Phosphoinositide regulation by the CCC complex promotes phagosome maturation and host defense

Abstract

The evolutionarily conserved COMMD/CCDC22/CCDC93 (CCC) complex regulates endolysosomal function and is required for effective antibacterial immunity. However, the mechanisms linking the CCC complex to macrophage function remain poorly understood. Using bone marrow-derived macrophages, we found that CCC deficiency impaired bacterial clearance and disrupted phagosome maturation, as evidenced by defective phagosomal membrane remodeling, reduced phagosome-endoplasmic reticulum contacts, and impaired phagosome-lysosome fusion. These defects were independent of the CCC complex interaction partner, Retriever. CCC-deficient macrophages exhibited excessive phosphatidylinositol 3-phosphate (PI(3)P) accumulation on phagosomal membranes due to markedly reduced recruitment of the PI(3)P phosphatase MTMR2. Restoration of normal PI(3)P levels rescued bactericidal activity, establishing aberrant PI(3)P regulation as the principal defect affecting CCC-deficient macrophages. These findings identify a previously unrecognized Retriever-independent function of the CCC complex in regulating PI(3)P dynamics during phagosome maturation, a process essential for efficient bacterial clearance and innate immune defense.