Journal
NATURE GENETICS
Volume 50, Issue 12, Pages 1716-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41588-018-0254-1
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Funding
- EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH & HUMAN DEVELOPMENT [DP2HD094656] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [T32GM007790, T32GM007365] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE ON DRUG ABUSE [R01DA015043] Funding Source: NIH RePORTER
- NICHD NIH HHS [DP2 HD094656, DP2 HD084069] Funding Source: Medline
- NIDA NIH HHS [R01 DA015043] Funding Source: Medline
- NIGMS NIH HHS [T32 GM007790, T32 GM007365] Funding Source: Medline
- NIH HHS [DP2 HD094656, T32-GM007365, R01 DA015043, 1DP2HD084069-01] Funding Source: Medline
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Phagocytosis is required for a broad range of physiological functions, from pathogen defense to tissue homeostasis, but the mechanisms required for phagocytosis of diverse substrates remain incompletely understood. Here, we developed a rapid magnet- based phenotypic screening strategy, and performed eight genome-wide CRISPR screens in human cells to identify genes regulating phagocytosis of distinct substrates. After validating select hits in focused miniscreens, orthogonal assays and primary human macrophages, we show 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 diseaseassociated gene TM2D3 can preferentially influence uptake of amyloid-beta 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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