Endocytosis mediated by an atypical CUBAM complex modulates slit diaphragm dynamics in nephrocytes

The vertebrate endocytic receptor CUBAM, consisting of three cubilin monomers complexed with a single amnionless molecule, plays a major role in protein reabsorption in the renal proximal tubule. Here, we show that Drosophila CUBAM is a tripartite complex composed of Amnionless and two cubilin paralogues, Cubilin and Cubilin2, and that it is required for nephrocyte slit diaphragm (SD) dynamics. Loss of CUBAM-mediated endocytosis induces dramatic morphological changes in nephrocytes and promotes enlarged ingressions of the external membrane and SD mislocalisation. These phenotypes result in part from an imbalance between endocytosis, which is strongly impaired in CUBAM mutants, and exocytosis in these highly active cells. Of note, rescuing receptor-mediated endocytosis by Megalin/ LRP2 or Rab5 expression only partially restores SD positioning in CUBAM mutants, suggesting a specific requirement of CUBAM in SD degradation and/or recycling. This finding and the reported expression of CUBAM in podocytes suggest a possible unexpected conserved role for this endocytic receptor in vertebrate SD remodelling.

Automated summary

The complex composed of Amnionless, Cubilin, and Cubilin2 is crucial for nephrocyte slit diaphragm (SD) dynamics in Drosophila. Loss of CUBAM-mediated endocytosis leads to dramatic morphological changes in nephrocytes and mislocalisation of SD, likely due to an imbalance between endocytosis and exocytosis. While rescuing receptor-mediated endocytosis can partially restore SD positioning in CUBAM mutants, suggesting a specific requirement of CUBAM in SD degradation and recycling.