Endosomal PI(3) P regulation by the COMMD/CCDC22/CCDC93 (CCC) complex controls membrane protein recycling

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.