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.