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

eLife

Anthony W Purcell¹  Justine D Mintern²  Emily Gruber²  Mireille H Lahoud²  Marnie E Blewitt³  Meredith O'Keeffe⁴  Rong Li⁵  Kristen J Radford⁶  Nicos A Nicola⁷  Ken Shortman⁸  Georg Ramm⁸  Peck Szee Tan⁹  William R Heath⁹  Kirsteen M Tullett⁹  Hae-Young Park⁹  Nicole Michael⁹  Cheng Huang⁹  Mark D Wright⁹  Irina Caminschi⁹  Jose A Villadangos^1,10  Jillian C Danne^1,11  Ralf B Schittenhelm^1,12  Alex J Fulcher^1,12  Peter E Czabotar^1,13  Linda M Wakim^1,14  Jian-Guo Zhang^1,14  Antonia N Policheni^1,14 

[1] Department of Biochemistry and Molecular Biology at the Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Melbourne, Australia;Department of Medical Biology, University of Melbourne, Parkville, Australia;Department of Microbiology and Immunology at the Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Melbourne, Australia;Ramaciotti Centre for Cryo-Electron Microscopy, Monash University, Clayton, Australia;Centre for Biomedical Research, Burnet Institute, Melbourne, Australia;Department of Biochemistry and Molecular Biology at the Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Melbourne, Australia;Department of Immunology, Monash University, Melbourne, Australia;Department of Microbiology and Immunology at the Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Melbourne, Australia;Infection and Immunity Program, Monash Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash University, Clayton, Australia;Mater Research Institute - University of Queensland, Translational Research Institute, Brisbane, Australia;Monash Micro Imaging Facility, Monash University, Clayton, Australia;Monash Proteomics and Metabolomics Facility, Monash Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash University, Clayton, Australia;Ramaciotti Centre for Cryo-Electron Microscopy, Monash University, Clayton, Australia;The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia;

关键词: dendritic cells;    DAMP recognition;    E3 ubiquitin ligase;    ubiquitination;    antigen presentation;   

DOI  :  10.7554/eLife.63452

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown