Publications & Reports

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

Tullett KM, Tan PS, Park HY, 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 JG, Lahoud MH
Infection and Immunity Program, Monash Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash University, Clayton, Australia.

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.

Link to publisher’s web site

Publication

  • Journal: eLife
  • Published: 02/12/2020
  • Volume: 9
  • Pagination: e63452

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