IPIP27A cooperates with OCRL to support endocytic traffic in the zebrafish pronephric tubule

Endocytosis is a fundamentally important process through which material is internalized into cells from the extracellular environment. In the renal proximal tubule, endocytosis of the abundant scavenger receptor megalin and its co-receptor cubilin play a vital role in retrieving low molecular weight proteins from the renal filtrate. Although we know much about megalin and its ligands, the machinery and mechanisms by which the receptor is trafficked through the endosomal system remain poorly defined. In this study, we show that inositol phosphatase interacting protein of 27 kDa (Ipip27A), an interacting partner of the Lowe syndrome protein oculocerebrorenal syndrome of Lowe (OCRL), is required for endocytic traffic of megalin within the proximal renal tubule of zebrafish larvae. Knockout of Ipip27A phenocopies the endocytic phenotype seen upon loss of OCRL, with a deficit in uptake of both fluid-phase and protein cargo, which is accompanied by a reduction in megalin abundance and altered endosome morphology. Rescue and co-depletion experiments indicate that Ipip27A functions together with OCRL to support proximal tubule endocytosis. The results therefore identify Ipip27A as a new player in endocytic traffic in the proximal tubule in vivo and support the view that defective endocytosis underlies the renal tubulopathy in Lowe syndrome and Dent-2 disease.

Automated summary

This study reveals that the 27 kDa protein Ipip27A is essential for endocytic trafficking of megalin in the proximal renal tubule of zebrafish larvae and functions together with OCRL in supporting proximal tubule endocytosis. Knockout of Ipip27A leads to endocytic phenotype similar to the loss of OCRL, with reduced uptake of fluid-phase and protein cargo, decreased megalin abundance, and altered endosome morphology. These findings identify Ipip27A as a new player in endocytic traffic in the proximal tubule and suggest that defective endocytosis may underlie renal tubulopathy in Lowe syndrome and Dent-2 disease.