1. RNF41 regulates the damage recognition receptor Clec9A and antigen cross-presentation in mouse dendritic cells
- Author
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Peter E. Czabotar, Peck Szee Tan, Jillian C. Danne, Marnie E. Blewitt, Rong Li, Emily Gruber, Nicos A. Nicola, Kristen J. Radford, Ken Shortman, Irina Caminschi, Cheng Huang, Anthony W. Purcell, Alex J. Fulcher, Mireille H. Lahoud, Hae-Young Park, Mark D. Wright, Georg Ramm, Antonia N. Policheni, Linda M. Wakim, Nicole Michael, Jose A Villadangos, Jian-Guo Zhang, Justine D. Mintern, Ralf B. Schittenhelm, William R. Heath, Meredith O'Keeffe, and Kirsteen M. Tullett
- Subjects
0301 basic medicine ,CD4-Positive T-Lymphocytes ,Mouse ,CD8-Positive T-Lymphocytes ,Mice ,0302 clinical medicine ,Immunology and Inflammation ,Cricetinae ,Biology (General) ,Receptors, Immunologic ,Mice, Knockout ,biology ,Chemistry ,General Neuroscience ,DAMP recognition ,Cross-presentation ,General Medicine ,Cell biology ,Ubiquitin ligase ,medicine.anatomical_structure ,E3 ubiquitin ligase ,Medicine ,Research Article ,Protein Binding ,QH301-705.5 ,T cell ,Science ,Ubiquitin-Protein Ligases ,Antigen presentation ,CHO Cells ,ubiquitination ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,Immune system ,Cricetulus ,Antigen ,medicine ,Animals ,Lectins, C-Type ,Antigens ,General Immunology and Microbiology ,Dendritic cell ,Dendritic Cells ,Mice, Inbred C57BL ,antigen presentation ,030104 developmental biology ,Gene Expression Regulation ,biology.protein ,030217 neurology & neurosurgery ,CD8 - 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.
- Published
- 2020