Regulation of immune receptor expression and turn-over by ubiquitin ligases

Primary Supervisor Email Number Webpage
Prof Jose Villadangos

Summary The Villadangos group studies the first event that triggers adaptive immune responses: the presentation of pathogen or tumour antigens to T cells by Dendritic Cells, B cells and Macrophages. We are characterizing the development, regulation and impairment of antigen presenting cells by pathogens, inflammatory mediators and tumours. We are also dissecting the biochemical machinery involved in antigen capture, processing and presentation. We use this knowledge to understand how T cell-dependent immunity is initiated and maintained, and apply it to design better vaccines and immunotherapies against infectious agents and cancer.

Project Details

Cell viability and function requires maintenance of the correct protein composition and distribution within the cell at all times. This proteostasis is regulated by mechanisms that control protein synthesis, localisation and degradation. Cells can also respond to external signals to alter proteostasis, allowing them to adapt to changes in their environment.   In cells of the immune system, expression of many important receptors is regulated by addition of the protein Ubiquitin by the MARCH family of ligases. MARCH ubiquitination thus plays major roles in immunity against pathogens and cancer. The MARCHs also play important roles in control of infection by viruses.  However we know very little about MARCH specificicity and regulation.
This project will employ biochemical techniques, microscopy, proteomics, and CRISPR-Cas9 technology to characterise the function of the MARCH family; identify novel MARCH substrates; and characterise the machinery involved in ubiquitination by MARCHs. Our goal is to develop novel therapeutic approaches to fight infection and cancer based on manipulation of membrane protein ubiquitination.
Further reading: L Young et al (2008) Nat. Immunol. 9: 1244-1252; J Moffat et al (2013) Curr. Opin. Immunol; 25: 109-114; H Liu et al (2016), J. Exp. Med. 213:1695-1703.

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