Sunday, June 1, 2025
6/1/2025
Molecular mechanisms that regulate the degradation of dying cells - Project Summary/Abstract Molecular mechanisms that regulate the degradation of dying cells During metazoan development and adulthood, many cells undergo cell suicide (apoptosis). In addition, pathological stresses often induce the necrosis of cells. Phagocytosis is a “cell-eating-cell” event in which dying and senescent cells, damaged axons and synapses, and invading pathogens are internalized by phagocytes and degraded inside phagosomes. Swift clearance of dying cells in mammals is critical for tissue remodeling, the resolution of the wound area, and the suppression of harmful inflammatory and autoimmune responses. Cancer research and treatment are also related to the clearance of dying cells. We have been studying the phagocytosis of cells that undergo apoptosis, a genetically controlled process of cell suicide in the nematode C. elegans. We have discovered many proteins that facilitate the recognition, engulfment, and degradation of dying cells. We have delineated several signaling pathways that drive each step of the dying cell-clearance process. These include a pathway that initiates the maturation of phagosomes by promoting the fusion of lysosomes to phagosomes. This pathway is driven by CED-1, a phagocytic receptor, and its downstream adaptors and effectors. We believe what we learn from C. elegans can be translated to humans and impact human health. Recently, we made two discoveries. (I) We found that the double-membrane autophagosomes, which are known to help clear intracellular protein aggregates and damaged organelles through autophagy, actively fuse to the single-membrane phagosomes and facilitate the degradation of the engulfed apoptotic cells. We coin the term autophagosome-phagosome fusion (AP-fusion). Our findings reveal a novel crosstalk between autophagy and phagosome processing. (II) We found that the precise temporal regulation of CED-1 on the surfaces of nascent phagosomes, which involves mechanisms that remove CED-1 from the phagosomal membrane, is necessary for the initiation of maturation. Here we propose to deepen and broaden our research premise by following these two discoveries. Investigate the novel mechanisms that regulate the AP-fusion (Project 1), the phagosome-induced autophagosome biogenesis (Project 2), and the temporal activation and inactivation of CED-1 on nascent phagosomes (Project 3). The outcome of the proposed projects will shed light on our understanding of how intracellular organelles participate in cell-cell interaction and further contribute to treating human diseases related to defects in phagocytosis and autophagy.
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