This project studies the degradation of apoptotic cells after they are internalized into phagocytes. During animal development and adulthood, cells undergoing apoptosis, a cell death process essential for animal development and homeostasis, are rapidly internalized by other cells via phagocytosis (engulfment) and degraded inside engulfing cells. The removal of apoptotic cells provides a safe means for eliminating unwanted and dangerous cells from the body. Furthermore, it prevents tissue injury, inflammatory responses, and auto-immune responses that could be induced by the content of dead cells. The study of apoptotic-cell removal has also inspired the development of novel cancer treatment strategies. Given the strong evolutionary conservation of developmental mechanisms, what we learn from C. elegans will be translated to humans. My long-term objective is to understand the molecular mechanism that controls the recognition, engulfment, and degradation of apoptotic cells, using the nematode Caenorhabditis elegans as a model organism. This project focuses on two aspects important for the degradation of the engulfed apoptotic cells, which are confined in a vacuolar structure called a ?phagosome?. Phagosomes undergo a ?maturation? process through a series of membrane trafficking events that lead to the incorporation of multiple types of intracellular organelles into phagosomes and the deposition of digestive enzymes into phagosomal lumen. As a result the cargo inside a phagosome is digested, the digested substances and the phagosomal membrane are exported, and a phagosome is resolved. Many questions remain unexplored regarding the degradation of a phagosome. Our studies will establish a novel functional relationship between autophagy and phagocytosis (Aims 1 and 2). In particular, we will demonstrate that autophagosomes, which are double-membrane intracellular organelles whose primary role is to clear cellular aggregates and inactive macromolecule complexes and organelles, is a new kind of organelles that are recruited to phagosomal surface and fuse with phagosomes (Aim 1). We will further explore whether the fusion between autophagosomes and phagosomes is a conserved event in mammals (Aim 2). In a separate project, we will investigate two propose mechanisms that regulate ?phagosome resolution?, the completion of degradation and the export of phagosomal contents (Aim 3). The proposed work will have broad impact in revealing novel mechanisms of intracellular signaling and membrane trafficking, which are essential for animal development.
This project studies how apoptotic cells (cells that commit suicide) and necrotic cells (cells die of injury) generated in animal bodies are digested by phagocytes, cells that eat other cells, after engulfment. The clearance of dying cells protects humans from the harmful inflammatory and auto-immune responses induced by the contents of the dying cells. Understanding the mechanisms controlling this process will have important therapeutic implications, in fighting chronic inflammatory and autoimmune diseases, and in developing new strategies to target cancer cells for engulfment and digestion.
|Haley, Ryan; Wang, Ying; Zhou, Zheng (2018) The small GTPase RAB-35 defines a third pathway that is required for the recognition and degradation of apoptotic cells. PLoS Genet 14:e1007558|
|Li, Zao; Venegas, Victor; Nagaoka, Yuji et al. (2015) Necrotic Cells Actively Attract Phagocytes through the Collaborative Action of Two Distinct PS-Exposure Mechanisms. PLoS Genet 11:e1005285|
|Huang, Shuyi; Jia, Kailiang; Wang, Ying et al. (2013) Autophagy genes function in apoptotic cell corpse clearance during C. elegans embryonic development. Autophagy 9:138-49|
|Li, Zao; Lu, Nan; He, Xiangwei et al. (2013) Monitoring the clearance of apoptotic and necrotic cells in the nematode Caenorhabditis elegans. Methods Mol Biol 1004:183-202|
|Shen, Qian; He, Bin; Lu, Nan et al. (2013) Phagocytic receptor signaling regulates clathrin and epsin-mediated cytoskeletal remodeling during apoptotic cell engulfment in C. elegans. Development 140:3230-43|
|Sun, Lin; Liu, Ou; Desai, Jigar et al. (2012) CED-10/Rac1 regulates endocytic recycling through the RAB-5 GAP TBC-2. PLoS Genet 8:e1002785|
|Lu, Nan; Shen, Qian; Mahoney, Timothy R et al. (2012) Two PI 3-kinases and one PI 3-phosphatase together establish the cyclic waves of phagosomal PtdIns(3)P critical for the degradation of apoptotic cells. PLoS Biol 10:e1001245|
|Lu, Nan; Zhou, Zheng (2012) Membrane trafficking and phagosome maturation during the clearance of apoptotic cells. Int Rev Cell Mol Biol 293:269-309|
|Lu, Nan; Shen, Qian; Mahoney, Timothy R et al. (2011) Three sorting nexins drive the degradation of apoptotic cells in response to PtdIns(3)P signaling. Mol Biol Cell 22:354-74|
|He, Bin; Yu, Xiaomeng; Margolis, Moran et al. (2010) Live-cell imaging in Caenorhabditis elegans reveals the distinct roles of dynamin self-assembly and guanosine triphosphate hydrolysis in the removal of apoptotic cells. Mol Biol Cell 21:610-29|
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