Biochemistry and Pharmacology - Research Publications

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Author: Caminschi, Irina × Author: Mintern, Justine × Author: Villadangos, Jose × End date: 2020 × Start date: 2020 ×

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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.