eLife (Dec 2020)
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 Wright,
- Marnie E Blewitt,
- William R Heath,
- Ken Shortman,
- Anthony W Purcell,
- Nicos A Nicola,
- Jian-Guo Zhang,
- Mireille H Lahoud
Affiliations
- Kirsteen M Tullett
- ORCiD
- Infection and Immunity Program, Monash Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash University, Clayton, Australia
- Peck Szee Tan
- ORCiD
- Infection and Immunity Program, Monash Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash University, Clayton, Australia
- Hae-Young Park
- Infection and Immunity Program, Monash Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash University, Clayton, Australia
- Ralf B Schittenhelm
- Monash Proteomics and Metabolomics Facility, Monash Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash University, Clayton, Australia
- Nicole Michael
- Infection and Immunity Program, Monash Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash University, Clayton, Australia
- Rong Li
- Centre for Biomedical Research, Burnet Institute, Melbourne, Australia
- Antonia N Policheni
- The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia; Department of Medical Biology, University of Melbourne, Parkville, Australia
- Emily Gruber
- Infection and Immunity Program, Monash Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash University, Clayton, Australia
- Cheng Huang
- Monash Proteomics and Metabolomics Facility, Monash Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash University, Clayton, Australia
- Alex J Fulcher
- Monash Micro Imaging Facility, Monash University, Clayton, Australia
- Jillian C Danne
- Ramaciotti Centre for Cryo-Electron Microscopy, Monash University, Clayton, Australia
- Peter E Czabotar
- The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia; Department of Medical Biology, University of Melbourne, Parkville, Australia
- Linda M Wakim
- Department of Microbiology and Immunology at the Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Melbourne, Australia
- Justine D Mintern
- Department of Biochemistry and Molecular Biology at the Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Melbourne, Australia
- Georg Ramm
- Infection and Immunity Program, 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
- Kristen J Radford
- Mater Research Institute - University of Queensland, Translational Research Institute, Brisbane, Australia
- Irina Caminschi
- Infection and Immunity Program, Monash Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash University, Clayton, Australia; Department of Microbiology and Immunology at the Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Melbourne, Australia
- Meredith O'Keeffe
- Infection and Immunity Program, Monash Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash University, Clayton, Australia
- Jose A Villadangos
- Department of Microbiology and Immunology at the Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Melbourne, Australia; Department of Biochemistry and Molecular Biology at the Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Melbourne, Australia
- Mark D Wright
- Department of Immunology, Monash University, Melbourne, Australia
- Marnie E Blewitt
- ORCiD
- The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia; Department of Medical Biology, University of Melbourne, Parkville, Australia
- William R Heath
- Department of Microbiology and Immunology at the Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Melbourne, Australia
- Ken Shortman
- The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia; Department of Medical Biology, University of Melbourne, Parkville, Australia
- Anthony W Purcell
- Infection and Immunity Program, Monash Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash University, Clayton, Australia
- Nicos A Nicola
- The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia; Department of Medical Biology, University of Melbourne, Parkville, Australia
- Jian-Guo Zhang
- The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia; Department of Medical Biology, University of Melbourne, Parkville, Australia
- Mireille H Lahoud
- ORCiD
- Infection and Immunity Program, Monash Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash University, Clayton, Australia
- DOI
- https://doi.org/10.7554/eLife.63452
- Journal volume & issue
-
Vol. 9
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.
Keywords
