A pathway for phagosome maturation during engulfment of apoptotic cells
A pathway for phagosome maturation during engulfment of apoptotic cells
Removal of apoptotic cells is critical for the physiological well-being of the organism and defects in corpse removal have been linked to disease states. Genes regulating corpse recognition and internalization have been identified, but few molecules involved in the processing of internalized corpses are known. Through a combination of targeted and unbiased reverse genetic screens in Caenorhabditis elegans, and studies in mammalian cells, we have identified genes required for maturation of apoptotic-cell-containing phagosomes. We have further ordered these candidates, which include the GTPases RAB-5 and RAB-7 and the HOPS complex, into a coherent linear pathway for the maturation of apoptotic cells within phagosomes. In depth analysis of two additional candidate genes, the phosphatidylinositol 3 kinase (PI(3)K) vps-34 (A001762) and dyn-1/dynamin, showed an accumulation of internalized, but undegraded, corpses within abnormal Rab5-negative phagosomes. We ordered these candidates in our pathway, with DYN-1 functioning upstream of VPS-34 in the recruitment and/or retention of RAB-5 to the phagosome. Finally, we have also identified a previously undescribed biochemical complex containing Vps34, dynamin and Rab5(GDP), thus providing a mechanism for Rab5 recruitment to the nascent phagosome.
- Institute for Molecular Systems Biology Switzerland
- ETH Zurich Switzerland
- University of Virginia United States
- University of Zurich Switzerland
- United States University United States
Dynamins, Recombinant Fusion Proteins, rab7 GTP-Binding Proteins, Apoptosis, 10124 Institute of Molecular Life Sciences, 1307 Cell Biology, Animals, Genetically Modified, Phosphatidylinositol 3-Kinases, Phagocytosis, rab GTP-Binding Proteins, Multiprotein Complexes, Phagosomes, 570 Life sciences; biology, Animals, Humans, RNA Interference, Caenorhabditis elegans, Caenorhabditis elegans Proteins, rab5 GTP-Binding Proteins
Dynamins, Recombinant Fusion Proteins, rab7 GTP-Binding Proteins, Apoptosis, 10124 Institute of Molecular Life Sciences, 1307 Cell Biology, Animals, Genetically Modified, Phosphatidylinositol 3-Kinases, Phagocytosis, rab GTP-Binding Proteins, Multiprotein Complexes, Phagosomes, 570 Life sciences; biology, Animals, Humans, RNA Interference, Caenorhabditis elegans, Caenorhabditis elegans Proteins, rab5 GTP-Binding Proteins
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