title: Phagocytic receptor signaling regulates clathrin and epsin-mediated cytoskeletal remodeling during apoptotic cell engulfment in C. elegans.
abstract: The engulfment and subsequent degradation of apoptotic cells by phagocytes is an evolutionarily conserved process that efficiently removes dying cells from animal bodies during development. Here, we report that clathrin heavy chain (CHC-1), a membrane coat protein well known for its role in receptor-mediated endocytosis, and its adaptor epsin (EPN-1) play crucial roles in removing apoptotic cells in Caenorhabditis elegans. Inactivating epn-1 or chc-1 disrupts engulfment by impairing actin polymerization. This defect is partially suppressed by inactivating UNC-60, a cofilin ortholog and actin server/depolymerization protein, further indicating that EPN-1 and CHC-1 regulate actin assembly during pseudopod extension. CHC-1 is enriched on extending pseudopods together with EPN-1, in an EPN-1-dependent manner. Epistasis analysis places epn-1 and chc-1 in the same cell-corpse engulfment pathway as ced-1, ced-6 and dyn-1. CED-1 signaling is necessary for the pseudopod enrichment of EPN-1 and CHC-1. CED-1, CED-6 and DYN-1, like EPN-1 and CHC-1, are essential for the assembly and stability of F-actin underneath pseudopods. We propose that in response to CED-1 signaling, CHC-1 is recruited to the phagocytic cup through EPN-1 and acts as a scaffold protein to organize actin remodeling. Our work reveals novel roles of clathrin and epsin in apoptotic-cell internalization, suggests a Hip1/R-independent mechanism linking clathrin to actin assembly, and ties the CED-1 pathway to cytoskeleton remodeling.
authors.affiliation: Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
authors.forename: Qian
authors.initials: Q
authors.lastname: Shen
authors.forename: Bin
authors.initials: B
authors.lastname: He
authors.forename: Nan
authors.initials: N
authors.lastname: Lu
authors.forename: Barbara
authors.initials: B
authors.lastname: Conradt
authors.forename: Barth D
authors.initials: BD
authors.lastname: Grant
authors.forename: Zheng
authors.initials: Z
authors.lastname: Zhou
mesh_terms: D000199:Actins / Q000737:chemistry / Q000378:metabolism; D033942:Adaptor Proteins, Vesicular Transport / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D000595:Amino Acid Sequence; D000818:Animals; D030801:Animals, Genetically Modified; D017209:Apoptosis / Q000502:physiology; D017173:Caenorhabditis elegans / Q000166:cytology* / Q000235:genetics / Q000502:physiology*; D029742:Caenorhabditis elegans Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D033922:Clathrin Heavy Chains / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D003599:Cytoskeleton / Q000502:physiology; D034281:Dynamins / Q000235:genetics / Q000502:physiology; D055785:Gene Knockdown Techniques; D017238:Genes, Helminth; D008565:Membrane Proteins / Q000235:genetics / Q000502:physiology; D008840:Microfilament Proteins / Q000235:genetics / Q000502:physiology; D008969:Molecular Sequence Data; D009154:Mutation; D010586:Phagocytes / Q000502:physiology; D011554:Pseudopodia / Q000502:physiology; D011956:Receptors, Cell Surface / Q000502:physiology; D015398:Signal Transduction
chemical_list: D000199:Actins; D033942:Adaptor Proteins, Vesicular Transport; D029742:Caenorhabditis elegans Proteins; D008565:Membrane Proteins; D008840:Microfilament Proteins; D011956:Receptors, Cell Surface; C495209:UNC-60 protein, C elegans; C422043:ced-1 protein, C elegans; C114154:epsin; D033922:Clathrin Heavy Chains; C511792:Dyn-1 protein, C elegans; D034281:Dynamins
keywords: Actin cytoskeleton; Apoptotic cell engulfment; C. elegans; Clathrin; Epsin; Membrane remodeling