Enfu Hui


Ideally, the immune system identifies tumors as threatening elements and deploys immune cells (T cells) to find and kill them. However, many tumor cells have evolved to employ a protein called PD-L1 to blind T cells from carrying out their functions and evade immune defenses. PD-L1 protects tumor cells by activating a "molecular brake" or “checkpoints” known as PD-1 to stop T cells. Remarkably, drugs that block PD-1 or its ligand PD-L1 have proven to release the PD-1 brake from T cells, and demonstrated unprecedented clinical activities in a variety of human cancers. Still, durable response is limited to a small subset of cancer patients. Identification of reliable predictive biomarkers, and targeting other immune checkpoints, either alone or in combination with PD-1 inhibitors, hold the promise of extending the therapy to more tumor types and a larger populations of patients. However, these efforts are slowed down by the incomplete molecular understanding of immune checkpoints.

We are a group of biochemists and cell biologists aiming to dissect the mechanisms of immune checkpoints, using cell-free membrane reconstitution, time-resolved live cell microscopy and cutting-edge cell biology approaches. We recently uncovered two novel aspects of PD-L1/PD-1 signaling. Intracellularly, we showed that the T cell costimulatory receptor CD28 is a primary target of PD-1 associated phosphatases. Extracellularly, we discovered that PD-L1, a key weapon of tumor cells, can be neutralized in cis by PD-1 expressed on the same cells. Now, we will continue to elucidate the PD-1 signaling pathway by identification of novel regulators and targets of PD-1. In addition, we are investigating whether and how additional immune brakes operate in conjunction with PD-1 to “turn off” T cell activity. We will identify the triggering molecules that turn these brakes on, and signal transducers these brakes recruit to suppress the immune response. Our findings could lead to the development of novel biomarkers and drug targets of cancer immunotherapy.

Select Publications

  • Zhao, Y., Harrison, D. L., Song, Y., Ji, J., Huang, J., and Hui, E. Antigen-Presenting Cell-Intrinsic PD-1 Neutralizes PD-L1 in cis to Attenuate PD-1 Signaling in T Cells. Cell Rep 2018;24:379-90 e376.
  • Hui, E., Cheung, J., Zhu, J., Su, X., Taylor, M. J., Wallweber, H. A., Sasmal, D. K., Huang, J., Kim, J. M., Mellman, I., and Vale, R. D. T cell costimulatory receptor CD28 is a primary target for PD-1-mediated inhibition. Science 2017;355, 1428-1433.
  • Carbone, C. B., Kern, N., Fernandes, R. A., Hui, E., Su, X., Garcia, K. C., and Vale, R. D. In vitro reconstitution of T cell receptor-mediated segregation of the CD45 phosphatase. Proceedings of the National Academy of Sciences of the United States of America 2017;114, E9338-E9345.
  • Su X, Ditlev JA, Hui E, Xing W, Banjade S, Okrut J, King DS, Taunton J, Rosen MK, Vale RD. Phase separation of signaling molecules promotes T cell receptor signal transduction. Science 2016;352(6285):595-9. doi: 10.1126/science.aad9964.
  • Chang, C. W., Hui, E., Bai, J., Bruns, D., Chapman, E. R., and Jackson, M. B. A structural role for the synaptobrevin 2 transmembrane domain in dense-core vesicle fusion pores. The Journal of Neuroscience 2015;35 (14) 5772-80.
  • Liu, H., Bai, H., Hui, E., Yang, L., Evans, C. S., Wang, Z., Kwon, S. E., and Chapman, E. R. Synaptotagmin 7 functions as a Ca2+-sensor for synaptic vesicle replenishment. Elife 2014;e01524.
  • Hui E, Vale RD. In vitro membrane reconstitution of the T-cell receptor proximal signaling network. Nature structural & molecular biology . 2014;21(2):133-42. doi: 10.1038/nsmb.2762
  • Hui E, Gaffaney JD, Wang Z, Johnson CP, Evans CS, Chapman ER. Mechanism and function of synaptotagmin-mediated membrane apposition. Nature structural & molecular biology . 2011;18(7):813-21. doi: 10.1038/nsmb.2075.
  • Zhang Z, Hui E, Chapman ER, Jackson MB. Regulation of exocytosis and fusion pores by synaptotagmin-effector interactions. Molecular biology of the cell . 2010;21(16):2821-31. doi: 10.1091/mbc.E10-04-0285.
  • Zhang Z, Hui E, Chapman ER, Jackson MB. Phosphatidylserine regulation of Ca2+-triggered exocytosis and fusion pores in PC12 cells. Molecular biology of the cell . 2009;20(24):5086-95. doi: 10.1091/mbc.E09-08-0691.
  • Hui E, Johnson CP, Yao J, Dunning FM, Chapman ER. Synaptotagmin-mediated bending of the target membrane is a critical step in Ca(2+)-regulated fusion. Cell . 2009;138(4):709-21. doi: 10.1016/j.cell.2009.05.049.
  • Shahin V, Datta D, Hui E, Henderson RM, Chapman ER, Edwardson JM. Synaptotagmin perturbs the structure of phospholipid bilayers. Biochemistry . 2008;47(7):2143-52. doi: 10.1021/bi701879g. PubMed PMID: 18205405; PubMed Central PMCID: PMC3095487.
  • Paddock BE, Striegel AR, Hui E, Chapman ER, Reist NE. Ca2+-dependent, phospholipid-binding residues of synaptotagmin are critical for excitation-secretion coupling in vivo. The Journal of Neuroscience 2008;28(30):7458-66. doi: 10.1523/JNEUROSCI.0197-08.2008.
  • Gaffaney JD, Dunning FM, Wang Z, Hui E, Chapman ER. Synaptotagmin C2B domain regulates Ca2+-triggered fusion in vitro: critical residues revealed by scanning alanine mutagenesis. The Journal of Biological Chemistry . 2008;283(46):31763-75. doi: 10.1074/jbc.M803355200.
  • Chicka MC, Hui E, Liu H, Chapman ER. Synaptotagmin arrests the SNARE complex before triggering fast, efficient membrane fusion in response to Ca2+. Nature structural & molecular biology . 2008;15(8):827-35. doi: 10.1038/nsmb.1463.
  • Hui E, Bai J, Chapman ER. Ca2+-triggered simultaneous membrane penetration of the tandem C2-domains of synaptotagmin I. Biophysical Journal 2006;91(5):1767-77. doi: 10.1529/biophysj.105.080325.
  • Czibener, C., Sherer, N. M., Becker, S. M., Pypaert, M., Hui, E., Chapman, E. R., Mothes, W., and Andrews, N. W. Ca2+ and synaptotagmin VII-dependent delivery of lysosomal membrane to nascent phagosomes. J Cell Biol 2006;174, 997-1007.
  • Hui E, Bai J, Wang P, Sugimori M, Llinas RR, Chapman ER. Three distinct kinetic groupings of the synaptotagmin family: candidate sensors for rapid and delayed exocytosis. Proceedings of the National Academy of Sciences of the United States of America. 2005;102(14):5210-4. doi: 10.1073/pnas.0500941102.


Enfu Hui obtained his Ph.D. in 2009 from UW Madison. He then completed his postdoctoral training at UCSF as a fellow of the Leukemia & Lymphoma Society. He joined the Division of Biological Sciences at UCSD in July 2016 and was named as a Searle Scholar and Pew Scholar.