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- Title
TMEM33 regulates intracellular calcium homeostasis in renal tubular epithelial cells.
- 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.
- 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. 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.
- Publication
Nature Communications, 2019, Vol 10, Issue 1, pN.PAG
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-019-10045-y