Publishing Group Nature Portfolio
Subjects:	13 14 14/34 631/80/86/1999 692/4022/1585/1589 692/4022/1585/4 9/74 9/97 Acute Kidney Injury - genetics Acute Kidney Injury - pathology Animals Apoptosis Calcium Calcium (intracellular) Calcium - metabolism Calcium homeostasis Cathepsins Cell Membrane - metabolism Cellular Biology Disease Models, Animal Embryo, Nonmammalian Endoplasmic reticulum Endoplasmic Reticulum - metabolism Endoplasmic Reticulum Stress Epithelial cells Epithelial Cells - cytology Epithelial Cells - metabolism Gene Knockdown Techniques HeLa Cells Homeostasis Human health and pathology Humanities and Social Sciences Humans Intracellular Ion channels Kidney diseases Kidney Tubules, Proximal - cytology Kidney Tubules, Proximal - metabolism Kidneys Life Sciences Liposomes Lysosomes - metabolism Membrane Proteins - genetics Membrane Proteins - metabolism Membrane Proteins - physiology Mice Mice, Knockout multidisciplinary Mutation Polycystic kidney Polycystic Kidney, Autosomal Dominant - genetics Polycystic Kidney, Autosomal Dominant - pathology Polycystin-2 Refilling RNA, Small Interfering - metabolism Rodents Science Science (multidisciplinary) Subcellular Processes Translocation TRPP Cation Channels - genetics TRPP Cation Channels - metabolism TRPP Cation Channels - physiology Urology and Nephrology Zebrafish Zebrafish Proteins - metabolism Zebrafish Proteins - physiology
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Summary:	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. Polycystin-2 (PC2) is an ion channel commonly found mutated in autosomal dominant polycystic kidney disease. Here Arhatte et al. identify transmembrane protein 33 (TMEM33) as a regulator of PC2 function at the endoplasmic reticulum, and find that deletion of TMEM33 protects mice from acute kidney injury.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	2041-1723 2041-1723
DOI:	10.1038/s41467-019-10045-y