RNF41 regulates the damage recognition receptor Clec9A and antigen cross-presentation in mouse dendritic cells

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. WrightMarnie E. Blewitt, William R. Heath, Ken Shortman, Anthony W. Purcell, Nicos A. Nicola, Jian-Guo Zhang, Mireille H. Lahoud

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11 Citations (Scopus)

Abstract

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.

Original languageEnglish
Article numbere63452
Number of pages31
JournaleLife
Volume9
DOIs
Publication statusPublished - 2 Dec 2020

Keywords

  • antigen presentation
  • DAMP recognition
  • dendritic cells
  • E3 ubiquitin ligase
  • immunology
  • inflammation
  • mouse
  • ubiquitination

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