Function of MARCH ubiquitin ligases
The MARCHs recognize their substrates via transmembrane region interactions (left); the RING-CH domain of the MARCH binds an E2 ligase, which then transfers ubiquitin (Ub) to receptor sites in the cytoplasmic tail of the target (centre), leaving a ubiquitinated substrate (right).
The maintenance of protein localisation and abundance are controlled in eukaryotic cells by a complex network of regulatory pathways which remain poorly understood. These pathways control the distribution of proteins within the cell (proteostasis) and are responsible for changes in protein expression and cell function in response to environmental cues such as the presence of pathogens. Addition of the small protein ubiquitin (Ub) to membrane proteins by Ub-ligases is a major mechanism of control of plasma membrane proteostasis. Therefore this project will (i) contribute to understand the role of ubiquitination in regulation of membrane proteostasis, an issue of fundamental importance in cell biology, and (ii) identify novel target proteins of MARCH ligases in cells of the immune system. These target proteins may be involved in immunoregulation, as other known substrates of the MARCHs. The result of this project will help develop novel therapeutic approaches to fight infection based on manipulation of membrane protein ubiquitination.
Professor Jose Villadangos
Dr Justine Mintern (University of Melbourne)
Dr Giuseppe Infusini (The Walter and Eliza Hall Institute)
Dr Satoshi Ishido (Showa Pharmaceutical University, Japan)
Dr Andrew Webb (The Walter and Eliza Hall Institute)
Dr Matthew Call (The Walter and Eliza Hall Institute)
Dr Melissa Call (The Walter and Eliza Hall Institute)
Young LJ, Wilson NS, Schnorrer P, Proietto P, Ten Broeke T, Matsuki Y, Mount AM, Belz GT, O’Keeffe, Ohmura-Hoshino MM, Ishido S, Stoorvogel W, Heath WR, Shortman K, Villadangos JA. Differential MHC class II synthesis and ubiquitination confers distinct antigen-presenting properties on conventional and plasmacytoid dendritic cells. Nat Immunol 2008; 9: 1244-1252.
Moffat JM, Mintern JD, Villadangos AJ. Control of MHC II antigen presentation by ubiquitination. Curr. Opin. Immunol 2013; 25: 109-114.
Liu H, Darwiche R, Guan J, Vuong V, Ishido S, La Gruta NL, Gray DH, Villadangos* JA, Mintern JD*. Ubiquitin ligase MARCH 8 cooperates with CD83 to control surface MHC II expression in thymic epithelium and CD4 T cell selection. J Exp Med 2016; In press. * Corresponding authors.
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