Adan Pinto-Fernandez1,2, Mariolina Salio3, Tom Partridge4, Jianzhou Chen5, George Vere6, Helene Greenwood6, Cyriel Sebastiaan Olie6, Andreas Damianou6, Hannah Claire Scott6, Henry Jack Pegg7, Alessandra Chiarenza7, Laura Díaz-Saez6,8, Paul Smith6,8, Claudia Gonzalez-Lopez3, Bhavisha Patel7, Emma Anderton7, Neil Jones7, Tim R Hammonds7, Kilian Huber6,8, Ruth Muschel5, Persephone Borrow4, Vincenzo Cerundolo3, Benedikt M Kessler9,10. 1. TDI Mass Spectrometry Laboratory, Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Oxford, Roosevelt Drive, Oxford, OX3 7FZ, UK. adan.pintofernandez@ndm.ox.ac.uk. 2. Chinese Academy of Medical Sciences Oxford Institute, Nuffield Department of Medicine, University of Oxford, Oxford, Roosevelt Drive, Oxford, OX3 7FZ, UK. adan.pintofernandez@ndm.ox.ac.uk. 3. MRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, OX3 9DS, UK. 4. Nuffield Department of Clinical Medicine, University of Oxford, Roosevelt Drive, Oxford, OX3 7FZ, UK. 5. CRUK/MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford, OX3 7DQ, UK. 6. TDI Mass Spectrometry Laboratory, Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Oxford, Roosevelt Drive, Oxford, OX3 7FZ, UK. 7. CRUK Therapeutic Discovery Laboratories, London Bioscience Innovation Centre, London, NW1 0NH, UK. 8. Centre for Medicines Discovery, Nuffield Department of Medicine, University of Oxford, Oxford, Roosevelt Drive, Oxford, OX3 7FZ, UK. 9. TDI Mass Spectrometry Laboratory, Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Oxford, Roosevelt Drive, Oxford, OX3 7FZ, UK. benedikt.kessler@ndm.ox.ac.uk. 10. Chinese Academy of Medical Sciences Oxford Institute, Nuffield Department of Medicine, University of Oxford, Oxford, Roosevelt Drive, Oxford, OX3 7FZ, UK. benedikt.kessler@ndm.ox.ac.uk.
Abstract
BACKGROUND: Interferon (IFN) signalling pathways, a key element of the innate immune response, contribute to resistance to conventional chemotherapy, radiotherapy, and immunotherapy, and are often deregulated in cancer. The deubiquitylating enzyme USP18 is a major negative regulator of the IFN signalling cascade and is the predominant human protease that cleaves ISG15, a ubiquitin-like protein tightly regulated in the context of innate immunity, from its modified substrate proteins in vivo. METHODS: In this study, using advanced proteomic techniques, we have significantly expanded the USP18-dependent ISGylome and proteome in a chronic myeloid leukaemia (CML)-derived cell line. USP18-dependent effects were explored further in CML and colorectal carcinoma cellular models. RESULTS: Novel ISGylation targets were characterised that modulate the sensing of innate ligands, antigen presentation and secretion of cytokines. Consequently, CML USP18-deficient cells are more antigenic, driving increased activation of cytotoxic T lymphocytes (CTLs) and are more susceptible to irradiation. CONCLUSIONS: Our results provide strong evidence for USP18 in regulating antigenicity and radiosensitivity, highlighting its potential as a cancer target.
BACKGROUND: Interferon (IFN) signalling pathways, a key element of the innate immune response, contribute to resistance to conventional chemotherapy, radiotherapy, and immunotherapy, and are often deregulated in cancer. The deubiquitylating enzyme USP18 is a major negative regulator of the IFN signalling cascade and is the predominant human protease that cleaves ISG15, a ubiquitin-like protein tightly regulated in the context of innate immunity, from its modified substrate proteins in vivo. METHODS: In this study, using advanced proteomic techniques, we have significantly expanded the USP18-dependent ISGylome and proteome in a chronic myeloid leukaemia (CML)-derived cell line. USP18-dependent effects were explored further in CML and colorectal carcinoma cellular models. RESULTS: Novel ISGylation targets were characterised that modulate the sensing of innate ligands, antigen presentation and secretion of cytokines. Consequently, CML USP18-deficient cells are more antigenic, driving increased activation of cytotoxic T lymphocytes (CTLs) and are more susceptible to irradiation. CONCLUSIONS: Our results provide strong evidence for USP18 in regulating antigenicity and radiosensitivity, highlighting its potential as a cancer target.
