Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 7 de 7
Filtrar
1.
Nature ; 568(7751): E3, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30911170

RESUMO

In this Letter, a citation to 'Fig. 1e' has been corrected to 'Fig. 1d' in the sentence starting "By contrast, the anti-tumour response…". This has been corrected online.

2.
Nature ; 566(7743): 270-274, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30728504

RESUMO

There is growing evidence that tumour neoantigens have important roles in generating spontaneous antitumour immune responses and predicting clinical responses to immunotherapies1,2. Despite the presence of numerous neoantigens in patients, complete tumour elimination is rare, owing to failures in mounting a sufficient and lasting antitumour immune response3,4. Here we show that durable neoantigen-specific immunity is regulated by mRNA N6-methyadenosine (m6A) methylation through the m6A-binding protein YTHDF15. In contrast to wild-type mice, Ythdf1-deficient mice show an elevated antigen-specific CD8+ T cell antitumour response. Loss of YTHDF1 in classical dendritic cells enhanced the cross-presentation of tumour antigens and the cross-priming of CD8+ T cells in vivo. Mechanistically, transcripts encoding lysosomal proteases are marked by m6A and recognized by YTHDF1. Binding of YTHDF1 to these transcripts increases the translation of lysosomal cathepsins in dendritic cells, and inhibition of cathepsins markedly enhances cross-presentation of wild-type dendritic cells. Furthermore, the therapeutic efficacy of PD-L1 checkpoint blockade is enhanced in Ythdf1-/- mice, implicating YTHDF1 as a potential therapeutic target in anticancer immunotherapy.


Assuntos
Adenosina/análogos & derivados , Adenosina/metabolismo , Células Dendríticas/imunologia , Neoplasias/imunologia , RNA Mensageiro/metabolismo , Proteínas de Ligação a RNA/metabolismo , Animais , Apresentação de Antígeno/imunologia , Antígenos de Neoplasias/imunologia , Antígenos de Neoplasias/metabolismo , Antígeno B7-H1/metabolismo , Sítios de Ligação , Linfócitos T CD8-Positivos/imunologia , Catepsinas/antagonistas & inibidores , Catepsinas/biossíntese , Catepsinas/genética , Apresentação Cruzada/imunologia , Células Dendríticas/enzimologia , Feminino , Humanos , Metilação , Camundongos , Camundongos Endogâmicos C57BL , Neoplasias/terapia , Biossíntese de Proteínas , Proteínas/genética , RNA Mensageiro/química , Proteínas de Ligação a RNA/genética , Transcriptoma/genética
3.
Hum Mol Genet ; 24(5): 1350-62, 2015 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-25343992

RESUMO

Although misfolded proteins are ubiquitinated and cleared by the proteasome, they can accumulate in synapses in aged neurons to promote synaptic dysfunction in a variety of neurodegenerative diseases, including Huntington's disease (HD), which is caused by polyglutamine expansion in huntingtin. The mechanism behind this aging-related phenomenon is unknown and has been difficult to investigate using animals with short life spans. With brain tissues from longer-lived rhesus monkeys of different ages, we found that aging reduces ubiquitin-proteasomal activity and also increases the level of ubiquitin-conjugating enzyme UBE2N (Ubc13) in synaptosomes. Synaptosomal fractions from aged monkey brain increase in vitro ubiquitinated huntingtin, whereas depletion of UBE2N markedly reduces this increase. Overexpressing UBE2N increases the aggregation of mutant huntingtin, and reducing UBE2N attenuates huntingtin aggregation in cellular and mouse models of HD. Our studies suggest that increased UBE2N plays a critical role in the synaptosomal accumulation of mutant huntingtin with age.


Assuntos
Envelhecimento , Doença de Huntington/genética , Proteínas do Tecido Nervoso/metabolismo , Sinaptossomos/metabolismo , Enzimas de Conjugação de Ubiquitina/genética , Animais , Encéfalo/metabolismo , Modelos Animais de Doenças , Macaca mulatta/genética , Masculino , Camundongos , Proteínas do Tecido Nervoso/genética , Neurônios/metabolismo , Peptídeos/metabolismo , Complexo de Endopeptidases do Proteassoma/genética , Complexo de Endopeptidases do Proteassoma/metabolismo , Proteômica , Enzimas de Conjugação de Ubiquitina/metabolismo
4.
Cancer Cell ; 39(7): 945-957.e10, 2021 07 12.
Artigo em Inglês | MEDLINE | ID: mdl-34019807

RESUMO

Tumor-associated macrophages (TAMs) can dampen the antitumor activity of T cells, yet the underlying mechanism remains incompletely understood. Here, we show that C1q+ TAMs are regulated by an RNA N6-methyladenosine (m6A) program and modulate tumor-infiltrating CD8+ T cells by expressing multiple immunomodulatory ligands. Macrophage-specific knockout of an m6A methyltransferase Mettl14 drives CD8+ T cell differentiation along a dysfunctional trajectory, impairing CD8+ T cells to eliminate tumors. Mettl14-deficient C1q+ TAMs show a decreased m6A abundance on and a higher level of transcripts of Ebi3, a cytokine subunit. In addition, neutralization of EBI3 leads to reinvigoration of dysfunctional CD8+ T cells and overcomes immunosuppressive impact in mice. We show that the METTL14-m6A levels are negatively correlated with dysfunctional T cell levels in patients with colorectal cancer, supporting the clinical relevance of this regulatory pathway. Thus, our study demonstrates how an m6A methyltransferase in TAMs promotes CD8+ T cell dysfunction and tumor progression.


