Kirsteen M Tullett1, Peck Szee Tan1, Hae-Young Park1, Ralf B Schittenhelm2, Nicole Michael1, Rong Li3, Antonia N Policheni4,5, Emily Gruber1, Cheng Huang2, Alex J Fulcher6, Jillian C Danne7, Peter E Czabotar4,5, Linda M Wakim8, Justine D Mintern9, Georg Ramm1,7, Kristen J Radford10, Irina Caminschi1,8, Meredith O'Keeffe1, Jose A Villadangos8,9, Mark D Wright11, Marnie E Blewitt4,5, William R Heath8, Ken Shortman4,5, Anthony W Purcell1, Nicos A Nicola4,5, Jian-Guo Zhang4,5, Mireille H Lahoud1. 1. Infection and Immunity Program, Monash Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash University, Clayton, Australia. 2. Monash Proteomics and Metabolomics Facility, Monash Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash University, Clayton, Australia. 3. Centre for Biomedical Research, Burnet Institute, Melbourne, Australia. 4. The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia. 5. Department of Medical Biology, University of Melbourne, Parkville, Australia. 6. Monash Micro Imaging Facility, Monash University, Clayton, Australia. 7. Ramaciotti Centre for Cryo-Electron Microscopy, Monash University, Clayton, Australia. 8. Department of Microbiology and Immunology at the Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Melbourne, Australia. 9. Department of Biochemistry and Molecular Biology at the Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Melbourne, Australia. 10. Mater Research Institute - University of Queensland, Translational Research Institute, Brisbane, Australia. 11. Department of Immunology, Monash University, Melbourne, 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.
The dendritic cell receptor Clec9A facilitates processing of dead cell-derived antigens for cross-presentation and the induction of effective n class="Gene">CD8+ T cell immune responses. Here, we show that this process is regulated by E3 ubiquitin ligaseRNF41 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, RNF41ubiquitination 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.
Authors: Kirsteen M Tullett; Ingrid M Leal Rojas; Yoshihito Minoda; Peck S Tan; Jian-Guo Zhang; Corey Smith; Rajiv Khanna; Ken Shortman; Irina Caminschi; Mireille H Lahoud; Kristen J Radford Journal: JCI Insight Date: 2016-05-19
Authors: Irina Caminschi; Anna I Proietto; Fatma Ahmet; Susie Kitsoulis; Joo Shin Teh; Jennifer C Y Lo; Alexandra Rizzitelli; Li Wu; David Vremec; Serani L H van Dommelen; Ian K Campbell; Eugene Maraskovsky; Hal Braley; Gayle M Davey; Patricia Mottram; Nicholas van de Velde; Kent Jensen; Andrew M Lew; Mark D Wright; William R Heath; Ken Shortman; Mireille H Lahoud Journal: Blood Date: 2008-07-30 Impact factor: 22.113
Authors: Meng-Chieh Chiang; Kirsteen M Tullett; Yoke Seng Lee; Adi Idris; Yitian Ding; Kylie J McDonald; Andrew Kassianos; Ingrid M Leal Rojas; Varinder Jeet; Mireille H Lahoud; Kristen J Radford Journal: Eur J Immunol Date: 2015-11-23 Impact factor: 5.532
Authors: Delphine Masschaele; Leentje De Ceuninck; Joris Wauman; Dieter Defever; Frank Stenner; Sam Lievens; Frank Peelman; Jan Tavernier Journal: PLoS One Date: 2017-05-22 Impact factor: 3.240
Authors: Susan Ahrens; Santiago Zelenay; David Sancho; Pavel Hanč; Svend Kjær; Christoph Feest; Georgina Fletcher; Charlotte Durkin; Antonio Postigo; Mark Skehel; Facundo Batista; Barry Thompson; Michael Way; Caetano Reis e Sousa; Oliver Schulz Journal: Immunity Date: 2012-04-05 Impact factor: 31.745
Authors: Irina Caminschi; Fatma Ahmet; Klaus Heger; Jason Brady; Stephen L Nutt; David Vremec; Suzanne Pietersz; Mireille H Lahoud; Louis Schofield; Diana S Hansen; Meredith O'Keeffe; Mark J Smyth; Sammy Bedoui; Gayle M Davey; Jose A Villadangos; William R Heath; Ken Shortman Journal: J Exp Med Date: 2007-10-08 Impact factor: 14.307