Cystinosin regulates Na+/H+ exchanger 3 trafficking and function in kidney proximal tubular cells

Abstract Cystinosis is a systemic lysosomal storage disease resulting from mutations in the CTNS gene encoding the lysosomal cystine transporter cystinosin, leading to cystine accumulation in all organs. Despite cystinosin’s ubiquitous expression, renal Fanconi syndrome (FS) is the first clinical manifestation of cystinosis, which is not prevented by cystine reduction therapy with cysteamine. Here, we report a novel interaction of cystinosin and sodium/hydrogen (Na+/H+) exchanger proteins in the endosomes of yeast and mammalian cells. NHE3 is a major absorptive sodium transporter at the apical membrane of proximal tubular cells (PTCs). Cystinosin is required for the correct subcellular localization and trafficking of NHE3 and for sodium uptake. Introducing CTNS successfully rescues these defects in CTNS- deficient PTCs, whereas CTNS-LKG, encoding the lysosomal and plasma membrane isoform of cystinosin, did not. NHE3 mislocalization was confirmed in Ctns −/− mice and cystinosis patient kidney. Transplantation of wild-type hematopoietic stem and progenitor cells in Ctns −/− mice restores NHE3 expression at the brush border membrane and improves FS-related phenotypes. This study uncovers an evolutionary conserved novel role of cystinosin in NHE3 trafficking, offering insights into FS pathogenesis and potential new therapeutic avenues.