title: A conserved role for SNX9-family members in the regulation of phagosome maturation during engulfment of apoptotic cells.
abstract: Clearance of apoptotic cells is of key importance during development, tissue homeostasis and wound healing in multi-cellular animals. Genetic studies in the nematode Caenorhabditis elegans have identified a set of genes involved in the early steps of cell clearance, in particular the recognition and internalization of apoptotic cells. A pathway that orchestrates the maturation of phagosomes containing ingested apoptotic cells in the worm has recently been described. However, many steps in this pathway remain elusive. Here we show that the C. elegans SNX9-family member LST-4 (lateral signaling target) and its closest mammalian orthologue SNX33 play an evolutionary conserved role during apoptotic cell corpse clearance. In lst-4 deficient worms, internalized apoptotic cells accumulated within non-acidified, DYN-1-positive but RAB-5-negative phagosomes. Genetically, we show that LST-4 functions at the same step as DYN-1 during corpse removal, upstream of the GTPase RAB-5. We further show that mammalian SNX33 rescue C. elegans lst-4 mutants and that overexpression of truncated SNX33 fragments interfered with phagosome maturation in a mammalian cell system. Taken together, our genetic and cell biological analyses suggest that LST-4 is recruited through a combined activity of DYN-1 and VPS-34 to the early phagosome membrane, where it cooperates with DYN-1 to promote recruitment/retention of RAB-5 on the early phagosomal membrane during cell corpse clearance. The functional conservation between LST-4 and SNX33 indicate that these early steps of apoptotic phagosome maturation are likely conserved through evolution.
authors.affiliation: Institute of Molecular Life Sciences, University of Zurich, Zurich, Switzerland. johann.almendinger@imls.uzh.ch
authors.forename: Johann
authors.initials: J
authors.lastname: Almendinger
authors.forename: Kimon
authors.initials: K
authors.lastname: Doukoumetzidis
authors.forename: Jason M
authors.initials: JM
authors.lastname: Kinchen
authors.forename: Andres
authors.initials: A
authors.lastname: Kaech
authors.forename: Kodi S
authors.initials: KS
authors.lastname: Ravichandran
authors.forename: Michael O
authors.initials: MO
authors.lastname: Hengartner
mesh_terms: D000818:Animals; D017209:Apoptosis; D017173:Caenorhabditis elegans / Q000166:cytology* / Q000378:metabolism* / Q000648:ultrastructure; D029742:Caenorhabditis elegans Proteins / Q000737:chemistry / Q000378:metabolism*; D017124:Conserved Sequence / Q000235:genetics*; D051379:Mice; D008954:Models, Biological; D041681:NIH 3T3 Cells; D010587:Phagocytosis; D010588:Phagosomes / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D058305:Sorting Nexins / Q000737:chemistry / Q000378:metabolism*; D013329:Structure-Activity Relationship; D020696:rab5 GTP-Binding Proteins / Q000378:metabolism
chemical_list: D029742:Caenorhabditis elegans Proteins; D058305:Sorting Nexins; C559094:lst-4 protein, C elegans; D020696:rab5 GTP-Binding Proteins