Phagocytosis, the regulated uptake of large particles (>0.5 μm in diameter), is essential for tissue homeostasis and is also an early, critical component of the innate immune response. Phagocytosis can be conceptually divided into three stages: phagosome, formation, maturation, and resolution. Each of these involves multiple reactions that require exquisite spatial and temporal orchestration. The molecular events underlying these stages are being unraveled and the current state of knowledge is briefly summarized in this article.

Summary Phagocytosis is required for a broad range of physiological functions, from pathogen defense to tissue homeostasis, but mechanisms required for phagocytosis of diverse substrates remain incompletely understood. Here, we develop a rapid magnet-based phenotypic screening strategy, and perform eight genome-wide CRISPR screens in human cells to identify genes regulating phagocytosis of distinct substrates. After validating select hits in focused mini-screens, orthogonal assays and primary human macrophages, we demonstrate that 1) the previously-uncharacterized gene NHLRC2 is a central player in phagocytosis, regulating RhoA-Rac1 signaling cascades that control actin polymerization and filopodia formation, 2) very long chain fatty acids are essential for efficient phagocytosis of certain substrates, and 3) the previously-uncharacterized Alzheimer’s disease-associated gene TM2D3 can preferentially influence uptake of amyloid-β aggregates. These findings illuminate new regulators and core principles of phagocytosis, and more generally establish an efficient method for unbiased identification of cellular uptake mechanisms across diverse physiological and pathological contexts.

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Phosphatidylinositol 4-phosphate undergoes striking multiphasic changes during phagosome formation and maturation. The molecular mechanisms underlying these changes and the role of phosphatidylinositol 4-phosphate in phagolysosome formation are investigated.