Project: Regulation of Complement by Membrane Receptor Ubiquitination
Villadangos Group
A fundamental component of our innate immune system is the complement system. The complement system consists of more than 50 plasma proteins and receptors that interact with pathogens, thereby providing an immediate line of defence against pathogenic intruders. The most abundant complement protein is C3. The activation of C3 must be tightly controlled, as binding of C3 to healthy cells can induce severe damage and can lead to autoimmunity. We have discovered that C3 forms a complex with MHC class II molecules (MHC II), expressed by Dendritic Cells. The C3 that is attached to MHC II is marked by the regulatory protein ubiquitin, a process called ubiquitination, which leads to internalization and degradation of MHC II-C3. This is a highly significant finding because formation of MHC II-C3 complexes may be a novel mechanism for capturing and eliminating potentially harmful C3.
In this project, we will investigate the molecular mechanisms behind the MHC II-C3 complex formation and the regulation of C3 levels through ubiquitination. We will unravel which pathways of complement activation are involved and characterize the MHC II carbohydrate structure that enables C3 binding through a variety of biochemical techniques, supplemented with immunological techniques including spectral flow cytometry, cell culture, and animal models. These findings may contribute to the development of therapeutic strategies for complement-mediated diseases by manipulating receptor ubiquitination.
Further reading:
P Schriek, ... and JA Villadangos. 2022. Marginal zone B cells acquire dendritic cell functions by trogocytosis. Science 375:eabf7470. PMID: 35143312.
Dimitrios C. Mastellos, George Hajishengallis & John D. Lambris. A guide to complement biology, pathology and therapeutic opportunity. Nature Reviews Immunology volume 24, pages118–141 (2024)
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Villadangos Group
6 vacancies
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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.
All our projects are open to Honours/Master of Biomedical Science students and PhD/MPhil graduate researchers
Villadangos Group Current Projects
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Improving the formation of protective immunity against human viruses
PhD/MPhil, Master of Biomedical Science, Honours
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MR1 – a molecular alarm system for bacterial infection
PhD/MPhil, Master of Biomedical Science, Honours
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Regulation of Complement by Membrane Receptor Ubiquitination
PhD/MPhil, Master of Biomedical Science, Honours
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Harnessing the power of RNA technology for vaccines and therapeutics
PhD/MPhil, Master of Biomedical Science, Honours
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Investigating the role of dendritic cell O-GlcNAcylation in adipose tissue homeostasis and immune function
PhD/MPhil, Master of Biomedical Science, Honours
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Understanding the causes of immune paralysis and lethal secondary infections in sepsis and trauma patients
PhD/MPhil, Master of Biomedical Science, Honours
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The immune signature of sepsis
PhD/MPhil, Master of Biomedical Science, Honours
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Regulating macrophage 'eating' for cancer and pathogen control
PhD/MPhil, Master of Biomedical Science, Honours
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Trogocytosis: a novel communication system between cells of the immune system
PhD/MPhil, Master of Biomedical Science, Honours
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A novel link between metabolism and immune function: O-GlcNAc glycosylation
PhD/MPhil, Master of Biomedical Science, Honours