Dr Stephen Graham

Molecular mechanisms of membrane trafficking and viral infection

Biography

In 2018 Stephen collaborated with the Wellcome Trust as part of their Researcher Stories initiative. Read the full article at the Wellcome Trust website or watch the video below.

After replication viruses face a logistical challenge: How do they ensure progeny virions are efficiently released from host cells? While human pathogens such as herpes simplex virus and vaccinia virus (the smallpox vaccine) are known to subvert host-cell intracellular membrane trafficking pathways in order to leave infected cells, little is known about the molecular mechanisms used to achieve this. We are using a combination of cell biology, biochemistry, biophysics and structural biology to define the interactions between host cell and virus proteins that enable enveloped viruses to exit infected cells and thereby spread the infection to new hosts.

In order to establish a fruitful infection viruses must evade the immune surveillance systems of the host. I am interested in how viruses directly interfere with innate and intrinstic immune responses during infection, how they modify the surface of infected cells to minimise the adaptive immune response, and how some viruses have even managed to hijack mammalian innate immune proteins and ‘re-program’ these to suit the needs of the virus.

Group Members:
Tomasz Benedyk, Ben Butt, Kamal Nahas, Henry Barrow, Monique Merchant

Publications

Key publications:

W.N.D. Gao, C. Gao, J.E. Deane, D.C.J. Carpentier, G.L. Smith, S.C. Graham (2022) The crystal structure of vaccinia virus protein E2 and perspectives on the prediction of novel viral protein folds. Journal of General Virology 103: 001716 [doi: 10.1099/jgv.0.001716]
T.H. Benedyk, J. Muenzner, V. Connor, Y. Han, K. Brown, K.J. Wijesinghe, Y. Zhuang, S. Colaco, G.A. Stoll, O.S. Tutt, S. Svobodova, D.I. Svergun, N.A. Bryant, J.E. Deane, A.E. Firth, C.M. Jeffries, C.M. Crump^, S.C. Graham^ (2021) pUL21 is a viral phosphatase adaptor that promotes herpes simplex virus replication and spread. PLoS Pathogens, 17: e1009824 [doi: 10.1371/journal.ppat.1009824]
C. Conceicao*, N. Thakur*, S. Human, J.T. Kelly, L. Logan, D. Bialy, S. Bhat, P. Stevenson-Leggett, A.K. Zagrajek, P. Hollinghurst, M. Varga, C. Tsirigoti, M. Tully, C. Chiu, K. Moffat, A.P. Silesian, J.A. Hammond, H.J. Maier, E. Bickerton, H. Shelton, I. Dietrich, S.C. Graham, D. Bailey (2020) The SARS-CoV-2 Spike protein has a broad tropism for mammalian ACE2 proteins. PLoS Biology 18: e3001016 [doi: 10.1371/journal.pbio.3001016]
T.K. Soh*, C.T.R. Davies*, J. Muenzner*, L.M. Hunter, H.G. Barrow, V. Connor, C.R. Bouton, C. Smith, E. Emmott, R. Antrobus, S.C. Graham^, M.P. Weekes^, C.M. Crump^ (2020) Temporal Proteomic Analysis of Herpes Simplex Virus 1 Infection Reveals Cell-Surface Remodeling via pUL56-Mediated GOPC Degradation. Cell Reports, 33: 108235 [doi: 10.1016/j.celrep.2020.108235]
B.G. Butt, D.J. Owen, C.M. Jeffries, L. Ivanova, C.H. Hill, J.W. Houghton, M.F. Ahmed, R. Antrobus, D.I. Svergun, J.J. Welch, C.M. Crump, S.C. Graham (2020) Insights into herpesvirus assembly from the structure of the pUL7:pUL51 complex. eLife, 9: e53789 [doi: 10.7554/eLife.53789]
C. Gao, M.A. Pallett, T.I. Croll, G.L. Smith, S.C. Graham (2019) Molecular basis of cullin-3 (Cul3) ubiquitin ligase subversion by vaccinia virus protein A55. Journal of Biological Chemistry, 294: 6416–6429 [doi: 10.1074/jbc.RA118.006561]
A. Albecka, D.J. Owen, L. Ivanova, J. Brun, R. Liman, L. Davies, M.F. Ahmed, S. Colaco, M. Hollinshead, S.C. Graham^ and C.M. Crump^ (2017) Dual function of the pUL7-pUL51 tegument protein complex in HSV-1 infection. Journal of Virology, 81: e02196-16 [doi: 10.1128/JVI.02196-16]