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1.
Mol Cell ; 81(6): 1187-1199.e5, 2021 03 18.
Artigo em Inglês | MEDLINE | ID: mdl-33581076

RESUMO

Type I interferons (IFNs) are critical cytokines in the host defense against invading pathogens. Sustained production of IFNs, however, is detrimental to the host, as it provokes autoimmune diseases. Thus, the expression of IFNs is tightly controlled. We report that the mRNA 5' cap-binding protein 4EHP plays a key role in regulating type I IFN concomitant with controlling virus replication, both in vitro and in vivo. Mechanistically, 4EHP suppresses IFN-ß production by effecting the miR-34a-induced translational silencing of Ifnb1 mRNA. miR-34a is upregulated by both RNA virus infection and IFN-ß induction, prompting a negative feedback regulatory mechanism that represses IFN-ß expression via 4EHP. These findings demonstrate the direct involvement of 4EHP in virus-induced host response, underscoring a critical translational silencing mechanism mediated by 4EHP and miR-34a to impede sustained IFN production. This study highlights an intrinsic regulatory function for miRNA and the translation machinery in maintaining host homeostasis.


Assuntos
Fator de Iniciação 4E em Eucariotos/imunologia , Imunidade Inata , MicroRNAs/imunologia , Biossíntese de Proteínas/imunologia , Infecções por Vírus de RNA/imunologia , Vírus de RNA/imunologia , Animais , Fator de Iniciação 4E em Eucariotos/genética , Células HEK293 , Humanos , Interferon beta/genética , Interferon beta/imunologia , Camundongos , Camundongos Transgênicos , MicroRNAs/genética , Infecções por Vírus de RNA/genética , Vírus de RNA/genética
2.
FEBS J ; 290(10): 2508-2524, 2023 05.
Artigo em Inglês | MEDLINE | ID: mdl-35247033

RESUMO

Post-transcriptional regulation of messenger RNAs (mRNAs) (i.e., mechanisms that control translation, stability and localization) is a critical focal point in spatiotemporal regulation of gene expression in response to changes in environmental conditions. The human genome encodes ~ 2000 microRNAs (miRNAs), each of which could control the expression of hundreds of protein-coding mRNAs by inducing translational repression and/or promoting mRNA decay. While mRNA degradation is a terminal event, translational repression is reversible and can be employed for rapid response to internal or external cues. Recent years have seen significant progress in our understanding of how miRNAs induce degradation or translational repression of the target mRNAs. Here, we review the recent findings that illustrate the cellular machinery that contributes to miRNA-induced silencing, with a focus on the factors that could influence translational repression vs. decay.


Assuntos
MicroRNAs , Humanos , MicroRNAs/metabolismo , Biossíntese de Proteínas , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Regulação da Expressão Gênica , Estabilidade de RNA/genética
3.
Cell Signal ; 84: 110037, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33975011

RESUMO

The mRNA translation machinery is tightly regulated through several, at times overlapping, mechanisms that modulate its efficiency and accuracy. Due to their fast rate of growth and metabolism, cancer cells require an excessive amount of mRNA translation and protein synthesis. However, unfavorable conditions, such as hypoxia, amino acid starvation, and oxidative stress, which are abundant in cancer, as well as many anti-cancer treatments inhibit mRNA translation. Cancer cells adapt to the various internal and environmental stresses by employing specialised transcript-specific translation to survive and gain a proliferative advantage. We will highlight the major signaling pathways and mechanisms of translation that regulate the global or mRNA-specific translation in response to the intra- or extra-cellular signals and stresses that are key components in the process of tumourigenesis.


