Phagocytic Removal of Apoptotic and Necrotic Cells

Summary

Principal Investigator: Zheng Zhou
Affiliation: Texas Medical Center
Country: USA
Abstract: In animals, cells undergoing apoptosis and necrosis are rapidly internalized by other cells via phagocytosis (engulfment) and degraded inside phagocytes. The removal of these dying cells provides a safe means for eliminating unwanted and dangerous cells from the body and actively modulates immune responses. The study of apoptotic cell removal will shed light on inflammatory and auto-immune disorders, many of which are associated with an inefficient clearance of apoptotic cells from the human body. This study is also closely related to cancer research and treatment. My long-term objective is to understand the molecular mechanism that controls the recognition, engulfment, and degradation of apoptotic and necrotic cells. I use the nematode Caenorhabditis elegans, a small round worm as a model organism to identify genes and delineate pathways that control these evolutionarily conserved events and will apply the knowledge to understand similar processes in mammals, including humans. We have identified novel signaling events both upstream and downstream of C. elegans phagocytic receptor CED-1, which have provided conceptual advances in our understanding of how apoptotic cells are removed by engulfing cells. In the next project period we propose to broaden our research scope by investigating the mechanisms behind these events. We have identified phosphatidylserine (PS) as one of the "eat me" signals exposed on the surface of apoptotic cells and activate CED-1. We will further study the molecular mechanisms for the exposure and recognition of PS and other potential "eat me" signals in both apoptotic and engulfing cells (Aim 1). We will expand our study to the recognition and phagocytosis of necrotic touch neurons, which die in a caspase-independent manner and may employ unique mechanisms to attract engulfing cells (Aim 1). We have discovered that phagocytic receptor CED-1 not only initiates the engulfment, but also promotes the degradation of apoptotic cells through the recruitment and activation of downstream mediator DYN-1, the C. elegans ortholog of mammalian large GTPase dynamin. We will study the mechanism leading to the transient enrichment of DYN-1 to the surface of extending pseudopodia and phagosomes, which is important for its functions in both engulfment and phagosome maturation. One particular hypothesis to test is that the CED-1 pathway recruits DYN-1 via the collaborative efforts of CED-6 and phosphatidylinositol 4,5- phosphate (PI(4,5)P2) (Aim 2). We have established C. elegans as a unique model system for studying the degradation of apoptotic cells inside phagosomes, a process not well studied, and have identified the specific functions of two Rab GTPases, a PI3 kinase and its product phosphatidylinositol 3-phosphate (PI(3)P) in phagosome maturation. To reveal the mechanism of PI(3)P function and the relationship between PI(3)P and Rab GTPases, we will identify downstream effectors of PI(3)P and the events that they regulate (Aim 3). PUBLIC HEALTH RELEVANCE: This project studies how unwanted cells (cells that commit suicide or die due to injuries) are recognized, internalized, and digested by their engulfing cells, a process that protects human bodies from their harmful effects. Understanding the mechanisms controlling this process will have important therapeutic implications, since many inflammatory and auto-immune diseases are closely related to defects in removing dying cells from human bodies, and will further help develop new strategies to specifically eliminate tumor cells. This project will be conducted in a small round worm the nematode C. elegans, which uses evolutionarily conserved mechanisms to control cell death, and provides a powerful means to reveal the principle for biological actions in a relatively simple system.
Funding Period: ----------------2003 - ---------------2012-
more information: NIH RePORT

Top Publications

  1. ncbi C. elegans Dynamin mediates the signaling of phagocytic receptor CED-1 for the engulfment and degradation of apoptotic cells
    Xiaomeng Yu
    Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas 77030, USA
    Dev Cell 10:743-57. 2006
  2. pmc Monitoring the clearance of apoptotic and necrotic cells in the nematode Caenorhabditis elegans
    Zao Li
    Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX, USA
    Methods Mol Biol 1004:183-202. 2013
  3. pmc Autophagy genes function in apoptotic cell corpse clearance during C. elegans embryonic development
    Shuyi Huang
    Center for Autophagy Research, University of Texas Southwestern Medical Center, Dallas, TX, USA
    Autophagy 9:138-49. 2013
  4. pmc Phagocytic receptor signaling regulates clathrin and epsin-mediated cytoskeletal remodeling during apoptotic cell engulfment in C. elegans
    Qian Shen
    Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA
    Development 140:3230-43. 2013
  5. pmc Phagosome maturation during the removal of apoptotic cells: receptors lead the way
    Zheng Zhou
    Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX 77030, USA
    Trends Cell Biol 18:474-85. 2008
  6. pmc Two alternative mechanisms that regulate the presentation of apoptotic cell engulfment signal in Caenorhabditis elegans
    VICTOR VENEGAS
    Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX 77030, USA
    Mol Biol Cell 18:3180-92. 2007
  7. pmc Phagocytic receptor CED-1 initiates a signaling pathway for degrading engulfed apoptotic cells
    Xiaomeng Yu
    Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas, United States of America
    PLoS Biol 6:e61. 2008
  8. pmc The small GTPase Rab2 functions in the removal of apoptotic cells in Caenorhabditis elegans
    Paolo M Mangahas
    Program in Developmental Biology, Baylor College of Medicine, Houston, TX 77030, USA
    J Cell Biol 180:357-73. 2008
  9. pmc Detecting apoptotic cells and monitoring their clearance in the nematode Caenorhabditis elegans
    Nan Lu
    Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX, USA
    Methods Mol Biol 559:357-70. 2009
  10. pmc 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
    Nan Lu
    Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas, United States of America
    PLoS Biol 10:e1001245. 2012