Assuntos
Adenosina/análogos & derivados , Linfócitos T CD8-Positivos/imunologia , Ativação Linfocitária/imunologia , Metiltransferases/metabolismo , Metiltransferases/fisiologia , Neoplasias/patologia , Macrófagos Associados a Tumor/metabolismo , Adenosina/química , Animais , Carcinoma Pulmonar de Lewis/imunologia , Carcinoma Pulmonar de Lewis/metabolismo , Carcinoma Pulmonar de Lewis/patologia , Neoplasias Colorretais/imunologia , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Citocinas/metabolismo , Feminino , Humanos , Melanoma Experimental/imunologia , Melanoma Experimental/metabolismo , Melanoma Experimental/patologia , Metiltransferases/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Antígenos de Histocompatibilidade Menor/metabolismo , Neoplasias/imunologia , Neoplasias/metabolismo , Receptores de Citocinas/metabolismo , Microambiente Tumoral , Macrófagos Associados a Tumor/patologia
5.
J Clin Invest ; 127(7): 2719-2724, 2017 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-28628038

RESUMO

Huntington's disease is a neurodegenerative disorder caused by a polyglutamine repeat in the Huntingtin gene (HTT). Although suppressing the expression of mutant HTT (mHTT) has been explored as a therapeutic strategy to treat Huntington's disease, considerable efforts have gone into developing allele-specific suppression of mHTT expression, given that loss of Htt in mice can lead to embryonic lethality. It remains unknown whether depletion of HTT in the adult brain, regardless of its allele, could be a safe therapy. Here, we report that permanent suppression of endogenous mHTT expression in the striatum of mHTT-expressing mice (HD140Q-knockin mice) using CRISPR/Cas9-mediated inactivation effectively depleted HTT aggregates and attenuated early neuropathology. The reduction of mHTT expression in striatal neuronal cells in adult HD140Q-knockin mice did not affect viability, but alleviated motor deficits. Our studies suggest that non-allele-specific CRISPR/Cas9-mediated gene editing could be used to efficiently and permanently eliminate polyglutamine expansion-mediated neuronal toxicity in the adult brain.


Assuntos
Alelos , Sistemas CRISPR-Cas , Edição de Genes , Regulação da Expressão Gênica , Proteína Huntingtina , Doença de Huntington , Animais , Modelos Animais de Doenças , Células HEK293 , Humanos , Proteína Huntingtina/biossíntese , Proteína Huntingtina/genética , Doença de Huntington/genética , Doença de Huntington/metabolismo , Doença de Huntington/terapia , Camundongos , Camundongos Mutantes , Peptídeos/genética , Peptídeos/metabolismo
6.
Nat Commun ; 8(1): 579, 2017 09 18.
Artigo em Inglês | MEDLINE | ID: mdl-28924165

RESUMO

The hypothalamus has a vital role in controlling food intake and energy homeostasis; its activity is modulated by neuropeptides and endocrine factors. Mesencephalic astrocyte-derived neurotrophic factor (MANF) is a neurotrophic factor that is also localized in the endoplasmic reticulum (ER) in neurons. Here we show that MANF is highly enriched in distinct nuclei of the mouse hypothalamus, and that MANF expression in the hypothalamus is upregulated in response to fasting. Increasing or decreasing hypothalamic MANF protein levels causes hyperphagia or hypophagia, respectively. Moreover, MANF triggers hypothalamic insulin resistance by enhancing the ER localization and activity of PIP4k2b, a kinase known to regulate insulin signaling. Our findings indicate that MANF influences food intake and body weight by modulating hypothalamic insulin signaling.MANF is a neurotrophic factor that is secreted but also mediates the unfolded protein response acting intracellularly. Here, the authors show that MANF expression in the brain is influenced by nutritional cues, and hypothalamic MANF influences food intake and systemic energy homeostasis.


Assuntos
Peso Corporal/fisiologia , Ingestão de Alimentos/fisiologia , Hipotálamo/metabolismo , Fatores de Crescimento Neural/metabolismo , Animais , Western Blotting , Peso Corporal/genética , Ingestão de Alimentos/genética , Estresse do Retículo Endoplasmático/genética , Feminino , Expressão Gênica , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Fatores de Crescimento Neural/genética , Células PC12 , Interferência de RNA , Ratos , Reação em Cadeia da Polimerase Via Transcriptase Reversa
7.
Drug Des Devel Ther ; 9: 2179-88, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25931812

RESUMO

Huntington's disease (HD) is caused by a genetic mutation that results in polyglutamine expansion in the N-terminal regions of huntingtin. As a result, this polyQ expansion leads to the misfolding and aggregation of mutant huntingtin as well as age-dependent neurodegeneration. The genetic mutation in HD allows for generating a variety of animal models that express different forms of mutant huntingtin and show differential pathology. Studies of these animal models have provided an important insight into the pathogenesis of HD. Mouse models of HD include transgenic mice, which express N-terminal or full-length mutant huntingtin ubiquitously or selectively in different cell types, and knock-in mice that express full-length mutant Htt at the endogenous level. Large animals, such as pig, sheep, and monkeys, have also been used to generate animal HD models. This review focuses on the different features of commonly used transgenic HD mouse models as well as transgenic large animal models of HD, and also discusses how to use them to identify potential therapeutics. Since HD shares many pathological features with other neurodegenerative diseases, identification of therapies for HD would also help to develop effective treatment for different neurodegenerative diseases that are also caused by protein misfolding and occur in an age-dependent manner.


Assuntos
Animais Geneticamente Modificados , Doença de Huntington/tratamento farmacológico , Doença de Huntington/genética , Animais , Modelos Animais de Doenças , Técnicas de Introdução de Genes , Humanos , Proteína Huntingtina , Doença de Huntington/patologia , Camundongos , Camundongos Transgênicos , Mutação , Proteínas do Tecido Nervoso/genética , Primatas , Ovinos , Suínos
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA