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Studying membrane phospholipid asymmetry through C.elegans model

Phospholipids are major components of plasma membrane and organelle membranes that maintain the integrity of the cell or organelles by creating a semi-impermeable barrier from their outside environment. In normal cells, phospholipids are asymmetrically distributed in inner and outer leaflets of plasma membrane, with phosphatidylcholine (PC) and sphingomyelin (SM) predominantly in the outside leaflet and phosphatidylserine (PS) and phosphatidylethanolamine (PE) in the inner leaflet of plasma membrane. Phospholipid asymmetry is also seen with membrane organelles. More and more studies have indicated that phospholipid asymmetry may play critical roles in many important biological and cellular processes. For example, phospholipid asymmetry helps target proteins to appropriate subcellular sites or organelles for specific cellular processes (e.g. organelle fusion/division or apoptosis), maintain biophysical properties of specific membranes, sustain cell shape, facilitate membrane vesicle trafficking/fusion/budding, regulate activities of membrane proteins, and transduce intracellular signals. On the other hand, alteration of phospholipid asymmetry (for example, the externalization of PS by a cell) can also play important roles in activating cellular or biological processes such as blood coagulation, recognition and removal of apoptotic cells, cytokinesis, and cell fusion. It is very likely that phospholipid asymmetry or alteration of phospholipid asymmetry can have other crucial cellular functions that have yet to be discovered and characterized. It has been suggested that an energy-dependent, active phospholipid transbilayer movement is needed to establish and maintain the phospholipid asymmetry. In addition, constant and dynamic membrane trafficking between plasma membrane and organelles (endocytosis, exocytosis, vesicle fusion and division) and modifications or hydrolysis of phospholipids by lipid enzymes such as phospholipases also contribute to the generation or alteration of phospholipid asymmetry. In my laboratory, we are interested in addressing three fundamental questions regarding phospholipid asymmetry using a combination of genetic, functional genomic, cell biological, and biochemical approaches

1. Why does a cell need to generate and maintain phospholipid asymmetry, and in certain situations, alter this asymmetry?
2. What is the molecular machinery or network that generates and maintains the phospholipid asymmetry?
3. How does alteration of phospholipid asymmetry impact the functions and the activities of a cell?

Related Publications:

Wang, X.C., Wu, Y.C., Fadok, V., Lee, M.C., Gengyo-Ando, K., Cheng, L.C., Ledwich, D., Hsu, P.K., Chen, J.Y., Chou, B.K., Henson, P., Mitani, S., and Xue, D. (2003). Cell Corpse Engulfment Mediated by C. elegans Phosphatidylserine Receptor Through CED-5 and CED-12. Science 302, 1563-1566.( and ).  and 

Wang, X.C., Wang, J., Gengyo-Ando, K., Gu, L.C., Sun, C.L., Yang, C.L., Shi, Y., Kobayashi, T., Shi, Y.G., Mitani, S., Xie, X.S., and Xue, D. (2007). "C. elegans mitochondrial factor WAH-1 promotes phosphatidylserine externalization in apoptotic cells through phospholipid scramblase SCRM-1". Nature Cell Biology 9, 541-549. ( and ).  ()

Darland-Ransom, M., Wang, X.C., Sun, C.L., Mapes, J., Gengyo-Ando, K., Mitani, S. and Xue, D. (2008). Role of C. elegans TAT-1 protein in maintaining plasma membrane phosphatidylserine asymmetry. Science 320, 528-531. ( and ). 

Wang, X.C., Li W., Zhao, D.F., Liu, B., Shi, Y., Chen, B.H., Yang, H.W., Guo, P.F., Geng, X., Shang, Z.H., Peden, E., Kage-Nakadai, E., Mitani, S., and Xue, D. (2010). C. elegans transthyretin-like protein TTR-52 mediates recognition of apoptotic cells by the CED-1 phagocyte receptor. Nature Cell Biology 12, 655-664. ( and ) 

 Mapes, J., Chen, Y.Z., Kim, A., Mitani, S., Kang, B.H., and Xue, D. (2012). CED-1, CED-7, and TTR-52 act in a pathway to regulate exoplasmic phosphatidylserine expression on apoptotic and phagocytic cells. Current Biology 22, 1267-1275. ( and ). Faculty of 1000

Morton, LA, Yang H, Saludes JP, Fiorini Z, Beninson L, Chapman ER, Fleshner M, Xue D, Yin H (2013). MARCKS-ED Peptide as a Curvature and Lipid Sensor. ACS Chemical Biology 8: 218-225. ( and PDF)

Chen, Y.Z., Mapes, J., Lee, E.S. and Xue, D. (2013). Caspase-mediated activation of Caenorhabditis elegans CED-8 promotes apoptosis and PS externalization. Nature Communications 4:2726 doi: 10.1038/ncomms3726. ( and )

Nakagawa, A., Sullivan, K., and Xue, D. (2014). Caspase-activated phosphoinositide binding by CNT-1 promotes apoptosis by inhibiting the AKT pathway. Nature Structural & Molecular Biology 21, 1082-1090 ( and ).

Yang, H.W.*, Chen, Y.Z.*, Zhang, Y.*, Wang, X.H., Zhao, X., Godfroy, J.I., Liang, L., Zhang, M., Zhang, T.Y., Yuan, Q., Royal, M.A., Driscoll, M.D., Xia, N.S., Yin, H., and Xue, D. (2015). A lysine-rich motif in the phosphatidylserine receptor PSR-1 mediates recognition and removal of apoptotic cells. Nature Communications , 6: 5717 doi: 10.1038/ncomms6717. *Equal contribution. ( and ). 

Neumann, B., Coakley, S., Giordano-Santini, R., Linton, C., Lee, E.S., Nakagawa, A., Xue, D., and Hilliard, M.A. (2015). EFF-1-mediated regenerative axonal fusion requires components of the apoptotic pathway. Nature 517, 219–222 ( and ).

Sullivan, K.*, Nakagawa, A.*, Xue, D.#, and Espinosa, J.M.# (2015). Human ACAP2 is a homolog of C. elegans CNT-1 that promotes apoptosis in cancer cells. Cell Cycle 14, 1771-1778. *Equal contribution. #Co-corresponding authors. ( and ).

Review Articles

Fadeel, B. and Xue, D. (2005). PS externalization: from corpse clearance to drug delivery. Cell Death Differentiation 13, 360-362. ()

Fadeel, B., Quinn, P., Xue, D., and Kagan, V. (2007). Fat(al) attraction: oxidized lipids act as 'eat-me' signals. HFSP Journal 1: 225–229. (PDF)

Fadeel, B. and Xue, D. (2009). The ins and outs of phospholipid asymmetry in the plasma membrane: roles in health and disease. Critical Reviews In Biochemistry & Molecular Biology 44: 264–277. ( and )

Klöditz, K., Chen, Y.Z., Xue, D., and Fadeel, B. (2017). Programmed cell clearance: From nematodes to humans. Biochemical and Biophysical Research Communications, 482: 491-497 ( and ).