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