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. 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. We believe that what is learnt from C. elegans will be translated to humans. These project studies mechanisms that drive the degradation of apoptotic cells, which are internalized into host cells, confined in a vacuolar structure called """"""""phagosome"""""""". Phagosomes undergo a """"""""maturation"""""""" process through a series of membrane trafficking events and the end result is the degradation of cargos in the lumen. Our studies will reveal the temporal regulation mechanisms of the production (Aim 1) and turnover (Aim 2) of phosphatidylinositol 3-phosphate (PI3P), a lipid second messenger that plays an essential role in initiating phagosome maturation, on phagosomes, and how PI3P triggers the maturation process (Aims 3). Our study of the PI3P signaling mechanisms will shed light not only on the degradation of apoptotic cells, but also broadly, on the molecular mechanisms behind other PI3P-mediated membrane trafficking events, including endocytic trafficking and autophagy.
This project studies how apoptotic cells (cells that commit suicide) generated in animal bodies are engulfed and digested by other cells, a process that protects humans from the harmful inflammatory and auto-immune responses that apoptotic cells would induce if they are left in the body. Understanding the mechanisms controlling this process will have important therapeutic implications, in fighting chronic inflammatory and auto- immune diseases, and in developing new strategies to remove cancer cells through 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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