Abstract
Cell surface receptors control how cells respond to their environment. Many cell surface receptors recycle from endosomes to the plasma membrane via a recently discovered pathway, which includes sorting-nexin SNX17, Retriever, WASH, and CCC complexes. Here, using mammalian cells, we discover that PIKfyve and its upstream PI3-kinase VPS34 positively regulate this pathway. VPS34 produces phosphatidylinositol 3-phosphate (PI3P), which is the substrate for PIKfyve to generate PI3,5P2. We show that PIKfyve controls recycling of cargoes including integrins, receptors that control cell migration. Furthermore, endogenous PIKfyve colocalizes with SNX17, Retriever, WASH, and CCC complexes on endosomes. Importantly, PIKfyve inhibition results in displacement of Retriever and CCC from endosomes. In addition, we show that recruitment of SNX17 is an early step and requires VPS34. These discoveries suggest that VPS34 and PIKfyve coordinate an ordered pathway to regulate recycling from endosomes and suggest how PIKfyve functions in cell migration.
Highlights
44 The functions of many cell-surface receptors are controlled in part via the regulation of their exposure to the cell surface
The localization of FAM21 to endosomes requires the generation of either phosphatidylinositol 3-phosphate 84 (PI3P), PI3,5P2 and/or phosphatidylinositol 5-phosphate (PI5P). Consistent with this finding, FAM21 binds multiple phosphorylated phosphoinositide lipids in vitro, including PI3P (Jia et al, 2010). These findings suggest that that the SNX17-Retriever-CCC-WASH recycling pathway may be ordered by a phosphoinositide cascade, where PI3P is necessary for the recruitment of SNX17 to WASH complex-containing endosomes, and PI3P-dependent recruitment of PIKfyve generates PI3,5P2 and/or PI5P which facilitates the recruitment the CCC and Retriever complexes
The studies reported here reveal that PIKfyve has roles at endosomes and has a direct role in the regulation of the SNX17-Retriever-CCC-WASH complex
Summary
44 The functions of many cell-surface receptors are controlled in part via the regulation of their exposure to the cell surface. Multiple types of receptors are regulated via endocytosis and regulated recycling. These include G-protein-coupled receptors (GPCRs), post synaptic receptors for neurotransmitters, nutrient transporters, and cell adhesion proteins. An important endosomal recycling pathway was recently discovered that is regulated in part by the Retriever complex. The Retriever complex acts with the sorting nexin, SNX17, the WASH complex, and the CCC complex which includes CCDC22 (coiled-coil domain containing 22)–CCDC93 (coiled-coil domain containing 93), and several of ten COMMD (copper metabolism MURR1 domain)-containing proteins (Chen et al, 2019; McNally and Cullen, 2018; Simonetti and Cullen, 2019; Wang et al, 2018) to regulate trafficking of cargoes and membranes from early endosomes back to the cell surface. Proteomic studies revealed that this pathway traffics over 120 cell surface proteins in
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