mTORC1-signaling switches megalin function from endocytosis to cell cycle progression

Area of Science:

• Cell Biology
• Molecular Biology
• Biochemistry

Background:

• The mechanistic target of rapamycin (mTOR) pathway is crucial for eukaryotic cell growth, regulating metabolism, translation, autophagy, and the cell cycle.
• Genetic deletion of renal mTORC1 causes Fanconi-like syndrome, characterized by reduced renal cortex, impaired tubular epithelial transport, and disrupted endocytic machinery.

Purpose of the Study:

• To identify the role of mTORC1-induced phosphorylation at serine 4577 (S4577) on the scavenger receptor megalin.
• To investigate how this phosphorylation affects megalin's function in endocytosis, cell proliferation, and cell division.

Main Methods:

• Analysis of renal mTORC1 deletion effects on megalin.
• Investigation of megalin S4577 phosphorylation site.
• Assessment of endocytosis rates and megalin-ARH interactions.
• Cell proliferation assays in wildtype, megalin-deficient, and ARH-deficient cells.
• Cell cycle analysis of megalin S4577 phosphorylation.

Main Results:

• mTORC1-induced megalin phosphorylation at S4577 reduced endocytosis rates.
• Phosphorylation increased megalin's affinity for the adaptor protein ARH, promoting cell proliferation and proteolytic processing.
• Megalin and ARH localize to the spindle pole during mitosis and are crucial for cell proliferation and cytokinesis.
• Absence of S4577 phosphorylation favors cell growth and clathrin-mediated endocytosis, while its presence promotes cell proliferation and division.

Conclusions:

• mTORC1-induced megalin S4577 phosphorylation plays a dual role: it enhances cell proliferation and division by modulating ARH interaction and localization during cytokinesis.
• Megalin and ARH are essential for membrane vesicle trafficking to the intercellular bridge pole during cytokinesis, likely for abscission.
• Nutrient availability differentially influences cell proliferation via lysosomal and non-lysosomal pathways.