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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. © 2020, Tullett et al.


Kirsteen M Tullett, Peck Szee Tan, Hae-Young Park, Ralf B Schittenhelm, Nicole Michael, Rong Li, Antonia N Policheni, Emily Gruber, Cheng Huang, Alex J Fulcher, Jillian C Danne, Peter E Czabotar, Linda M Wakim, Justine D Mintern, Georg Ramm, Kristen J Radford, Irina Caminschi, Meredith O'Keeffe, Jose A Villadangos, Mark D Wright, Marnie E Blewitt, William R Heath, Ken Shortman, Anthony W Purcell, Nicos A Nicola, Jian-Guo Zhang, Mireille H Lahoud. RNF41 regulates the damage recognition receptor Clec9A and antigen cross-presentation in mouse dendritic cells. eLife. 2020 Dec 02;9

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PMID: 33264090

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