Assuntos
Neoplasias , Biossíntese de Proteínas , Aminoácidos/metabolismo , Humanos , Neoplasias/genética , Neoplasias/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ribossomos/genética
4.
Free Radic Biol Med ; 125: 25-35, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29605448

RESUMO

Polymorphonuclear leukocytes, or neutrophils, are specialist phagocytic cells of the innate immune system. Their primary role is host defence against micro-organisms, which they kill via phagocytosis, followed by release of reactive oxygen species (ROS) and proteolytic enzymes within the phagosome. ROS are generated via the action of the NADPH oxidase (also known as NOX2), in a process termed the 'Respiratory Burst'. This process consumes large amounts of oxygen, which is converted into the highly-reactive superoxide radical O2- and H2O2. Subsequent activation of myeloperoxidase (MPO) generates secondary oxidants and chloroamines that are highly microbiocidal in nature, which together with proteases such as elastase and gelatinase provide a toxic intra-phagosomal environment able to kill a broad range of micro-organisms. However, under certain circumstances such as during an auto-immune response, neutrophils can be triggered to release ROS and proteases extracellularly causing damage to host tissues, modification of host proteins, lipids and DNA and dysregulation of oxidative homeostasis. This review describes the range of ROS species produced by human neutrophils with a focus on the implications of neutrophil redox products in autoimmune inflammation.


Assuntos
Doenças Autoimunes/etiologia , Doenças Autoimunes/patologia , Neutrófilos/patologia , Estresse Oxidativo , Espécies Reativas de Oxigênio/metabolismo , Animais , Humanos , Oxirredução
5.
PLoS One ; 10(4): e0124627, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25853250

RESUMO

BACKGROUND: Children with severe neurodisability (ND) commonly suffer from chronic respiratory symptoms that impact greatly on quality of life, and lead to recurrent hospital admissions. This morbidity (and its causes) is poorly described, despite being well recognised by paediatricians. In this study, we characterised respiratory symptoms in children with ND at times of stability and deterioration. We also assessed the relationship between respiratory symptoms, lower airway inflammatory markers and levels of infection/colonisation. METHODS: ND children were recruited upon admission for elective surgery (Elective-ND [n = 16]), or acutely upon admission to Intensive Care (PICU-ND [n = 19]), and compared to healthy control children [n = 12]. Parents completed a validated respiratory symptom questionnaire in which symptoms associated with activity were removed (total maximal score of 108). Bronchoalveolar lavage (BAL) was collected, and BAL neutrophil counts, IL-8 and TGFß-1 levels measured. BAL microbial analysis was performed using a 16S/18S rRNA gene based assay and Pseudomonas aeruginosa PCR. RESULTS: All ND children had high levels of respiratory symptoms (median [IQR] symptom score PICU-ND, 55[38-64]; Elective-ND, 26[7-45]; Control, 4[0-7]: p<0.01), which affected their families, particularly at nighttime. Elective-ND patients with a total respiratory symptom score >20 invariably had BAL neutrophilia. Elective patients with 16S/18S microbial rDNA positive BAL had higher neutrophil counts (positive, 33[18-70]%; negative, 8[4-38]%: p<0.05) and generally higher symptom scores (positive, 17[5-32]; negative, 5[0-9]: p = 0.097). Streptococcus mitis was commonly identified in BAL from ND children; Pseudomonas aeruginosa was not identified in any sample. CONCLUSIONS: Children with severe ND often have high levels of chronic respiratory symptoms, which may relate to lower airway inflammation. Bacterial airway colonisation, particularly with oral commensals, may play a role in both symptom generation and inflammation.


Assuntos
Transtornos do Neurodesenvolvimento/microbiologia , Sistema Respiratório/microbiologia , Infecções Respiratórias/microbiologia , Infecções Estreptocócicas/microbiologia , Adolescente , Líquido da Lavagem Broncoalveolar/microbiologia , Estudos de Casos e Controles , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Transtornos do Neurodesenvolvimento/complicações , Transtornos do Neurodesenvolvimento/fisiopatologia , Transtornos do Neurodesenvolvimento/psicologia , Neutrófilos/patologia , Qualidade de Vida/psicologia , RNA Ribossômico 16S/genética , Sistema Respiratório/fisiopatologia , Infecções Respiratórias/complicações , Infecções Respiratórias/fisiopatologia , Infecções Respiratórias/psicologia , Índice de Gravidade de Doença , Infecções Estreptocócicas/complicações , Infecções Estreptocócicas/fisiopatologia , Infecções Estreptocócicas/psicologia , Streptococcus mitis/genética , Streptococcus mitis/isolamento & purificação , Inquéritos e Questionários
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