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Using vaccinia virus to understand Rho GTPase regulation and crosstalk

  • Full or part time
    Dr M Way
  • Application Deadline
    Saturday, May 18, 2019
  • Funded PhD Project (Students Worldwide)
    Funded PhD Project (Students Worldwide)

Project Description

This 4-year PhD studentship is offered in Dr Michael Way’s Group based at the Francis Crick Institute (the Crick).

Viruses are obligate intracellular parasites that critically depend on their hosts to generate new progeny. To achieve this goal, viruses have evolved numerous strategies to subvert and hijack many host cellular processes to facilitate their entry, replication, survival and cell-to-cell spread. Understanding how viruses exploit their hosts offers a unique opportunity to obtain a mechanistic understanding of a wide variety of cellular processes. It also provides important insights into the underlying cause of disease and helps identify potential targets for therapeutic intervention.

Our research uses Vaccinia virus as a model system to interrogate many aspects of cell biology via a multidisciplinary approach that includes quantitative live cell imaging and biochemistry. Our work has uncovered important insights into the regulation and function of Src and Rho GTPase signalling, membrane trafficking, DNA damage response, cytoskeletal dynamics, actin and microtubule-based transport as well as cell migration (Lab website - https://michaelway0.wixsite.com/waylab).

The proposed project will examine the role of Rho GTPases in Vaccinia infection and use the virus as a tool to understand Rho GTPase signalling. Rho GTPases are "molecular switches" controlling many cellular processes including cytoskeletal dynamics and cell migration. Historically, studies focused on RhoA, Rac and Cdc42. However, the human genome encodes 22 Rho GTPases, the cellular function of many of which remains to be fully established.

We previously demonstrated that Vaccinia regulates Rho GTPase signalling at two stages in its replication cycle. At the latter stages of infection, Vaccinia induces cell migration by inhibiting RhoA signalling via F11, a viral protein that binds directly to RhoA (Valderrama et al., 2006 Science). Once bound, RhoA is inactivated by the RhoGAP activity of myosin-9A, which also binds F11 (Handa et al., 2013 Cell Host & Microbe). Ultimately, F11-mediated inhibition of RhoA signalling late in infection promotes viral spread by stimulating cell migration, increasing microtubule dynamics, and enhancing virus release by modulating the cortical actin beneath the plasma membrane.

Soon after infection, Vaccinia-infected cells undergo a phase of contraction and blebbing that is reminiscent of cell behavior during tumour cell migration. We found that F11 is also required for this process. Interestingly, F11-induced cell contraction is dependent on RhoC and not RhoA signalling (Durkin et al., 2017 Dev Cell). Our study revealed that RhoC activity is inhibited by a complex of RhoD and the kinase, PAK6. F11 antagonizes this inhibition early during infection to allow RhoC driven contractility.

The proposed project will investigate (1) how this new signalling pathway and RhoGTPase interplay contributes to 3D cell migration, (2) how RhoD-PAK6 inhibits RhoC, and (3) how Vaccinia activates RhoC and other RhoGTPases.

Talented and motivated students passionate about doing research are invited to apply for this PhD position. The successful applicant will join the Crick PhD Programme in September 2019 and will register for their PhD at one of the Crick partner universities (Imperial College London, King’s College London or UCL).

Applicants should hold or expect to gain a first/upper second-class honours degree or equivalent in a relevant subject and have appropriate research experience as part of, or outside of, a university degree course and/or a Masters degree in a relevant subject.

APPLICATIONS MUST BE MADE ONLINE VIA OUR WEBSITE (ACCESSIBLE VIA THE ‘APPLY NOW’ LINK ABOVE) BY 12:00 (NOON) MARCH 18 2018. APPLICATIONS WILL NOT BE ACCEPTED IN ANY OTHER FORMAT.

Funding Notes

Successful applicants will be awarded a non-taxable annual stipend of £22,000 plus payment of university tuition fees. Students of all nationalities are eligible to apply.

References

1. Pfanzelter, J., Mostowy, S. and Way, M. (2018)

Septins suppress the release of vaccinia virus from infected cells.

Journal of Cell Biology 217: 2911-2929. PubMed abstract

2. Durkin, C. H., Leite, F., Cordeiro, J. V., Handa, Y., Arakawa, Y., Valderrama, F. and Way, M. (2017)

RhoD inhibits RhoC-ROCK-dependent cell contraction via PAK6.

Developmental Cell 41: 315-329.e317. PubMed abstract

3. Snetkov, X., Weisswange, I., Pfanzelter, J., Humphries, A. C. and Way, M. (2016)

NPF motifs in the vaccinia virus protein A36 recruit intersectin-1 to promote Cdc42:N-WASP-mediated viral release from infected cells.

Nature Microbiology 1: 16141. PubMed abstract

4. Abella, J. V. G., Galloni, C., Pernier, J., Barry, D. J., Kjær, S., Carlier, M.-F. and Way, M. (2016)

Isoform diversity in the Arp2/3 complex determines actin filament dynamics.

Nature Cell Biology 18: 76-86. PubMed abstract

5. Handa, Y., Durkin, C. H., Dodding, M. P. and Way, M. (2013)

Vaccinia virus F11 promotes viral spread by acting as a PDZ-containing scaffolding protein to bind Myosin-9A and inhibit RhoA signaling.

Cell Host & Microbe 14: 51-62. PubMed abstract

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