Detail Information

Publications15

  1. ncbi C. elegans Dynamin mediates the signaling of phagocytic receptor CED-1 for the engulfment and degradation of apoptotic cells
    Xiaomeng Yu
    Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas 77030, USA
    Dev Cell 10:743-57. 2006
    ..We propose that DYN-1 mediates the signaling of the CED-1 pathway by organizing an intracellular vesicle pool and promoting vesicle delivery to phagocytic cups and phagosomes to support pseudopod extension and apoptotic cell degradation...
  2. pmc Monitoring the clearance of apoptotic and necrotic cells in the nematode Caenorhabditis elegans
    Zao Li
    Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX, USA
    Methods Mol Biol 1004:183-202. 2013
    ..These methods are based on Differential Interference Contrast (DIC) microscopy or fluorescence microscopy using GFP-based reporters...
  3. pmc Autophagy genes function in apoptotic cell corpse clearance during C. elegans embryonic development
    Shuyi Huang
    Center for Autophagy Research, University of Texas Southwestern Medical Center, Dallas, TX, USA
    Autophagy 9:138-49. 2013
    ..Together, these data demonstrate that autophagy proteins play an important role in cell corpse clearance during nematode embryonic development, and likely function in parallel to known pathways involved in corpse removal...
  4. pmc Phagocytic receptor signaling regulates clathrin and epsin-mediated cytoskeletal remodeling during apoptotic cell engulfment in C. elegans
    Qian Shen
    Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA
    Development 140:3230-43. 2013
    ..Our work reveals novel roles of clathrin and epsin in apoptotic-cell internalization, suggests a Hip1/R-independent mechanism linking clathrin to actin assembly, and ties the CED-1 pathway to cytoskeleton remodeling. ..
  5. pmc Phagosome maturation during the removal of apoptotic cells: receptors lead the way
    Zheng Zhou
    Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX 77030, USA
    Trends Cell Biol 18:474-85. 2008
    ..Here, we discuss these exciting new findings, focusing on the mechanisms that regulate the interactions between intracellular organelles and phagosomes...
  6. pmc Two alternative mechanisms that regulate the presentation of apoptotic cell engulfment signal in Caenorhabditis elegans
    VICTOR VENEGAS
    Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX 77030, USA
    Mol Biol Cell 18:3180-92. 2007
    ....
  7. pmc Phagocytic receptor CED-1 initiates a signaling pathway for degrading engulfed apoptotic cells
    Xiaomeng Yu
    Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas, United States of America
    PLoS Biol 6:e61. 2008
    ....
  8. pmc The small GTPase Rab2 functions in the removal of apoptotic cells in Caenorhabditis elegans
    Paolo M Mangahas
    Program in Developmental Biology, Baylor College of Medicine, Houston, TX 77030, USA
    J Cell Biol 180:357-73. 2008
    ..We propose that UNC-108 acts on phagosomal surfaces to promote phagosome maturation and suggest that mammalian Rab2 may have a similar function in the degradation of apoptotic cells...
  9. pmc Detecting apoptotic cells and monitoring their clearance in the nematode Caenorhabditis elegans
    Nan Lu
    Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX, USA
    Methods Mol Biol 559:357-70. 2009
    ..elegans embryos and adults and for monitoring their clearance during embryonic development. These methods are based on Differential Interference Contrast microscopy and on fluorescence microscopy using GFP-based reporters...
  10. pmc 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
    Nan Lu
    Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas, United States of America
    PLoS Biol 10:e1001245. 2012
    ..They further shed light on how the temporally controlled reversible phosphorylation of phosphoinositides regulates the progression of multi-step cellular events...
  11. pmc Membrane trafficking and phagosome maturation during the clearance of apoptotic cells
    Nan Lu
    Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas, USA
    Int Rev Cell Mol Biol 293:269-309. 2012
    ..Here, we discuss these exciting new findings, which have significantly deepened and broadened our understanding of the mechanisms that regulate the interaction between intracellular organelles and phagosomes...
  12. pmc Three sorting nexins drive the degradation of apoptotic cells in response to PtdIns(3)P signaling
    Nan Lu
    Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX 77030, USA
    Mol Biol Cell 22:354-74. 2011
    ....
  13. pmc Live-cell imaging in Caenorhabditis elegans reveals the distinct roles of dynamin self-assembly and guanosine triphosphate hydrolysis in the removal of apoptotic cells
    Bin He
    Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX 77030, USA
    Mol Biol Cell 21:610-29. 2010
    ....
  14. pmc Cellular and nuclear degradation during apoptosis
    Bin He
    Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX 77030, USA
    Curr Opin Cell Biol 21:900-12. 2009
    ..Here we highlight recent discoveries made in invertebrate models and mammalian systems, focusing on the molecular mechanisms that regulate the efficient degradation of apoptotic cells...
  15. pmc Glial precursors clear sensory neuron corpses during development via Jedi-1, an engulfment receptor
    Hsiao Huei Wu
    The Center for Molecular Neuroscience, Kennedy Center for Human Development, and Department of Biochemistry, Vanderbilt University Medical School, Nashville, Tennessee, USA
    Nat Neurosci 12:1534-41. 2009
    ..Together, these results suggest a cellular and molecular mechanism by which neuronal corpses are culled during DRG development...