Cell and Developmental Biology University of Michigan

Research

Interaction between host cell and pathogens.

We use biochemical and cell biological approaches to understand the nature of interaction between different toxins and viruses with their host cell. Specifically, we are studying how cholera toxin and polyoma/SV40 virus hijack cellular machineries to cause disease. Both the toxin and viruses bind to receptors at the plasma membrane to initiate infection. The receptor-toxin or receptor-virus complex is endocytosed and traffic backwards along the secretory pathway to reach the lumen of the endoplasmic reticulum (ER). From this compartment, these toxic agents are transported across the ER membrane into the cytosol. Once in the cytosol, cholera toxin induces a signaling cascade which leads to massive water secretion resulting in diarrhea. Polyoma and SV40 virus, upon reaching the cytosol, are transported into the nucleus where transcription and replication of the viral DNA genome ensue, leading to infection of the host cell.

How the toxin and the viruses are transported from the cell surface to the ER and subsequently transported out of the ER into the cytosol are processes that remain largely mysterious. Our overall goal is to clarify the cellular entry mechanism of both cholera toxin and polyoma/SV40 virus. Insights into these mechanisms will not only lead to a better understanding of how certain toxins and viruses infect their host cell, but will also clarify important aspects of basic cellular processes.

Lab Members

• Faye Bradbury
  Research Investigator
• Kaleena Bernardi-Dezsi
  Research Fellow
• Takamasa Inoue
  Research Fellow
• Jeffrey Williams
  Research Lab Technician
• Paul Moore
  Graduate Student
• Christopher Walczak
  Graduate Student

Publications

Representative Publications

1. Lencer, W.I and Tsai, B (2003). The intracellular voyage of cholera toxin: going retro. Trends Biochem. Sci. 28, 639-645.
2. Magnuson, B., Rainey, E.K., Benjamin, T., Baryshev, M., Mkrtchian, S., and Tsai, B. (2005). ERp29 triggers a conformational change in polyomavirus to stimulate membrane binding. Mol. Cell 20,289-300.
3. Low, J.A., Magnuson, B., Tsai, B., and Imperiale, M. J. (2006). Identification of gangliosides GD1b and GT1b as receptors for BK virus. J. Virol. 80,1361-1366.
4. Forster, L.M., Sivick, K., Park, Y-N., Arvan, P., Lencer, W., and Tsai, B. (2006). Protein disulfide isomerase-like proteins play opposing roles during retro-translocation. J. Cell Biology 173, 253-259.
5. Rainey-Barger,E.K., Mkrtchian, S., and Tsai, B. (2007). Dimerization of ERp29, a PDI-like protein, is essential for its diverse functions. Mol. Biol. Cell 18, 1253-1260.
6. Tsai, B. Penetration of non-enveloped viruses into the cytoplasm. (2007). Annu. Rev. Cell Dev. Biol. 23, 23-43.
7. Rainey-Barger, E.K., Magnuson, B., and Tsai, B. (2007). A chaperone-activated non-enveloped virus perforates the physiologically relevant ER membrane. J. Virol. 81, 12996-13004.
8. Lam, A.D., Tryoen-Toth, P., Tsai, B., Vitale, V., and Stuenkel, E.L. (2008). SNARE-catalyzed fusion events are regulated by syntaxin1A-lipid interactions. Mol. Biol. Cell 19, 485-497.
9. Bernardi, K.M., Forster, M.L., Lencer, W.I. and Tsai, B. (2008). Derlin-1 facilitates the retro-translocation of cholera toxin. Mol. Biol. Cell 19, 877-884.
10. Rainey-Barger, E.K., Mkrchian, S., and Tsai, B. (2009). The C-terminal domain of ERp29 mediates polyomavirus binding, unfolding, and infection. J. Virol. 83, 1483-1491.
11. Jiang, M., Abend, J.R., Tsai, B., and Imperiale, M.J. (2009). Early events during BK virus entry and disassembly. J. Virol. 83, 1350-1358.
12. Forster, M. L., Mahn, J., and Tsai, B. (2009). Generating an unfoldase from thioredoxin-like domains . J. Biol. Chem. 284, 13045-13056.
13. Qian, M., Cai, D., Verhey, K.J., and Tsai, B. (2009). A lipid receptor sorts polyomavirus from the endolysosome to the endoplasmic reticulum to cause infection . PloS Pathog. 5, e1000465.
14. Erickson, K.D., Garcea, R.L., and Tsai, B. (2009). Ganglioside GT1b is a putative host cell receptor for the Merkel cell polyomavirus . J. Virology 83, 10275-10279.
15. Bernardi, K.M., Williams, J.M., Kikkert, M., van Voorden, S., Wiertz, E.J., Ye, Y., and Tsai, B. (2010). The E3 ubiquitin ligases Hrd1 and gp78 bind to and promote cholera toxin retro-translocation Mol. Biol. Cell 21, 140-151.
16. Moore, P., Bernardi, K.M., and Tsai, B. (2010). The Ero1a-PDI redox cycle regulates retro-translocation of cholera toxin . Mol. Biol. Cell 21, 1305-1313.
17. Tsai, B., and Qian, M. (2010). Cellular entry of polyomaviruses . Curr. Topics Micro. & Immuno. 343, 177-194.
18. Qian, M., and Tsai, B. (2010). Lipids and proteins play opposing roles to regulate polyomavirus infection. J. Virology 84, 9840-9852.
19. Tsai, B. and Inoue, T. (2010). A virus takes an L turn to find its receptor . Cell Host Microbe 8, 301-302.
20. Walczak, C.P. and Tsai, B. A PDI family network acts distinctly and coordinately with ERp29 to facilitate polyomavirus infection J. Virology.
21. Bradbury, F.A., and Tsai, B. (2011). Functional versus decoy receptor-regulated entry of polyomaviruses. Future Virology 6, 5-7.
22. Inoue, T., and Tsai, B. (2011). A large and intact viral particle penetrates the endoplasmic reticulum membrane to reach the cytosol. PloS Pathogen 7, e1002037.
23. Goodwin, E., Lipovsky, A., Inoue, T., Magaldi, T., Edwards, A.P.B., Yates, K.E., Paton, A.W., Paton, J.C., Atwood, W., Tsai, B., and DiMaio, D. (2011). BiP and multiple DNA J molecular chaperones in the endoplasmic reticulum are required for efficient SV40 infection. mBio 2, e00101-11.
24. Inoue, T., Moore, P., and Tsai, B. (2011). How viruses and toxins disassemble to enter cells. Annu. Rev. Micro. 65, 287-305.
25. Walczak, C.P., Bernardi, K.M., and Tsai B. (2012).Endoplasmic Reticulum-Dependent Redox Reactions Control Endoplasmic Reticulum-Associated Degradation and Pathogen Entry. Antioxid Redox Signal 16, 809-818.
26. Inoue, T., and Tsai, B. (2013). How viruses use the endoplasmic reticulum for entry, replication, and assembly. Cold Spring Harb. Perspect. Biol 5, pii: a013250.
27. Williams, J.M., Inoue, T., Banks, L, and Tsai, B. (2013). The ERdj5-Sel1L complex facilitates cholera toxin retro-translocation. Mol. Biol. Cell (in press).