Cystinosin is involved in Na+/H+ Exchanger 3 trafficking in the proximal tubular cells: new insights in the renal Fanconi syndrome in cystinosis

Cystinosis is a systemic lysosomal storage disease resulting from a defective CTNS gene, leading to the accumulation of cystine in all organs. Despite the ubiquitous expression of cystinosin, the renal Fanconi syndrome (FS) is the first manifestation of cystinosis that presents early in life of the patients while other complications appear years later. Additionally, the cystine reduction therapy, cysteamine, does not prevent the FS. While the matter is still unresolved, it is apparent that specific function(s) of cystinosin in the proximal tubular cells (PTCs) beyond cystine transport explain the early tubular defects in cystinosis. Here, we report a novel interaction of cystinosin with the sodium/hydrogen (Na+/H+) exchanger proteins in the endosomes in both yeast and mammalian cells. One isoform of Na+/H+ exchanger, NHE3, is a major absorptive sodium transporter at the apical membrane of the proximal tubules. Cystinosin was found to play a significant role in NHE3 subcellular localization, trafficking, and resulting sodium uptake in PTCs. Interestingly, introduction of CTNS successfully rescued these defects in CTNS-deficient PTCs, whereas CTNS-LKG, the lysosomal and plasma membrane isoform of cystinosin, did not. NHE3 mislocalization was confirmed in Ctns-/- mice and cystinosis patient kidney. Interestingly, transplantation of wild-type hematopoietic stem and progenitor cells in Ctns-/- mice restored NHE3 expression at the brush border membrane. This study uncovers a new role of cystinosin in the trafficking of NHE3 in the PTCs that is evolutionary conserved, offering new insights in the pathogenesis of the renal FS in cystinosis and potential new therapeutic avenue for this pathology.