TMEM33 regulates intracellular calcium homeostasis in renal tubular epithelial cells

Arhatte, Malika; Gunaratne, Gihan S.; El Boustany, Charbel; Kuo, Ivana Y.; Moro, C�line; Duprat, Fabrice; Plaisant, Magali; Duval, H�l�ne; 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; Honor�, Eric; Patel, Amanda

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

Citation

Arhatte, M., Gunaratne, G. S., El Boustany, C., Kuo, I. Y., Moro, C., Duprat, F., Plaisant, M., Duval, H., Li, D., Picard, N., Couvreux, A., Duranton, C., Rubera, I., Pagnotta, S., Lacas-Gervais, S., Ehrlich, B. E., Marchant, J. S., Savage, A. M., van Eeden, F. J. M., Wilkinson, R. N., …Patel, A. (2019). TMEM33 regulates intracellular calcium homeostasis in renal tubular epithelial cells. Nature Communications, 10(1), Article 2024. https://doi.org/10.1038/s41467-019-10045-y

• Journal Article Type: Article
• Acceptance Date: Apr 16, 2019
• Online Publication Date: May 2, 2019
• Publication Date: May 2, 2019
• Deposit Date: Nov 12, 2019
• Publicly Available Date: Nov 14, 2019
• Journal: Nature Communications
• Electronic ISSN: 2041-1723
• Publisher: Nature Publishing Group
• Peer Reviewed: Peer Reviewed
• Volume: 10
• Issue: 1
• Article Number: 2024
• DOI: https://doi.org/10.1038/s41467-019-10045-y
• Keywords: General Biochemistry, Genetics and Molecular Biology; General Physics and Astronomy; General Chemistry
• Public URL: https://nottingham-repository.worktribe.com/output/3230673
• Publisher URL: https://www.nature.com/articles/s41467-019-10045-y
• Contract Date: Nov 12, 2019