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2023-24 Bloomsbury Colleges PhD Studentship - Project 3

Project 3 – Composition and structure of the COPII coat in immunoglobulin secretion from the plasma cell

The Bloomsbury Colleges group was set up in 2004 and consists of five institutions: Birkbeck, London School of Hygiene & Tropical Medicine (LSHTM), the Royal Veterinary College (RVC), the School of Oriental and African Studies (SOAS), and the UCL Institute of Education (UCL–IOE). These studentships were set up to increase collaboration and interdisciplinary research opportunities across the colleges.

Applications are invited for a three-year PhD studentship, to start in the academic year 2023-24 based at the London School of Hygiene & Tropical Medicine (LSHTM) as the lead institution.

Funding

The studentship will provide:

for the duration of the award.

Project details

For details of studentships available at other Bloomsbury colleges but in collaboration with the London School of Hygiene & Tropical Medicine, please see the Bloomsbury Colleges website. Please apply directly to the lead institution only.

Project 3: Composition and structure of the COPII coat in immunoglobulin secretion from the plasma cell

Supervisory Team

Background

B lymphocytes are the blood cells responsible for immunoglobulin (Ig, or antibody) production and secretion, a fundamental process for the humoral immune response to infections and vaccines.

To become antibody factories, B lymphocytes are activated and then differentiate into plasma cells. This requires huge changes in the cell’s secretory membranes and particularly involves rapid growth of the endoplasmic reticulum (ER), the site of protein synthesis, as well as changes to the downstream pathway control points.

In mammalian cells, the zones of protein export from the ER are termed the ER exit site (ERES). Transport of immunoglobulins (as well as thousands of other newly synthesised proteins) from the ER to the Golgi apparatus is mediated by the COPII coat complex, which remodels membranes into coated carriers while concentrating cargo into them. While the basic functions of COPII components have been well characterised in yeast, its regulation in the more complex mammalian systems (where multiple COPII paralogues are present) and particularly in specialised secretory cells remains poorly understood.

Antibodies can come in different varieties known as isotypes or classes of which there are 5 in mammalian cells; IgA, IgD, IgE, IgG, IgM. The Ig class secreted by a B cell is dependent on B cell maturation and performs different roles during the immune response. IgG is secreted as a monomer while IgM is much larger, forming a pentameric structure of 45-50 nm diameter, which has implications for cargo export and transport carriers.

This project aims to understand the mechanisms behind secretion of different types of immunoglobulins from B-cells. Preliminary data from our labs suggest differentiating B cells express specific COPII paralogues. This project will build on our observations to investigate outstanding questions:

1. Is paralogue specificity associated with specific changes in secretion, for example cargo load, or expression of certain Ig isotype that have very different sizes.

2. Does COPII composition differ between naïve undifferentiated B cells and plasma cells?

3. What are the morphological changes in ERES organisation upon differentiation?

This project will have important implications both in terms of human health and response to infection, and also for optimised antibody production in biomedical/pharma applications.

Methodologies

You will use a combination of cell biology, biochemistry, light microscopy and cryo-electron tomography to reveal the role of the COPII coat complex in export of different classes of Igs from the endoplasmic reticulum (ER).

This will include B cell in vitro activation assays, confocal microscopy, real-time PCR, mathematical modelling, CRISPR gene editing, cryo electron microscopy and tomography, cryo FIB/SEM, cryo-correlative microscopy.

Subject areas/keywords

B cells, antibody secretion, COPII complex, membrane trafficking, fluorescence microscopy, cryo-electron microscopy.

Key references

  1. Zanetti, G., Pahuja, K.B., Studer, S., Shim, S., Schekman, R. (2011) COPII and the regulation of protein sorting in mammals. Nat. Cell Biol. 14:20-28
  2. Kirk, S.J., and Ward, T.H. (2007) COPII under the microscope. Semin. Cell Dev. Biol. 18:435-447
  3. Kirk, S.J., Cliff, J.M., Thomas, J.A., and Ward, T.H. (2010) Biogenesis of secretory organelles during B cell differentiation. J. Leukoc. Biol. 87:245-255
  4. Hutchings, J., Stancheva, V.G., Brown, N.R., Cheung, A.C.M., Miller, E.A., Zanetti, G. (2021) Structure of the complete, membrane-assembled COPII coat reveals a complex interaction network. Nat. Commun. 12:2034

Further details about the project may be obtained from:

Deadline for applications

The deadline for applications is 23:59 (GMT) on Sunday 5 February 2023.

Eligibility

Applicants must meet minimum LSHTM entry requirements. Please see the specific project details above for any further requirements.

This studentship is open to applicants assessed as both ‘Home’ and ‘Overseas’ fee status.  For further information about Fee Status Assessments please see the School’s Admissions policies.

Successful applicants who are nationals of low income countries and lower middle income countries (LLMICs) may be eligible for an LSHTM bursary to cover the fee top up costs. LLMIC applicants who are short-listed for interview, will be contacted by the LSHTM Scholarships Team at that time to provide further details of the LSHTM bursary scheme as per our UKRI international recruitment statement.  

Successful international applicants who are not from an LLMIC will be required to cover the tuition fee top up costs from other sources (e.g. other scholarship or bursary awards). Awardees may not use their Bloomsbury studentship stipend to top up fees. 

To apply

Information about the MPhil/PhD programme structure at LSHTM, as well as application guidance and a link to the portal, can be found on the School’s Research Degrees and Doctoral College pages.

To apply for this studentship, applicants should submit an application for research degree study via the LSHTM application portal. The applicant should apply via the Faculty of the Primary Supervisor for their proposed project. ‘2023-24 Bloomsbury PhD Studentship’ must be selected in the Funding Section on the application. Students should submit a research proposal based on the advertisement for this project.

Incomplete applications will not be considered for this studentship.

Applications for this project will only be reviewed and processed after the deadline. All applications that are submitted before the deadline will be considered equally, regardless of submission date.  

By submitting an application for this funding applicants agree to its Terms & Conditions.

Deadline

The application deadline for this project is 23:59 (GMT) on Sunday 5 February 2023.