Engulfment of apoptotic cells in C. elegans is mediated by integrin alpha/SRC signaling

Abstract

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.