Deletion of the deISGylating enzyme USP18 enhances tumour cell antigenicity and radiosensitivity.
Br J Cancer
; 124(4): 817-830, 2021 02.
Article
em En
| MEDLINE
| ID: mdl-33214684
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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Ubiquitinas
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Neoplasias Colorretais
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Leucemia Mielogênica Crônica BCR-ABL Positiva
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Citocinas
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Ubiquitina Tiolesterase
Limite:
Humans
Idioma:
En
Ano de publicação:
2021
Tipo de documento:
Article