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Ubiquitination mechanisms in the endoplasmic reticulum that regulate innate immune signalling pathways – links to cancer and beyond


Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences

About the Project

Supervisor(s): John Christianson (https://www.ndorms.ox.ac.uk/team/john-christianson) / Eileen Parkes (Oncology - https://www.oncology.ox.ac.uk/team/eileen-parkes)

Project Outline:


Innate immunity is an indispensable facet of mammalian defence mechanisms protecting us from infection by viral and bacterial pathogens. The pathways underpinning innate immunity are also emerging as important factors in cancer inflammation, as well as contributors to auto-immune and neurodegenerative disorders. In one such pathway, a cytoplasmic sensor cGAS recognises pathogenic (non-self) or mislocalised DNA and activates STING, a polytopic membrane protein embedded in the endoplasmic reticulum (ER) whose oligomerisation and efflux from this organelle initiates the signalling cascade that activates a Type I interferon response (1). Fine tuning of this response is paramount, and ubiquitination of STING has emerged as an important post-translational modification capable of modulating these signalling events. Establishing how ubiquitination and its conjugating machinery impact the cGAS-STING pathway is important to fully understand the cellular determinants impacting immune signalling and assessing their potential for pharmacological intervention.

This DPhil project will aim to biochemically and functionally characterise ER-resident ubiquitination machinery that modulates the cGAS-STING signalling pathway in order to delineate its regulation of the interferon response. Recently, our lab identified a multi-subunit ER-resident ubiquitin ligase (E3) complex organised around RNF26, whose constituents modulate signalling through STING to scale the magnitude of the interferon response (2). We are now investigating how each component of this RNF26 complex impacts STING to contribute to the response, focusing on defining protein-protein interactions, key functional domains, ubiquitin linkages, complex assembly, and its synergy (or competition) with other ubiquitin ligases.

This DPhil project will employ a range of cutting-edge and traditional methodologies including; CRISPR/Cas9-mediated genomic editing, proximity labelling, protein purification, fluorescence microscopy, cell-based and in vitro assays, western blotting, flow cytometry, and quantitative proteomics. It would be suitable for students with a background (or interest) in cell biology, biochemistry or immunology, with an interest in the ubiquitin-proteasome system, immune signalling, protein trafficking and/or proteomics.

Collectively this research will develop insights into the fundamental cellular controls of immune signalling. Along with ongoing work in the lab, it will form part of our broad effort to explore and define ubiquitination events and mechanisms at the ER responsible for essential cellular homeostatic functions.

For further information, please visit our website at
https://www.ndorms.ox.ac.uk/team/john-christianson

Themes


Cell biology of the ubiquitin-proteasome system
Signalling mechanisms in the endoplasmic reticulum
Immune signalling
Protein trafficking

The Research Group


This multifaceted project is led by Dr. John Christianson, Associate Professor and a Cancer Research UK Senior Research Fellow at the Botnar Research Centre in the Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences. The Christianson Group recently moved from the Ludwig Institute for Cancer Research – Oxford and is currently recruiting members for an expanding group that will soon include 2 post-docs, a DPhil student, a Research Associate, as well as visiting and rotation students. Dr. Parkes is a Clinical Career Development Fellow in the Department of Oncology. Her research interests are in the role of the cGAS-STING pathway in cancer and its exploitation for clinical benefit.

Training


The Botnar Research Centre plays host to the University of Oxford's Institute of Musculoskeletal Sciences, which enables and encourages research and education into the causes of musculoskeletal disease including cancer and their treatment. Training will be provided in techniques including state of the art molecular and cell biology, compound screening and proteomics.

A core curriculum of lectures will be taken in the first term to provide a solid foundation in a broad range of subjects including musculoskeletal biology, inflammation, epigenetics, translational immunology, data analysis and the microbiome. Students will also be required to attend regular seminars within the Department and those relevant in the wider University.

Students will be expected to present data regularly in Departmental seminars, the Christianson Group, and to attend external conferences to present their research globally, with limited financial support from the Department.

The student will interact closely with members of research groups in the Botnar Research Centre. They will also benefit from the lab’s collaborations with researchers at the Target Discovery Institute, Structural Genomics Consortium, Kennedy Institute, Dunn School of Pathology, and Weatherall Institute for Molecular Medicine

Students will have access to various courses run by the Medical Sciences Division Skills Training Team and other Departments. All students are required to attend a 2-day Statistical and Experimental Design course at NDORMS and run by the IT department (information will be provided once accepted to the programme).

How to Apply


The Department accepts applications throughout the year but it is recommended that, in the first instance, you contact the relevant supervisor(s) or the Graduate Studies Officer, Sam Burnell (), who will be able to advise you of the essential requirements.

Interested applicants should have, or expect to obtain, a first or upper second-class BSc degree or equivalent in a relevant subject and will also need to provide evidence of English language competence (where applicable). The application guide and form are found online and the DPhil by research will commence in October 2021.

Applications should be made to the following programme using the specified course code:

D.Phil in Molecular and Cellular Medicine (course code: RD_MP1)

For further information, please visit http://www.ox.ac.uk/admissions/graduate/applying-to-oxford


References

1. Hopfner K and Hornung V (2020) Molecular mechanisms and cellular functions of cGAS–STING signalling. Nature Reviews Molecular Cell Biology. 197: 1-21 (https://www.nature.com/articles/s41580-020-0244-x)
2. Fenech EJ, Lari F, Charles PD, Fischer R, Thezenas ML, Bagola K, Paton AW, Paton JC, Gyrd-Hansen M, Kessler BM, Christianson JC (2020) Interaction mapping of endoplasmic reticulum ubiquitin ligases identifies modulators of innate immune signaling. eLife 2020;9:e57306 DOI: 10.7554/eLife.573 (https://elifesciences.org/articles/57306)

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