RESUMEN
Over the past 15 years, protein acetylation has emerged as a globally important post-translational modification that fine-tunes major cellular processes in many life forms. This dynamic regulatory system is critical both for complex eukaryotic cells and for the viruses that infect them. HIV-1 accesses the host acetylation network by interacting with several key enzymes, thereby promoting infection at multiple steps during the viral life cycle. Inhibitors of host histone deacetylases and bromodomain-containing proteins are now being pursued as therapeutic strategies to enhance current antiretroviral treatment. As more acetylation-targeting compounds are reaching clinical trials, it is time to review the role of reversible protein acetylation in HIV-infected CD4(+) T cells.
Asunto(s)
Linfocitos T CD4-Positivos/metabolismo , Infecciones por VIH/metabolismo , VIH-1/inmunología , Interacciones Huésped-Patógeno , Modelos Inmunológicos , Procesamiento Proteico-Postraduccional , Acetilación , Fármacos Anti-VIH/farmacología , Fármacos Anti-VIH/uso terapéutico , Linfocitos T CD4-Positivos/efectos de los fármacos , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/virología , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/inmunología , Infecciones por VIH/virología , VIH-1/efectos de los fármacos , VIH-1/metabolismo , VIH-1/patogenicidad , Histona Acetiltransferasas/antagonistas & inhibidores , Histona Acetiltransferasas/metabolismo , Inhibidores de Histona Desacetilasas/farmacología , Inhibidores de Histona Desacetilasas/uso terapéutico , Histona Desacetilasas/química , Histona Desacetilasas/metabolismo , Histonas/metabolismo , Interacciones Huésped-Patógeno/efectos de los fármacos , Humanos , Isoenzimas/antagonistas & inhibidores , Isoenzimas/metabolismo , Procesamiento Proteico-Postraduccional/efectos de los fármacosAsunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/mortalidad , Anciano de 80 o más Años , Compuestos de Anilina/administración & dosificación , Anticuerpos Monoclonales Humanizados/administración & dosificación , Compuestos Bicíclicos Heterocíclicos con Puentes/administración & dosificación , Ciclopentanos/administración & dosificación , Supervivencia sin Enfermedad , Femenino , Glicina/administración & dosificación , Glicina/análogos & derivados , Humanos , Masculino , Pirazinas/administración & dosificación , Piridinas/administración & dosificación , Pirimidinas/administración & dosificación , Estudios Retrospectivos , Sulfonamidas/administración & dosificación , Tasa de SupervivenciaAsunto(s)
Anilidas/uso terapéutico , Anticuerpos Monoclonales Humanizados/uso terapéutico , Carcinoma Basocelular/tratamiento farmacológico , Carcinoma Basocelular/mortalidad , Piridinas/uso terapéutico , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/mortalidad , Antineoplásicos Inmunológicos/uso terapéutico , Carcinoma Basocelular/patología , Supervivencia sin Enfermedad , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Femenino , Humanos , Infusiones Intravenosas , Masculino , Invasividad Neoplásica/patología , Estadificación de Neoplasias , Pronóstico , Estudios Prospectivos , Medición de Riesgo , Neoplasias Cutáneas/patología , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
The vast majority of polymorphisms for human dermatologic diseases fall in noncoding DNA regions, leading to difficulty interpreting their functional significance. Recent work using chromosome conformation capture technology in combination with chromatin immunoprecipitation (ChIP) has provided a systematic means of linking noncoding variants in active enhancer loci to putative gene targets. Here, we apply H3K27ac HiChIP high-resolution contact maps, generated from primary human T-cell subsets (CD4+ naïve, T helper type 17, and regulatory T cells), to 21 dermatologic conditions associated with single nucleotide polymorphisms from 106 genome-wide association studies. This "enhancer connectome" identified 1,492 HiChIP gene targets from 542 noncoding SNPs (P ≤ 5.0 × 10-8). SNP-containing enhancers from inflammatory skin conditions were significantly enriched at the HLA locus and also targeted several key factors from the JAK-STAT signaling pathway, but nonimmune conditions were not. A focused profiling of systemic lupus erythematosus HiChIP genes identified enhancer interactions with factors important for effector CD4+ T-cell differentiation and function, including IRF8 and members of the Ikaros family of zinc-finger proteins. Our results show the ability of the enhancer connectome to nominate functionally relevant candidates from genome-wide association study-identified variants, representing a powerful tool to guide future studies into the genomic regulatory mechanisms underlying dermatologic diseases.
Asunto(s)
Elementos de Facilitación Genéticos/genética , Histonas/genética , Inflamación/genética , Lupus Eritematoso Sistémico/genética , Enfermedades de la Piel/genética , Linfocitos T Reguladores/fisiología , Células Th17/fisiología , Diferenciación Celular , Cromatina , Inmunoprecipitación de Cromatina , Conectoma , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Humanos , Factor de Transcripción Ikaros/genética , Factores Reguladores del Interferón/genética , Quinasas Janus/metabolismo , Polimorfismo de Nucleótido Simple , Factores de Transcripción STAT , Transducción de SeñalRESUMEN
The expansion of CD8+CD28- T cells, a population of terminally differentiated memory T cells, is one of the most consistent immunological changes in humans during aging. CD8+CD28- T cells are highly cytotoxic, and their frequency is linked to many age-related diseases. As they do not accumulate in mice, many of the molecular mechanisms regulating their fate and function remain unclear. In this paper, we find that human CD8+CD28- T cells, under resting conditions, have an enhanced capacity to use glycolysis, a function linked to decreased expression of the NAD+-dependent protein deacetylase SIRT1. Global gene expression profiling identified the transcription factor FoxO1 as a SIRT1 target involved in transcriptional reprogramming of CD8+CD28- T cells. FoxO1 is proteasomally degraded in SIRT1-deficient CD8+CD28- T cells, and inhibiting its activity in resting CD8+CD28+ T cells enhanced glycolytic capacity and granzyme B production as in CD8+CD28- T cells. These data identify the evolutionarily conserved SIRT1-FoxO1 axis as a regulator of resting CD8+ memory T cell metabolism and activity in humans.
Asunto(s)
Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Metabolismo Energético/genética , Memoria Inmunológica , Sirtuina 1/deficiencia , Biomarcadores , Antígenos CD28/metabolismo , Citotoxicidad Inmunológica , Proteína Forkhead Box O1/genética , Proteína Forkhead Box O1/metabolismo , Regulación de la Expresión Génica , Humanos , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismoRESUMEN
Transcriptional latency of HIV is a last barrier to viral eradication. Chromatin-remodeling complexes and post-translational histone modifications likely play key roles in HIV-1 reactivation, but the underlying mechanisms are incompletely understood. We performed an RNAi-based screen of human lysine methyltransferases and identified the SET and MYND domain-containing protein 2 (SMYD2) as an enzyme that regulates HIV-1 latency. Knockdown of SMYD2 or its pharmacological inhibition reactivated latent HIV-1 in T cell lines and in primary CD4+ T cells. SMYD2 associated with latent HIV-1 promoter chromatin, which was enriched in monomethylated lysine 20 at histone H4 (H4K20me1), a mark lost in cells lacking SMYD2. Further, we find that lethal 3 malignant brain tumor 1 (L3MBTL1), a reader protein with chromatin-compacting properties that recognizes H4K20me1, was recruited to the latent HIV-1 promoter in a SMYD2-dependent manner. We propose that a SMYD2-H4K20me1-L3MBTL1 axis contributes to HIV-1 latency and can be targeted with small-molecule SMYD2 inhibitors.