The CCC complex directs phagosomal maturation and bactericidal activity in macrophages through PI(3)P regulation

Phagocytosis, the process by which immune cells ingest and eliminate invading pathogens, is essential for host defense. During this process, phagosomes mature through the recruitment of several effector proteins, such as V-ATPases, proteases, and other enzymes, to effectively degrade the pathogen they contain. These maturation events are thought to be regulated by phosphoinositide transitions, which facilitate phagosome-lysosome fusion. The evolutionarily conserved COMMD/CCDC22/CCDC93 (CCC) complex regulates endosomal recycling and has been identified on phagosomes. Nevertheless, its role in phagosome maturation has not been previously demonstrated. Here, we show that the CCC complex is essential for efficient bacterial clearance by bone marrow-derived macrophages (BMDMs) and the temporal remodeling of phagosomal protein composition. We further reveal that the CCC complex regulates phagosome-lysosome fusion and identify excessive phosphatidylinositol-3-phosphate (PI(3)P) accumulation on phagosome membranes in CCC deficient states, leading to impaired phagosome function. Collectively, our findings uncover a previously unknown role for the CCC complex in innate immune defense.