Authors: Jesse M Zaretsky; Angel Garcia-Diaz; Daniel S Shin; Helena Escuin-Ordinas; Willy Hugo; Siwen Hu-Lieskovan; Davis Y Torrejon; Gabriel Abril-Rodriguez; Salemiz Sandoval; Lucas Barthly; Justin Saco; Blanca Homet Moreno; Riccardo Mezzadra; Bartosz Chmielowski; Kathleen Ruchalski; I Peter Shintaku; Phillip J Sanchez; Cristina Puig-Saus; Grace Cherry; Elizabeth Seja; Xiangju Kong; Jia Pang; Beata Berent-Maoz; Begoña Comin-Anduix; Thomas G Graeber; Paul C Tumeh; Ton N M Schumacher; Roger S Lo; Antoni Ribas Journal: N Engl J Med Date: 2016-07-13 Impact factor: 91.245
Authors: Sayuri Yoshihama; Jason Roszik; Isaac Downs; Torsten B Meissner; Saptha Vijayan; Bjoern Chapuy; Tabasum Sidiq; Margaret A Shipp; Gregory A Lizee; Koichi S Kobayashi Journal: Proc Natl Acad Sci U S A Date: 2016-05-09 Impact factor: 11.205
Authors: Jeffrey J Ishizuka; Robert T Manguso; Collins K Cheruiyot; Kevin Bi; Arpit Panda; Arvin Iracheta-Vellve; Brian C Miller; Peter P Du; Kathleen B Yates; Juan Dubrot; Ilana Buchumenski; Dawn E Comstock; Flavian D Brown; Austin Ayer; Ian C Kohnle; Hans W Pope; Margaret D Zimmer; Debattama R Sen; Sarah K Lane-Reticker; Emily J Robitschek; Gabriel K Griffin; Natalie B Collins; Adrienne H Long; John G Doench; David Kozono; Erez Y Levanon; W Nicholas Haining Journal: Nature Date: 2018-12-17 Impact factor: 49.962
Authors: J M Michot; C Bigenwald; S Champiat; M Collins; F Carbonnel; S Postel-Vinay; A Berdelou; A Varga; R Bahleda; A Hollebecque; C Massard; A Fuerea; V Ribrag; A Gazzah; J P Armand; N Amellal; E Angevin; N Noel; C Boutros; C Mateus; C Robert; J C Soria; A Marabelle; O Lambotte Journal: Eur J Cancer Date: 2016-01-05 Impact factor: 9.162
Authors: Martin McLaughlin; Emmanuel C Patin; Malin Pedersen; Anna Wilkins; Magnus T Dillon; Alan A Melcher; Kevin J Harrington Journal: Nat Rev Cancer Date: 2020-03-11 Impact factor: 60.716
Authors: Huayang Liu; Javad Golji; Lauren K Brodeur; Franklin S Chung; Julie T Chen; Rosalie S deBeaumont; Caroline P Bullock; Michael D Jones; Grainne Kerr; Li Li; Daniel P Rakiec; Michael R Schlabach; Sosathya Sovath; Joseph D Growney; Raymond A Pagliarini; David A Ruddy; Kenzie D MacIsaac; Joshua M Korn; E Robert McDonald Journal: Nat Med Date: 2018-12-17 Impact factor: 53.440
Authors: N Jacquelot; M P Roberti; D P Enot; S Rusakiewicz; N Ternès; S Jegou; D M Woods; A L Sodré; M Hansen; Y Meirow; M Sade-Feldman; A Burra; S S Kwek; C Flament; M Messaoudene; C P M Duong; L Chen; B S Kwon; A C Anderson; V K Kuchroo; B Weide; F Aubin; C Borg; S Dalle; O Beatrix; M Ayyoub; B Balme; G Tomasic; A M Di Giacomo; M Maio; D Schadendorf; I Melero; B Dréno; A Khammari; R Dummer; M Levesque; Y Koguchi; L Fong; M Lotem; M Baniyash; H Schmidt; I M Svane; G Kroemer; A Marabelle; S Michiels; A Cavalcanti; M J Smyth; J S Weber; A M Eggermont; L Zitvogel Journal: Nat Commun Date: 2017-09-19 Impact factor: 14.919
Authors: André Catic; Edda Fiebiger; Gregory A Korbel; Daniël Blom; Paul J Galardy; Hidde L Ploegh Journal: PLoS One Date: 2007-07-25 Impact factor: 3.240
Authors: Moshe Sade-Feldman; Yunxin J Jiao; Jonathan H Chen; Michael S Rooney; Michal Barzily-Rokni; Jean-Pierre Eliane; Stacey L Bjorgaard; Marc R Hammond; Hans Vitzthum; Shauna M Blackmon; Dennie T Frederick; Mehlika Hazar-Rethinam; Brandon A Nadres; Emily E Van Seventer; Sachet A Shukla; Keren Yizhak; John P Ray; Daniel Rosebrock; Dimitri Livitz; Viktor Adalsteinsson; Gad Getz; Lyn M Duncan; Bo Li; Ryan B Corcoran; Donald P Lawrence; Anat Stemmer-Rachamimov; Genevieve M Boland; Dan A Landau; Keith T Flaherty; Ryan J Sullivan; Nir Hacohen Journal: Nat Commun Date: 2017-10-26 Impact factor: 14.919