TMEM33 regulates intracellular calcium homeostasis in renal tubular epithelial cells.

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.

• Authors: 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
• Journal: Nature communications (Nat Commun) Vol. 10 Issue 1 Pg. 2024 (05 02 2019) ISSN: 2041-1723 [Electronic] England
• PMID: 31048699 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• 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

Topics

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