Central role of interferon regulatory factor-1 (IRF-1) in controlling retinoic acid inducible gene-I (RIG-I) expression
Central role of interferon regulatory factor-1 (IRF-1) in controlling retinoic acid inducible gene-I (RIG-I) expression
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DOI：
10.1002/jcp.21128
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发表时间：
2007-11-01
影响因子：
5.6
通讯作者：
Fisher, Paul B.
中科院分区：
文献类型：
--
作者：
Su, Zao-Zhong;Sarkar, Devanand;Fisher, Paul B.
维甲酸诱导基因-I(RIG-1)通过感知dsRNA和诱导型干扰素(IFN)的产生，发挥着抵御病毒感染的第一道防线的作用。RIG-I本身的表达受干扰素-α/β和dsRNA的诱导。为了了解RIG-1基因表达调控的分子机制，我们克隆了RIG-1启动子，并分析了其对干扰素-β和dsRNA处理的活性。在基础状态下，正常细胞的RIG-1mRNA水平和启动子活性显著高于肿瘤细胞。在正常细胞和癌细胞中，干扰素-β和dsRNA均可诱导RIG-1的表达。在RIG-1启动子近端有一个单一的IRF-I结合位点，是基础的、干扰素-β和dsRNA介导的RIG-1启动子诱导的关键调节因子。干扰素-β和双链RNA处理增加了IRF-I与RIG-1启动子的结合。IRF-I在正常细胞中的表达也高于在癌细胞中的表达，并且是由干扰素-β诱导的，其诱导动力学与RIG-1相似。这些结果证实，通过调控RIG-1的表达，IRF-I在抗病毒免疫中发挥重要作用。IRF-I是一种肿瘤抑制因子，RIG-1的表达谱以及IRF-I对RIG-1的调控以及RIG-1中Caspase募集结构域的存在表明RIG-1可能也具有肿瘤抑制作用。
Retinoic acid inducible gene-I (RIG-1) functions as the first line of defense against viral infection by sensing dsRNA and inducing type I interferon (IFN) production. The expression of RIG-I itself is induced by IFN-alpha/beta and dsRNA. To comprehend the molecular mechanism of expression regulation, we cloned the RIG-1 promoter and analyzed its activity upon IFN-beta and dsRNA treatment. Under basal condition, RIG-1 mRNA level and promoter activity were significantly higher in normal cells versus their tumor counterparts. In both normal and cancer cells, RIG-1 expression was induced by IFN-beta and dsRNA. A single IRF-I binding site in the proximal promoter functioned as a crucial regulator of basal, IFN-beta- and dsRNA-mediated induction of the RIG-1 promoter. IFN-beta and dsRNA treatment increased IRF-I binding to the RIG-1 promoter. IRF-I expression was also higher in normal cells than in cancer cells and it was induced by IFN-beta with similar kinetics as RIG-1. These results confirm that by controlling RIG-1 expression, IRF-I plays an essential role in anti-viral immunity. IRF-I is a tumor suppressor and the expression profile of RIG-1 together with its regulation by IRF-I and the presence of a caspase-recruitment domain in RIG-1 suggest that RIG-1 might also possess tumor suppressor properties.