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1.
Proc Natl Acad Sci U S A ; 120(50): e2315163120, 2023 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-38055744

RESUMO

Interferon-induced ubiquitin (Ub)-like modifier ISG15 covalently modifies host and viral proteins to restrict viral infections. Its function is counteracted by the canonical deISGylase USP18 or Ub-specific protease 18. Notwithstanding indications for the existence of other ISG15 cross-reactive proteases, these remain to be identified. Here, we identify deubiquitinase USP16 as an ISG15 cross-reactive protease by means of ISG15 activity-based profiling. Recombinant USP16 cleaved pro-ISG15 and ISG15 isopeptide-linked model substrates in vitro, as well as ISGylated substrates from cell lysates. Moreover, interferon-induced stimulation of ISGylation was increased by depletion of USP16. The USP16-dependent ISG15 interactome indicated that the deISGylating function of USP16 may regulate metabolic pathways. Targeted enzymes include malate dehydrogenase, cytoplasmic superoxide dismutase 1, fructose-bisphosphate aldolase A, and cytoplasmic glutamic-oxaloacetic transaminase 1. USP16 may thus contribute to the regulation of a subset of metabolism-related proteins during type-I interferon responses.


Assuntos
Citocinas , Interferon Tipo I , Citocinas/metabolismo , Ubiquitinas/genética , Ubiquitinas/metabolismo , Endopeptidases/genética , Endopeptidases/metabolismo , Peptídeo Hidrolases/metabolismo , Interferon Tipo I/genética , Interferon Tipo I/metabolismo , Enzimas Desubiquitinantes
2.
Br J Cancer ; 124(4): 817-830, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33214684

RESUMO

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.


Assuntos
Neoplasias Colorretais/enzimologia , Neoplasias Colorretais/imunologia , Citocinas/metabolismo , Leucemia Mielogênica Crônica BCR-ABL Positiva/enzimologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/imunologia , Ubiquitina Tiolesterase/metabolismo , Ubiquitinas/metabolismo , Variação Antigênica , Linhagem Celular Tumoral , Neoplasias Colorretais/radioterapia , Técnicas de Inativação de Genes , Células HCT116 , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/radioterapia , Tolerância a Radiação/genética , Tolerância a Radiação/imunologia , Ubiquitina Tiolesterase/deficiência , Ubiquitina Tiolesterase/genética
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