Engulfment of apoptotic cells in C. elegans is mediated by integrin alpha/SRC signaling.
BACKGROUND
Engulfment of apoptotic cells is important for cellular homeostasis and the development of multicellular organisms. Previous studies have shown that more than one engulfment receptors act upstream of the conserved signaling module CED-2/CrkII-CED-5/Dock180-CED-12/ELMO for cell corpse removal in C. elegans, but little is known about their identities, except for PSR-1.


RESULTS
We show that in C. elegans, integrin functions as an engulfment receptor in the recognition and subsequent phagocytosis of apoptotic cells. Mutations in the integrin alpha gene ina-1 result in inefficient engulfment of apoptotic cells. The INA-1 extracellular domain binds to the surface of apoptotic cells in vivo. This binding requires the phospholipid scramblase SCRM-1, which promotes the exposure of phosphatidylserine, a key "eat me" signal in apoptotic cells. Furthermore, we identify an essential role of the nonreceptor tyrosine kinase SRC-1 in INA-1-mediated cell corpse removal. INA-1 and SRC-1 both act in the engulfing cells during the engulfment process and are colocalized in the phagocytic cups extending around apoptotic cells. Finally, our genetic and biochemical data suggest that SRC-1 relays the scrm-1-dependent engulfment signal from INA-1 to the conserved motility-promoting signaling complex CED-2/CrkII-CED-5/Dock180-CED-12/ELMO for CED-10/Rac activation, probably by interactions with CED-2 and the INA-1 cytoplasmic domain, leading to the internalization of apoptotic cells.


CONCLUSIONS
Our findings provide evidence that integrin functions as an engulfment receptor at the whole-organism level and reveal a nonconventional signaling pathway in which SRC provides a FAK-independent linkage between integrin alpha and the common motility-promoting signaling module CED-2/CrkII-CED-5/Dock180-CED-12/ELMO to promote the internalization of apoptotic cells.
Hsu
Tsung-Yuan
TY
Institute of Molecular and Cellular Biology, National Taiwan University, Number 1, Section 4, Roosevelt Road, Taipei 10617, Taiwan.
Wu
Yi-Chun
YC
D000818:Animals; D030801:Animals, Genetically Modified; D017209:Apoptosis / Q000235:genetics / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins; D001483:Base Sequence; D017173:Caenorhabditis elegans / Q000166:cytology* / Q000196:embryology / Q000235:genetics / Q000502:physiology*; D029742:Caenorhabditis elegans Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D002352:Carrier Proteins / Q000235:genetics / Q000502:physiology; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000502:physiology; D017931:DNA Primers / Q000235:genetics; D018509:DNA, Helminth / Q000235:genetics; D017238:Genes, Helminth; D016023:Integrins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D008565:Membrane Proteins / Q000235:genetics / Q000502:physiology; D009154:Mutation; D010587:Phagocytosis / Q000235:genetics / Q000502:physiology*; D011494:Protein Kinases / Q000235:genetics / Q000502:physiology*; D021122:Protein Subunits; D011554:Pseudopodia / Q000502:physiology; D034622:RNA Interference; D015398:Signal Transduction; D020798:Two-Hybrid System Techniques
D051017:Apoptosis Regulatory Proteins; C438369:CED-12 protein, C elegans; C479695:CED-2 protein, C elegans; C111579:CED-5 protein, C elegans; D029742:Caenorhabditis elegans Proteins; D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; D017931:DNA Primers; D018509:DNA, Helminth; C521951:Ina-1 protein, C elegans; D016023:Integrins; D008565:Membrane Proteins; D021122:Protein Subunits; D011494:Protein Kinases; C471235:SRC-1 protein, C elegans