Abstract
Protein recycling through the endolysosomal system relies on molecular assemblies that interact with cargo proteins, membranes, and effector molecules. Among them, the COMMD/CCDC22/CCDC93 (CCC) complex plays a critical role in recycling events. While CCC is closely associated with retriever, a cargo recognition complex, its mechanism of action remains unexplained. Herein we show that CCC and retriever are closely linked through sharing a common subunit (VPS35L), yet the integrity of CCC, but not retriever, is required to maintain normal endosomal levels of phosphatidylinositol-3-phosphate (PI(3)P). CCC complex depletion leads to elevated PI(3)P levels, enhanced recruitment and activation of WASH (an actin nucleation promoting factor), excess endosomal F-actin and trapping of internalized receptors. Mechanistically, we find that CCC regulates the phosphorylation and endosomal recruitment of the PI(3)P phosphatase MTMR2. Taken together, we show that the regulation of PI(3)P levels by the CCC complex is critical to protein recycling in the endosomal compartment.
Highlights
Protein recycling through the endolysosomal system relies on molecular assemblies that interact with cargo proteins, membranes, and effector molecules
We have previously reported that the CCC complex regulates the trafficking of cargoes that are retriever-independent, such as ATP7A, TGN46, and CIMPR27, suggesting that CCC and retriever are functionally distinct
Using HeLa cells generated through CRISPR/Cas[9] genome editing, we examined the trafficking of a retromer cargo protein, GLUT1, in CCC-deficient (COMMD3 and CCDC93), retrieverdeficient (VPS35L, VPS26C), and FAM45A-deficient cells
Summary
Protein recycling through the endolysosomal system relies on molecular assemblies that interact with cargo proteins, membranes, and effector molecules. The levels of cell surface receptors and transporters in eukaryotic cells are critical for maintaining major physiological functions, including uptake of nutrients, electrolyte transport, growth factor signaling, cell migration, and cell adhesion Once internalized, these plasma membrane proteins can be delivered to lysosomes for degradation, transported to the transGolgi network (TGN) or recycled back to the plasma membrane[1]. VPS26C and VPS35L are homologous to the retromer subunits, VPS26A/B and VPS35, respectively, only VPS26C interacts with the C-terminal tail of SNX17 This factor in turn uses its FERM domain to couple to NPxY/NxxY motif-containing cargo proteins such as β1 integrin, EGFR, LDLR, and LRP1 to ensure recycling back to the plasma membrane[21,22,23,24,25,26]. Previous studies have identified that the CCC protein complex, which consists of CCDC22, CCDC93, and any of the 10
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call