Biochemistry and Pharmacology - Research Publications

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Author: Mintern, Justine × Author: Villadangos, Jose × End date: 2020 × Start date: 2020 × Type: Journal Article ×

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    RNF41 regulates the damage recognition receptor Clec9A and antigen cross-presentation in mouse dendritic cells
    Tullett, KM ; Tan, PS ; Park, H-Y ; Schittenhelm, RB ; Michael, N ; Li, R ; Policheni, AN ; Gruber, E ; Huang, C ; Fulcher, AJ ; Danne, JC ; Czabotar, PE ; Wakim, LM ; Mintern, JD ; Ramm, G ; Radford, KJ ; Caminschi, I ; O'Keeffe, M ; Villadangos, JA ; Wright, MD ; Blewitt, ME ; Heath, WR ; Shortman, K ; Purcell, AW ; Nicola, NA ; Zhang, J-G ; Lahoud, MH (ELIFE SCIENCES PUBLICATIONS LTD, 2020-12-02)
    The dendritic cell receptor Clec9A facilitates processing of dead cell-derived antigens for cross-presentation and the induction of effective CD8+ T cell immune responses. Here, we show that this process is regulated by E3 ubiquitin ligase RNF41 and define a new ubiquitin-mediated mechanism for regulation of Clec9A, reflecting the unique properties of Clec9A as a receptor specialized for delivery of antigens for cross-presentation. We reveal RNF41 is a negative regulator of Clec9A and the cross-presentation of dead cell-derived antigens by mouse dendritic cells. Intriguingly, RNF41 regulates the downstream fate of Clec9A by directly binding and ubiquitinating the extracellular domains of Clec9A. At steady-state, RNF41 ubiquitination of Clec9A facilitates interactions with ER-associated proteins and degradation machinery to control Clec9A levels. However, Clec9A interactions are altered following dead cell uptake to favor antigen presentation. These findings provide important insights into antigen cross-presentation and have implications for development of approaches to modulate immune responses.
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    Endoplasmic reticulum chaperones stabilize ligand-receptive MR1 molecules for efficient presentation of metabolite antigens
    McWilliam, HEG ; Mak, JYW ; Awad, W ; Zorkau, M ; Cruz-Gomez, S ; Lim, HJ ; Yan, Y ; Wormald, S ; Dagley, LF ; Eckle, SBG ; Corbett, AJ ; Liu, H ; Li, S ; Reddiex, SJJ ; Mintern, JD ; Liu, L ; McCluskey, J ; Rossjohn, J ; Fairlie, DP ; Villadangos, JA (NATL ACAD SCIENCES, 2020-10-06)
    The antigen-presenting molecule MR1 (MHC class I-related protein 1) presents metabolite antigens derived from microbial vitamin B2 synthesis to activate mucosal-associated invariant T (MAIT) cells. Key aspects of this evolutionarily conserved pathway remain uncharacterized, including where MR1 acquires ligands and what accessory proteins assist ligand binding. We answer these questions by using a fluorophore-labeled stable MR1 antigen analog, a conformation-specific MR1 mAb, proteomic analysis, and a genome-wide CRISPR/Cas9 library screen. We show that the endoplasmic reticulum (ER) contains a pool of two unliganded MR1 conformers stabilized via interactions with chaperones tapasin and tapasin-related protein. This pool is the primary source of MR1 molecules for the presentation of exogenous metabolite antigens to MAIT cells. Deletion of these chaperones reduces the ER-resident MR1 pool and hampers antigen presentation and MAIT cell activation. The MR1 antigen-presentation pathway thus co-opts ER chaperones to fulfill its unique ability to present exogenous metabolite antigens captured within the ER.