Letter abstract
Nature Cell Biology 10, 556 - 566 (2008)
Published online: 20 April 2008 | doi:10.1038/ncb1718
A pathway for phagosome maturation during engulfment of apoptotic cells
Jason M. Kinchen1,5, Kimon Doukoumetzidis2,5, Johann Almendinger2, Lilli Stergiou2,4, Annie Tosello-Trampont1, Costi D. Sifri3, Michael O. Hengartner2,6 & Kodi S. Ravichandran1,6
Removal of apoptotic cells is critical for the physiological well-being of the organism1 and defects in corpse removal have been linked to disease states2, 3. Genes regulating corpse recognition and internalization have been identified4, 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 Rab5GDP, thus providing a mechanism for Rab5 recruitment to the nascent phagosome.
- Beirne Carter Center for Immunology Research, University of Virginia, Charlottesville, VA 22908, USA.
- Institute of Molecular Biology, University of Zurich, CH-8057, Zurich, Switzerland.
- Department of Medicine, University of Virginia, Charlottesville VA 22908, USA.
- Present address: Institute of Molecular Systems Biology, ETH Zürich 8093 Zürich, Switzerland.
- These authors contributed equally to this work
- These authors contributed equally to this work
Correspondence to: Kodi S. Ravichandran1,6 e-mail: ravi@virginia.edu
Correspondence to: Michael O. Hengartner2,6 e-mail: Michael.Hengartner@molbio.unizh.ch
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