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A pathway for phagosome maturation during engulfment of apoptotic cells
Open accessAbstract
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.
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“Efferosomes containing apoptotic material follow a similar succession as phagosomes going from an early to late endosomal to phagolysosomal stages as indicated by differential association with marker proteins such as the small GTPases Rab5 and Rab7, Vsp34 and dynamin, Lamp-1, and finally lysosomal hydrolases (136) (Fig. 1).”
From Macrophage defense mechanisms against intracellular bacteria (2015) · cites this paper as [136]
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Metadata
- Authors
- Kinchen, J. M., Doukoumetzidis, K., Almendinger, J., Stergiou, L., Tosello-Trampont, A., Sifri, C. D., Hengartner, M. O., & Ravichandran, K. S.
- Affiliations
- University of Virginia (US)
- University of Zurich (CH)
- Corresponding author
- Hengartner, Michael O.
- Ravichandran, Kodi S.
- Venue
- Nature Cell Biology
- Published
- 2008-04-20
- Volume
- 10
- Issue
- 5
- Pages
- 556-566
- ISSN
- 1465-7392 (ISSN-L)
- 1476-4679
- PMC
- PMC2851549
- OpenAlex
- W2136243038
- Cited by
- 284
- References
- 89
- Citations by year
- 2026: 5 · 2025: 14 · 2024: 10 · 2023: 18 · 2022: 16 · 2021: 15 · 2020: 8 · 2019: 6 · 2018: 17 · 2017: 15 · 2016: 24 · 2015: 15 · 2014: 19 · 2013: 21 · 2012: 21
- FWCI
- 8.61
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Cell Biology (publishedVersion)
- PubMed (publishedVersion)
- Zurich Open Repository and Archive (University of Zurich) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Zurich Open Repository and Archive (University of Zurich) (submittedVersion)
- Zurich Open Repository and Archive (University of Zurich)
- Funders
- National Institute of General Medical Sciences (R01GM069998, R01GM064709)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Life Sciences › Immunology and Microbiology › Immunology › Phagocytosis and Immune Regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Autophagy in Disease and Therapy
- Keywords
- phagosome maturation, efferocytosis, corpse removal, Rab5, Rab7, HOPS complex, dynamin, phosphatidylinositol 3-kinase, Caenorhabditis elegans, phagocytosis, reverse genetic screen
- MeSH terms
- rab7 GTP-Binding Proteins, Animals, Humans, Phagocytosis, Phagosomes, Recombinant Fusion Proteins, Caenorhabditis elegans, Apoptosis, Phosphatidylinositol 3-Kinases, rab GTP-Binding Proteins, rab5 GTP-Binding Proteins, Caenorhabditis elegans Proteins, Animals, Genetically Modified, Dynamins, RNA Interference, Multiprotein Complexes
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