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Characterising the role of ubiquitylation in endo-lysosomal trafficking by highly sensitive ion mobility mass spectrometry


   Biosciences Institute

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  Prof M Trost, Dr Ben Raymond  No more applications being accepted  Competition Funded PhD Project (Students Worldwide)

About the Project

Background: The human body is faced with a constant onslaught of foreign material such as allergens, bacteria, viruses, fungi, and parasites and in turn has developed specialised cells of the innate immune system such as macrophages that form a first line of defence against these invaders. One of the key innate immune response is the uptake of foreign material through phagocytosis. The engulfment of the microbe leads to a de novo membranous vesicle called phagosome. Phagosomes fuse with a range of intracellular organelles such as endosomes and lysosomes to acquire enzymes that lead to the killing and degradation of the microbes. This process also leads to the production of antigens that are presented on the cell surface by major histocompatibility complex (MHC) to T cells for their activation. Phagocytosis and subsequent phagosome maturation and degradation is therefore paramount to the activation of the adaptive immune system.

Our lab is focused on studying the molecular mechanisms that control phagosome functions and how this alters immune signalling events within the cell as well as the cellular microenvironment. We have developed sophisticated tools to isolate phagosomes formed using bacteria-like particles, and this project will involve the mastering of these techniques. Our lab has also shown that the post-translational modification ubiquitylation plays an important role in the maturation of phagosomes. Ubiquitylation involves the covalent attachment of the small protein ubiquitin through the activity of ubiquitin-activating and ligating enzymes (E1, E2 and E3). Notably, ubiquitin itself can be ubiquitylated on seven different lysine residues and the N-terminus (M1, K6, K11, K29, K33, K48 and K63), leading to the assembly of polyubiquitin chains. These different chain types have an important role in regulating cell signalling, particularly in the immune system.

In recent years we have developed sensitive mass spectrometry-based proteomics approaches to characterise ubiquitylation in immune cells and on the phagosome. In this CASE studentship, we are collaborating with Bruker Daltonics, a leading mass spectrometry company. This will allow us to utilise state-of-the-art, ultra-sensitive mass spectrometry to tackle this challenging problem.

Objectives: The overarching aims of this project will be to investigate the role of ubiquitylation in the maturation of phagosomes and how this alters immune cell signalling. This project will involve learning mass spectrometry, cell culture, flow cytometry, immunofluorescence microscopy, and how to analyse large datasets. This project will also involve a 3-month placement with our industry partner, Bruker where you will get industry experience. 

HOW TO APPLY

Applications should be made by emailing [Email Address Removed] with:

·        a CV (including contact details of at least two academic (or other relevant) referees);

·        a covering letter – clearly stating your first choice project, and optionally 2nd ranked project, as well as including whatever additional information you feel is pertinent to your application; you may wish to indicate, for example, why you are particularly interested in the selected project(s) and at the selected University;

·        copies of your relevant undergraduate degree transcripts and certificates;

·        a copy of your IELTS or TOEFL English language certificate (where required);

·        a copy of your passport (photo page).

A GUIDE TO THE FORMAT REQUIRED FOR THE APPLICATION DOCUMENTS IS AVAILABLE AT https://www.nld-dtp.org.uk/how-apply. Applications not meeting these criteria may be rejected.

In addition to the above items, please email a completed copy of the Additional Details Form (as a Word document) to [Email Address Removed]. A blank copy of this form can be found at: https://www.nld-dtp.org.uk/how-apply.

Informal enquiries may be made to [Email Address Removed]

The deadline for all applications is 12noon on Monday 9th January 2023. 


Funding Notes

CASE studentships are funded by the Biotechnology and Biological Sciences Research Council (BBSRC) for 4 years. Funding will cover tuition fees at the UK rate only, a Research Training and Support Grant (RTSG) and stipend. We aim to support the most outstanding applicants from outside the UK and are able to offer a limited number of bursaries that will enable full studentships to be awarded to international applicants. These full studentships will only be awarded to exceptional quality candidates, due to the competitive nature of this scheme.

References

The E3 ubiquitin ligase RNF115 regulates phagosome maturation and host response to bacterial infection, (2022) EMBO J, accepted
Macrophage Scavenger Receptor 1 mediates lipid-induced inflammation in human obesity-related non-alcoholic fatty liver disease, (2022) Journal of Hepatology, May;76(5):1001-1012
Triggering MSR1 promotes JNK-mediated inflammation in IL-4 activated macrophages, EMBO Journal, (2019) Jun 3;38(11). pii: e100299. doi: 10.15252/embj.2018100299
The Parkinson’s disease kinase LRRK2 is a negative regulator of phagosome maturation and innate immunity to tuberculosis in macrophages, EMBO Journal (2018), May 22. pii: e98694. doi: 10.15252/embj.201798694
Delayed induction of type I and III interferons and nasal epithelial cell permissiveness to SARS-CoV-2, (2021) Nature Communications Dec 7;12(1):7092
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