The engulfment receptor CED-1/MEGF10 activates the GPCR LAT-1/ADGRL3 for apoptotic cell degradation

Authors

Liu, F., Yuan, L., Zheng, Q., Kang, Y., Wang, A., Li, K., Xie, Y., Chen, L., Li, P., Wang, H., Li, Z., Xiao, H.

Abstract

Efferocytosis, the clearance of apoptotic cells, is crucial for tissue homeostasis, inflammation suppression, and repair. While several G protein-coupled receptors (GPCRs) are involved, GPCRs' broader roles in efferocytosis remain unexplored. Through a genome-wide RNAi screen in Caenorhabditis elegans, we identified adhesion GPCR LAT-1 as a key regulator of apoptotic cell degradation by promoting phagosome maturation. Our secondary RNAi screen for transcriptional regulators revealed transcription factor AST-1 acts downstream of LAT-1 to mediate apoptotic cell degradation. We show the engulfment receptor CED-1 acts as a ligand for LAT-1, activating a Gs protein/adenylyl cyclase/PKA/AST-1 signaling cascade inducing transcription of vps-34 and piki-1, encoding phosphatidylinositol 3-kinases essential for PtdIns3P generation on phagosomes. This pathway maintains appropriate VPS-34 and PIKI-1 levels for efficient efferocytosis. Notably, LAT-1 is evolutionarily conserved, with homologs in Drosophila (CIRL) and mammals (ADGRL3) performing similar functions. These findings define a conserved CED-1/MEGF10-LAT-1/ADGRL3 axis orchestrating apoptotic cell clearance via a novel transcriptional regulatory pathway, providing new insight into molecular mechanisms underlying tissue homeostasis and diseases associated with defective efferocytosis, including autoimmunity and neurodegeneration.

Preprint server: bioRxiv
The authors list and abstract were imported from bioRxiv on 11 Jun 2026.

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