Toll-like receptor-dependent and -independent viperin gene expression and counter-regulation by PRDI-binding factor-1/BLIMP1
Toll-like receptor-dependent and -independent viperin gene expression and counter-regulation by PRDI-binding factor-1/BLIMP1
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DOI：
10.1074/jbc.m604516200
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发表时间：
2006-09-08
影响因子：
4.8
通讯作者：
Fitzgerald, Katherine A.
中科院分区：
文献类型：
--
作者：
Severa, Martina;Coccia, Eliana M.;Fitzgerald, Katherine A.
在这里，我们发现Viperin是一个高度诱导的基因，可以响应脂多糖（LPS）、双链RNA （poly(I-C)）或仙台病毒（SV）。Viperin唯一已知的功能与其抑制人类巨细胞病毒复制的能力有关。关于这个基因的调控的数据很少。在启动子的计算机分析中鉴定出两种干扰素（IFN）刺激反应元件（ISRE），它们在其他基因中结合IRF3或IFN刺激基因因子-3 （ISGF3）复合物。LPS和poly（I- c）在野生型细胞中诱导非常高水平的Viperin，但在TRIF、TBK1、IRF3或I型IFN α / β r缺乏的细胞中则没有。sv诱导的Viperin基因表达独立于toll样受体（TLR）信号传导，由视黄酸诱导基因（RIG-I）和下游适配器线粒体抗病毒信号传导（MAVS）介导。在单独缺乏TBK1或IKK epsilon的巨噬细胞中，病毒诱导的Viperin表达均未减弱。此外，irf3缺陷而非IFN α / β R缺陷的巨噬细胞仍然诱导Viperin响应SV。启动子报告子研究结合DNA免疫沉淀试验发现ISGF3复合物是Viperin基因表达的关键调节因子。此外，正调节结构域i结合因子1 （PRDI-BF1，也称为BLIMP1）结合ISRE位点，并以病毒诱导的方式与ISGF3结合竞争，抑制Viperin转录。总的来说，这些研究确定Viperin是一个严格调控的ISGF3靶基因，它被PRDI-BF1反调控。
Here we identify Viperin as a highly inducible gene in response to lipopolysaccharide (LPS), double-stranded RNA (poly(I-C)) or Sendai virus (SV). The only known function of Viperin relates to its ability to inhibit human Cytomegalovirus replication. Very little data are available on the regulation of this gene. In silico analysis of the promoter identified two interferon (IFN)-stimulated response elements (ISRE), which in other genes bind IRF3 or the IFN-stimulated gene factor-3 (ISGF3) complex. LPS and poly(I-C) induce very high levels of Viperin in wild type cells but not in cells deficient in TRIF, TBK1, IRF3, or the type I IFN alpha/beta R. SV-induced Viperin gene expression was mediated independently of Toll-like receptor (TLR) signaling by retinoic acid-inducible gene (RIG-I) and the downstream adapter, mitochondrial anti-viral signaling (MAVS). Virus-induced Viperin expression was not attenuated in macrophages deficient in either TBK1 or IKK epsilon alone. Moreover, IRF3-deficient, but not IFN alpha/beta R deficient, macrophages still induced Viperin in response to SV. Promoter reporter studies combined with DNA immunoprecipitation assays identified the ISGF3 complex as the key regulator of Viperin gene expression. Moreover, positive regulatory domain I-binding factor 1 (PRDI-BF1, also called BLIMP1) binds the ISRE sites and competes with ISGF3 binding in a virus inducible manner to inhibit Viperin transcription. Collectively, these studies identify Viperin as a tightly regulated ISGF3 target gene, which is counter-regulated by PRDI-BF1.