TMEM33 and polycystic kidney disease – TMEM33

Autosomal dominant polycystic kidney disease (ADPKD), the most common monogenic disease in humans, is a multisystem disorder characterized by renal and extrarenal cysts, as well as severe cardiovascular abnormalities including cerebral aneurysms and hypertension. ADPKD is caused by mutations in the PKD1 or PKD2 genes, encoding the polycystins PC1 and PC2 (also called TRPP2), respectively.
Using a proteomic strategy, we previously identified novel PC2 interacting proteins in arterial myocytes . Among those putative partners, we found several endoplasmic/sarcoplasmic reticulum (ER) transmembrane proteins either implicated in the regulation of intracellular Ca2+ homeostasis such as the IP3R types 1 and 3 or of as yet unknown function in mammals, including TMEM33.
TMEM33 is conserved during evolution and two paralogs, termed Pom33 and Per33, have been recently characterized in the yeast S.cerevisiae. Pom33 is enriched at nuclear pores, whereas Per33 showed a typical ER distribution. In Schizosaccharomyces pombe, the unique TMEM33 ortholog, Tts1p was shown to contribute to the maintenance of the cortical ER network. So far, no information is available about the function of the mammalian TMEM33, which is abundantly expressed in both the kidney and the vasculature.
In this proposal, we aim to investigate the role of the TMEM33/PC2 complex in the regulation of intracellular Ca2+ homeostasis in renal tubular epithelial cells and arterial myocytes, both cell types being affected in ADPKD. Our preliminary data indicate that TMEM33 controls PC2 calcium channel activity in the ER/SR. Moreover, our recent findings show that the knock-down of TMEM33 in zebra fish induces kidney cysts and arterial defects. The physiopathological role of TMEM33 will be further assessed in a mouse knock-out model, focusing on kidney cystogenesis and arterial aneurysm formation. These findings will enhance our understanding of the regulation of intracellular calcium homeostasis and will provide information about the molecular basis of ADPKD.