RRC ID 4251
Author Kinchen JM, Doukoumetzidis K, Almendinger J, Stergiou L, Tosello-Trampont A, Sifri CD, Hengartner MO, Ravichandran KS.
Title A pathway for phagosome maturation during engulfment of apoptotic cells.
Journal Nat. Cell Biol.
Abstract 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.
Volume 10(5)
Pages 556-66
Published 2008-5
DOI 10.1038/ncb1718
PII ncb1718
PMID 18425118
PMC PMC2851549
MeSH Animals Animals, Genetically Modified Apoptosis / physiology* Caenorhabditis elegans* / cytology Caenorhabditis elegans* / genetics Caenorhabditis elegans* / metabolism Caenorhabditis elegans Proteins / genetics Caenorhabditis elegans Proteins / metabolism* Dynamins / genetics Dynamins / metabolism Humans Multiprotein Complexes / genetics Multiprotein Complexes / metabolism Phagocytosis / physiology* Phagosomes / metabolism* Phosphatidylinositol 3-Kinases / genetics Phosphatidylinositol 3-Kinases / metabolism RNA Interference Recombinant Fusion Proteins / genetics Recombinant Fusion Proteins / metabolism rab GTP-Binding Proteins / genetics rab GTP-Binding Proteins / metabolism* rab5 GTP-Binding Proteins / genetics rab5 GTP-Binding Proteins / metabolism*
IF 19.064
Times Cited 139
WOS Category CELL BIOLOGY
Resource
C.elegans tm512