Virus Infection Induces Keap1 Binding to Cytokine Genes, Which Recruits NF-κB p50 and G9a-GLP and Represses Cytokine Transcription.
Virus Infection Induces Keap1 Binding to Cytokine Genes, Which Recruits NF-κB p50 and G9a-GLP and Represses Cytokine Transcription.
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病毒感染诱导KEAP1与细胞因子基因结合，该基因募集NF-κBP50和G9A-GLP并抑制细胞因子转录。
DOI：
10.4049/jimmunol.2100355
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发表时间：
2021-09-01
期刊：
影响因子：
--
通讯作者：
Kerppola TK
中科院分区：
文献类型：
--
作者：
Burns VE;Kerppola TK
促炎性细胞因子基因转录必须适度，以避免过度细胞因子产生的病理后果。病毒感染与调节细胞因子转录的机制之间的关系尚不完全清楚。我们研究了Keap 1对仙台病毒感染小鼠胚胎成纤维细胞诱导细胞因子基因的影响。病毒感染诱导Keap 1与Ifnb 1、Tnf和Il 6基因结合。Keap 1通过不需要Nrf 2的机制调节病毒对其转录的诱导。Keap 1是NFκB p50募集到这些基因所必需的，但不是NFκB p65或IRF 3募集到这些基因所必需的。Keap 1与NFκB p50和NFκB p65形成复合物，使用双分子荧光互补（BiFC）分析可观察到。这些BiFC复合物结合活细胞中的染色体，表明Keap 1可以结合与NFκB蛋白相关的染色质。病毒诱导G9 a-GLP赖氨酸甲基转移酶结合和细胞因子基因处的H3 K9 me 2修饰需要Keap 1。G9 a-GLP抑制剂解除了Keap 1的转录抑制，并增强了Keap 1和NFκB向细胞因子基因的募集。Keap 1、NFκB和G9 a-GLP募集、活性和转录效应之间的相互关系表明它们形成反馈回路，调节病毒诱导的细胞因子转录。Nrf 2抵消了Keap 1与细胞因子基因的结合以及Keap 1对NFκB p50和G9 a-GLP的募集。而Keap 1可以通过其在细胞质中的功能间接影响细胞因子的表达，这些发现表明Keap 1直接在细胞核中调节细胞因子的转录。Keap 1在病毒感染后与细胞因子基因结合，并通过募集NFκB p50和G9 a-GLP来调节其诱导。
Pro-inflammatory cytokine gene transcription must be moderated to avoid the pathological consequences of excess cytokine production. The relationships between virus infection and the mechanisms that moderate cytokine transcription are incompletely understood. We investigated the influence of Keap1 on cytokine gene induction by Sendai virus infection in mouse embryo fibroblasts. Virus infection induced Keap1 binding to the Ifnb1, Tnf and Il6 genes. Keap1 moderated viral induction of their transcription by mechanisms that did not require Nrf2. Keap1 was required for NFκB p50 recruitment, but not for NFκB p65 or IRF3 recruitment, to these genes. Keap1 formed complexes with NFκB p50 and NFκB p65, which were visualized using bimolecular fluorescence complementation (BiFC) analysis. These BiFC complexes bound chromosomes in live cells, suggesting that Keap1 could bind chromatin in association with NFκB proteins. Keap1 was required for viral induction of G9a-GLP lysine methyltransferase binding and H3K9me2 modification at cytokine genes. G9a-GLP inhibitors lifted transcription repression by Keap1, and enhanced Keap1 and NFκB recruitment to cytokine genes. The interrelationships among Keap1, NFκB and G9a-GLP recruitment, activities and transcriptional effects suggest that they form a feedback circuit, which moderates viral induction of cytokine transcription. Nrf2 counteracted Keap1 binding to cytokine genes and the recruitment of NFκB p50 and G9a-GLP by Keap1. Whereas Keap1 can influence cytokine expression indirectly through its functions in the cytoplasm, these findings evidence that Keap1 regulates cytokine transcription directly in the nucleus. Keap1 binds to cytokines genes upon virus infection and moderates their induction by recruiting NFκB p50 and G9a-GLP.
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影响因子：
7.3
作者：
Cheng CS;Feldman KE;Lee J;Verma S;Huang DB;Huynh K;Chang M;Ponomarenko JV;Sun SC;Benedict CA;Ghosh G;Hoffmann A
通讯作者：
Hoffmann A
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
作者：
Krausgruber T;Fortelny N;Fife-Gernedl V;Senekowitsch M;Schuster LC;Lercher A;Nemc A;Schmidl C;Rendeiro AF;Bergthaler A;Bock C
通讯作者：
Bock C
DOI：
10.1164/rccm.201102-0271oc
发表时间：
2011-10-15
影响因子：
24.7
作者：
Kong, Xiaoni;Thimmulappa, Rajesh;Biswal, Shyam
通讯作者：
Biswal, Shyam
DOI：
10.1084/jem.20112343
发表时间：
2012-04-09
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
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
通讯作者：
Tarakhovsky A
影响因子：
8.8
作者：
Pyaram, Kalyani;Kumar, Ajay;Chang, Cheong-Hee
通讯作者：
Chang, Cheong-Hee