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How does ISG15 regulate our innate immune response to viral infection?


   School of Biology

   Friday, December 03, 2021  Competition Funded PhD Project (Students Worldwide)

St Andrews United Kingdom Immunology Virology

About the Project

Research in the Hughes lab at the University of St Andrews focuses on antiviral responses and the regulation of innate immunity. As part of our first-line defence against viral infection, our cells produce cytokines, such as interferons (IFN). IFNs bind to receptors expressed on all nucleated cells resulting in activation of JAK/STAT signalling and the expression of hundreds of IFN-stimulated genes (ISGs). The main role of this large response is to create an unfavourable environment for virus replication and to limit transmission. However, it must be tightly regulated to avoid an over-exuberant immune response that would cause devastating autoinflammatory disease and tissue damage. Importantly, some ISGs play major roles in regulating the response, ensuring it is strong enough to combat the infection but not so strong that it causes disease. A very important protein that plays this role is ubiquitin-specific protease 18 (USP18); in fact, patients unable to produce USP18 suffer terribly from autoinflammatory diseases such as pseudo-TORCH syndrome as a result of a dysregulated IFN response. 

Intriguingly, people unable to produce a second protein, known as IFN-stimulated gene 15 (ISG15), also suffer from autoinflammatory diseases, showing that ISG15 is a major regulator of the IFN response (Hermann & Bogunovic, 2017). These patients have in-tact USP18 genes, yet the USP18 protein is barely detectable, thus linking ISG15-/--associated autoinflammatory disease to a lack of USP18. Our research is fascinated by the processes that regulate IFN signalling, and we have recently developed a tractable model to investigate ISG15 deficiency that we have used to uncover novel regulatory mechanisms (Holthaus et al. 2020). In exciting new research, we have shown that ISG15 is central to USP18’s ability to regulate signalling (Vasou et al. 2021). Not only has this added a new dimension the paradigm of cytokine signalling regulation, but it also opens new avenues of research beyond that of innate immune regulation. 

In ISG15-deficient cells, the USP18 protein is ubiquitinated by SKP2 (a component of the SCF Ub ligase complex) and rapidly degraded by the ubiquitin-proteasome system (UPS) making it unavailable to regulate IFN signalling (Zhang et al. 2015). Our research has shown that ISG15’s ability to stabilise USP18 is indirect (meaning, it does not need to bind to USP18 to do this, and so it is not a competitive inhibitor)(Vasou et al 2021).

This leads to several intriguing questions that this PhD project aims to address:

·     How does ISG15 protect USP18 from degradation?

·     What else does SKP2 targets during the IFN response? 

·     What pathway-specific interactions does ISG15 regulate during an antiviral response?

This highly focussed project will provide training in molecular virology, CRISPR/Cas9 genome editing, cutting-edge proteomics and state-of-the-art imaging.

You will be part of a productive and supportive research team that encourages personal development by providing training opportunities beyond the lab.

Please direct informal enquiries to Dr David Hughes ()

Lab website: https://hugheslab.weebly.com/

How To Apply

Please make a formal application to the School of Biology through our Online Application Portal.

We require the following documents; CV, personal statement, 2 references, academic qualifications, English language qualification (if applicable).

Keywords- Innate immunity, Virology, Immunology, Interferon, Ubiquitin


Funding Notes

Funded PhD Project (UK and international students (including EU)).
Funded by the School of Biology, University of St Andrews. The studentship covers tuition fees (Home and Overseas) and a living allowance for a duration of 3.5 years.

References

Hermann, M, & Bogunovic, D 2017, ‘ISG15: In Sickness and in Health’, Trends Immunol 38(2):79-93
Holthaus, D, Vasou, A, Bamford, C, Andrejeva, J, Paulus, C, Randall, RE, McLauchlan, J & Hughes, DJ 2020, 'Direct antiviral activity of interferon stimulated genes is responsible for resistance to paramyxoviruses in ISG15-deficient cells', The Journal of Immunology. https://doi.org/10.4049/jimmunol.1901472
Vasou, A, Nightingale, K, Cetkovska, V, Bamford, C, Andrejeva, J, Randall, RE, McLauchlan, J, Weekes, M & Hughes, DJ 2021, 'A co-opted ISG15-USP18 binding mechanism normally reserved for deISGylation controls type I IFN signalling', bioRxiv. https://www.biorxiv.org/content/10.1101/2021.06.01.446527v1
Zhang, X, Bogunovic, D, ... Pellegrini S 2015, ‘Human intracellular ISG15 prevents interferon-α/β over-amplification and auto-inflammation’, Nature 1;517(7532):89-93. https://doi:10.1038/nature13801

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