title: Integrin α PAT-2/CDC-42 signaling is required for muscle-mediated clearance of apoptotic cells in Caenorhabditis elegans.
abstract: Clearance of apoptotic cells by engulfment plays an important role in the homeostasis and development of multicellular organisms. Despite the fact that the recognition of apoptotic cells by engulfment receptors is critical in inducing the engulfment process, the molecular mechanisms are still poorly understood. Here, we characterize a novel cell corpse engulfment pathway mediated by the integrin α subunit PAT-2 in Caenorhabditis elegans and show that it specifically functions in muscle-mediated engulfment during embryogenesis. Inactivation of pat-2 results in a defect in apoptotic cell internalization. The PAT-2 extracellular region binds to the surface of apoptotic cells in vivo, and the intracellular region may mediate signaling for engulfment. We identify essential roles of small GTPase CDC-42 and its activator UIG-1, a guanine-nucleotide exchange factor, in PAT-2-mediated cell corpse removal. PAT-2 and CDC-42 both function in muscle cells for apoptotic cell removal and are co-localized in growing muscle pseudopods around apoptotic cells. Our data suggest that PAT-2 functions through UIG-1 for CDC-42 activation, which in turn leads to cytoskeletal rearrangement and apoptotic cell internalization by muscle cells. Moreover, in contrast to PAT-2, the other integrin α subunit INA-1 and the engulfment receptor CED-1, which signal through the conserved signaling molecules CED-5 (DOCK180)/CED-12 (ELMO) or CED-6 (GULP) respectively, preferentially act in epithelial cells to mediate cell corpse removal during mid-embryogenesis. Our results show that different engulfing cells utilize distinct repertoires of receptors for engulfment at the whole organism level.
authors.affiliation: Institute of Molecular and Cellular Biology, National Taiwan University, Taipei, Taiwan.
authors.forename: Hsiao-Han
authors.initials: HH
authors.lastname: Hsieh
authors.forename: Tsung-Yuan
authors.initials: TY
authors.lastname: Hsu
authors.forename: Hang-Shiang
authors.initials: HS
authors.lastname: Jiang
authors.forename: Yi-Chun
authors.initials: YC
authors.lastname: Wu
mesh_terms: D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins; D044482:Benzeneacetamides / Q000378:metabolism; D017173:Caenorhabditis elegans / Q000196:embryology / Q000235:genetics; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000378:metabolism; D003599:Cytoskeleton / Q000235:genetics / Q000378:metabolism; D047108:Embryonic Development; D000077542:Eptifibatide; D019204:GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism; D016023:Integrins / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D018482:Muscle, Skeletal / Q000196:embryology*; D010455:Peptides / Q000235:genetics / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D011725:Pyridines / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D051017:Apoptosis Regulatory Proteins; D044482:Benzeneacetamides; C438369:CED-12 protein, C elegans; C112888:CED-6 protein, C elegans; D029742:Caenorhabditis elegans Proteins; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D003598:Cytoskeletal Proteins; D020662:Guanine Nucleotide Exchange Factors; C521951:Ina-1 protein, C elegans; D016023:Integrins; D008565:Membrane Proteins; D010455:Peptides; D010750:Phosphoproteins; D011725:Pyridines; C504362:UIG-1 protein, C elegans; C081779:cdc-42 protein, C elegans; C422043:ced-1 protein, C elegans; C006879:acetyltropic acid 2-pyridylmethylamide; D019204:GTP-Binding Proteins; D000077542:Eptifibatide