Keap1 moderates the transcription of virus induced genes through G9a-GLP and NFκB p50 recruitment.
Keap1 moderates the transcription of virus induced genes through G9a-GLP and NFκB p50 recruitment.
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细胞必须控制由病毒感染诱导的基因，以减轻炎症的有害后果。我们研究了Keap 1调节仙台病毒感染小鼠胚胎成纤维细胞（MEFs）诱导的基因转录的机制。Keap 1 −/−缺失增加了病毒诱导基因的转录，而不依赖于Nrf 2。Keap 1调节早期病毒诱导的基因转录。病毒感染诱导Keap 1与Ifnb 1、Tnf和Il 6结合，并降低Keap 1与Cdkn 1a和Ccng 1的结合。病毒感染诱导G9 a-GLP和NFκB p50募集以及H3 K9 me 2沉积。Keap 1 −/−缺失消除了G9 a-GLP和NFκB p50募集以及H3 K9 me 2沉积，但它们不影响NFκB p65、IRF 3或cJun募集。G9 a-GLP抑制剂（BIX 01294、MS 012、BRD 4770）在Keap 1完整的MEFs中增强病毒诱导的基因转录，但在Keap 1 −/−缺失的MEFs中不增强。G9 a-GLP抑制剂增强了Keap 1与感染的MEFs中病毒诱导基因的结合，以及与未感染的MEFs中细胞周期基因的结合。G9 a-GLP抑制剂增加了具有完整Keap 1的MEFs中NFκB亚基的募集。G9 a-GLP抑制剂稳定了透化MEF中的Keap 1保留。G9 a-GLP赖氨酸甲基转移酶活性是Keap 1调节转录所必需的，并且它调节Keap 1与染色质的结合。Keap 1和G9 a-GLP对彼此募集和对病毒诱导的基因转录的调节的相互依赖的作用构成反馈回路。Keap 1和亲电子试剂tBHQ通过不同的机制降低病毒诱导的基因转录，它们调节不同NFκB亚基的募集。Keap 1、G9 a-GLP和NFκB p50调节病毒诱导的基因转录的机制表征可促进免疫调节剂的开发。对病毒感染的过度和适应不良免疫反应是导致COVID-19和其他疾病发病率和死亡率的主要因素。相反，免疫功能受抑制的个体对疫苗和病原体的免疫应答不足，使他们暴露于感染。Burns和Kerppola描述了调节病毒感染诱导的基因转录的分子机制。Keap 1、G9 a-GLP和NFκB p50调节病毒诱导的基因转录的机制表征确定了可调节免疫应答的治疗剂的新靶点。
Cells must control genes that are induced by virus infection to mitigate deleterious consequences of inflammation. We investigated the mechanisms whereby Keap1 moderates the transcription of genes that are induced by Sendai virus infection in mouse embryo fibroblasts (MEFs). Keap1−/− deletions increased the transcription of virus induced genes independently of Nrf2. Keap1 moderated early virus induced gene transcription. Virus infection induced Keap1 to bind Ifnb1, Tnf and Il6, and reduced Keap1 binding at Cdkn1a and Ccng1. Virus infection induced G9a-GLP and NFκB p50 recruitment, and H3K9me2 deposition. Keap1−/− deletions eliminated G9a-GLP and NFκB p50 recruitment, and H3K9me2 deposition, but they did not affect NFκB p65, IRF3 or cJun recruitment. G9a-GLP inhibitors (BIX01294, MS012, BRD4770) enhanced virus induced gene transcription in MEFs with intact Keap1, but not in MEFs with Keap1−/− deletions. G9a-GLP inhibitors augmented Keap1 binding to virus induced genes in infected MEFs, and to cell cycle genes in uninfected MEFs. G9a-GLP inhibitors augmented NFκB subunit recruitment in MEFs with intact Keap1. G9a-GLP inhibitors stabilized Keap1 retention in permeabilized MEFs. G9a-GLP lysine methyltransferase activity was required for Keap1 to moderate transcription, and it moderated Keap1 binding to chromatin. The interdependent effects of Keap1 and G9a-GLP on the recruitment of each other and on the moderation of virus induced gene transcription constitute a feedback circuit. Keap1 and the electrophile tBHQ reduced virus induced gene transcription through different mechanisms, and they regulated the recruitment of different NFκB subunits. Characterization of the mechanisms whereby Keap1, G9a-GLP and NFκB p50 moderate virus induced gene transcription can facilitate the development of immunomodulatory agents. Excess and maladaptive immune responses to virus infections are a major contributing factor to the morbidity and mortality of COVID-19 and other diseases. Conversely, inadequate immune responses to vaccines and pathogens by individuals with suppressed immune function expose them to infections. Burns and Kerppola characterize molecular mechanisms that moderate the transcription of genes that are induced by virus infection. Characterization of the mechanisms whereby Keap1, G9a-GLP and NFκB p50 moderate virus induced gene transcription identifies new targets for therapeutic agents that can modulate immune responsiveness.
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影响因子：
64.8
作者：
Boyd DF;Allen EK;Randolph AG;Guo XJ;Weng Y;Sanders CJ;Bajracharya R;Lee NK;Guy CS;Vogel P;Guan W;Li Y;Liu X;Novak T;Newhams MM;Fabrizio TP;Wohlgemuth N;Mourani PM;PALISI Pediatric Intensive Care Influenza (PICFLU) Investigators;Wight TN;Schultz-Cherry S;Cormier SA;Shaw-Saliba K;Pekosz A;Rothman RE;Chen KF;Yang Z;Webby RJ;Zhong N;Crawford JC;Thomas PG
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结构细胞是器官特异性免疫反应的关键调节剂。
影响因子：
64.8
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DOI：
10.1084/jem.20151646
发表时间：
2016-06-27
期刊：
The Journal of experimental medicine
影响因子：
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Antignano F;Braam M;Hughes MR;Chenery AL;Burrows K;Gold MJ;Oudhoff MJ;Rattray D;Halim TY;Cait A;Takei F;Rossi FM;McNagny KM;Zaph C
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DOI：
10.1164/rccm.201102-0271oc
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2011-10-15
影响因子：
24.7
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DOI：
10.1084/jem.20112343
发表时间：
2012-04-09
期刊：
The Journal of experimental medicine
影响因子：
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Fang TC;Schaefer U;Mecklenbrauker I;Stienen A;Dewell S;Chen MS;Rioja I;Parravicini V;Prinjha RK;Chandwani R;MacDonald MR;Lee K;Rice CM;Tarakhovsky A
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Tarakhovsky A