Deletion of the deISGylating enzyme USP18 enhances tumour cell antigenicity and radiosensitivity
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 signal...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , |
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| 格式: | Journal article |
| 語言: | English |
| 出版: |
Springer Nature
2020
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| _version_ | 1826303753080274944 |
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| author | Pinto-Fernandez, A Salio, M Partridge, T Chen, J Vere, G Greenwood, H Olie, CS Damianou, A Scott, HC Pegg, J Chiarenza, A Diaz-Saez, L Smith, P Gonzalez-Lopez, C Patel, B Jones, N Hammonds, T Huber, K Muschel, R Borrow, P Cerundolo, V Kessler, B |
| author_facet | Pinto-Fernandez, A Salio, M Partridge, T Chen, J Vere, G Greenwood, H Olie, CS Damianou, A Scott, HC Pegg, J Chiarenza, A Diaz-Saez, L Smith, P Gonzalez-Lopez, C Patel, B Jones, N Hammonds, T Huber, K Muschel, R Borrow, P Cerundolo, V Kessler, B |
| author_sort | Pinto-Fernandez, A |
| collection | OXFORD |
| description | 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.
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| first_indexed | 2024-03-07T06:07:30Z |
| format | Journal article |
| id | oxford-uuid:ee5b189d-abae-4aea-b1d1-4218e3cd11f1 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T06:07:30Z |
| publishDate | 2020 |
| publisher | Springer Nature |
| record_format | dspace |
| spelling | oxford-uuid:ee5b189d-abae-4aea-b1d1-4218e3cd11f12022-03-27T11:32:02ZDeletion of the deISGylating enzyme USP18 enhances tumour cell antigenicity and radiosensitivityJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:ee5b189d-abae-4aea-b1d1-4218e3cd11f1EnglishSymplectic ElementsSpringer Nature2020Pinto-Fernandez, ASalio, MPartridge, TChen, JVere, GGreenwood, HOlie, CSDamianou, AScott, HCPegg, JChiarenza, ADiaz-Saez, LSmith, PGonzalez-Lopez, CPatel, BJones, NHammonds, THuber, KMuschel, RBorrow, PCerundolo, VKessler, BBackground 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. |
| spellingShingle | Pinto-Fernandez, A Salio, M Partridge, T Chen, J Vere, G Greenwood, H Olie, CS Damianou, A Scott, HC Pegg, J Chiarenza, A Diaz-Saez, L Smith, P Gonzalez-Lopez, C Patel, B Jones, N Hammonds, T Huber, K Muschel, R Borrow, P Cerundolo, V Kessler, B Deletion of the deISGylating enzyme USP18 enhances tumour cell antigenicity and radiosensitivity |
| title | Deletion of the deISGylating enzyme USP18 enhances tumour cell antigenicity and radiosensitivity |
| title_full | Deletion of the deISGylating enzyme USP18 enhances tumour cell antigenicity and radiosensitivity |
| title_fullStr | Deletion of the deISGylating enzyme USP18 enhances tumour cell antigenicity and radiosensitivity |
| title_full_unstemmed | Deletion of the deISGylating enzyme USP18 enhances tumour cell antigenicity and radiosensitivity |
| title_short | Deletion of the deISGylating enzyme USP18 enhances tumour cell antigenicity and radiosensitivity |
| title_sort | deletion of the deisgylating enzyme usp18 enhances tumour cell antigenicity and radiosensitivity |
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