Spns1 is an iron transporter essential for megalin-dependent endocytosis.

Proximal tubule endocytosis is essential to produce protein free urine as well as to regulate system wide metabolic pathways, such as the activation of Vitamin D. We have determined that the proximal tubule expresses an endolysosomal membrane protein, protein spinster homolog1 (Spns1), which engenders a novel iron conductance that is indispensable during embryonic development. Conditional knockout of Spns1 with a novel Cre-LoxP construct specific to megalin-expressing cells led to the arrest of megalin receptor-mediated endocytosis as well as dextran pinocytosis in proximal tubules. The endocytic defect was accompanied by changes in megalin phosphorylation as well as enlargement of lysosomes confirming previous findings in Drosophila and Zebrafish. The endocytic defect was also accompanied by iron overload in proximal tubules. Remarkably, iron levels regulated the Spns1 phenotypes, because feeding an iron deficient diet or mating Spns1 knockout with divalent metal transporter1 (DMT1) knockout rescued the phenotypes. Conversely, iron loading wild type mice reproduced the endocytic defect, These data demonstrate a reversible, negative feedback for apical endocytosis, and raise the possibility that regulation of endocytosis, pinocytosis, megalin activation, and organellar size and function is nutrient-responsive.