University of Dundee

China Scholarship Council PhD programme - How does ester-linked ubiquitin chains regulate the immune system

The School of Life Sciences at the University of Dundee, joint with the China Scholarship Council (CSC), is proud to be able to offer a scholarship programme for postgraduate research students. The scholarship covers all tuition fees and research fees and provides living expenses and one return flight ticket to successful candidates. There are up to 5 scholarships of 4 years duration available.

Project Description

The research in my laboratory is focused on understanding how immune signalling networks are controlled by the interplay between protein phosphorylation and protein ubiquitylation events. Recently, we discovered that the complex ubiquitin chains formed when macrophages and other immune cells are stimulated by ligands that activate Toll-Like Receptors, or by Interleukin-1 family members, contain three ubiquitin linkage types formed by the action of five E3 ligases. Ubiquitin linked via Lys63 is catalysed by the E3 ligases TRAF6, Pellino1 and Pellino2, ubiquitin-linked via Met1 is catalysed by HOIP while ester-linked ubiquitin is catalysed by HOIL-1. We discovered that HOIL-1 is an atypical E3 ligase that forms ester linkages between the C-terminal carboxylate of ubiquitin and serine or threonine residues in proteins [1,2]. Until recently little was known about the function of the E3 ligase activity of HOIL-1, but in unpublished work, we have found that the loss of HOIL-1-catalysed ester-linked ubiquitin in immune cells has unexpected effects on the topology of the ubiquitin chains that are formed and on the production of inflammatory cytokines induced by different ligands.

The initial aims of the project are to identify the proteins that undergo HOIL-1-catalysed, ester-linked ubiquitylation in different immune cells, whether the ubiquitin chains attached to these proteins are initiated by ester-linked ubiquitin and/or whether they are attached to other ubiquitin molecules within complex hybrid ubiquitin chains. The project will require the development of methodology for identifying HOIL-1-catalysed ubiquitylation of proteins, which will be based on mass spectrometry and exploit immune cells from mice expressing an E3 ligase-inactive HOIL-1 mutant that we have generated. The project will also involve the use of a variety of state-of-the-art techniques used in cell biology, cell signalling, immunology, molecular biology and protein chemistry.

How the project develops will depend on the findings made, and the ingenuity and perseverance of the student working on the project.

References

1.Kelsall, I.R., Zhang, J., Knebel, A., Arthur, J.S.C. and Cohen, P. (2019) Proc. Nat. Acad. Sci. USA 116, 13293-13298#

2.Strickson, S., et al. (2017) 114, E3481-E3489

3.Cohen, P. and Strickson, S. (2017) 24, 1153-1159