IFNβ-dependent increases in STAT1, STAT2, and IRF9 mediate resistance to viruses and DNA damage.
IFNβ-dependent increases in STAT1, STAT2, and IRF9 mediate resistance to viruses and DNA damage.
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DOI：
10.1038/emboj.2013.203
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发表时间：
2013-10-16
期刊：
影响因子：
11.4
通讯作者：
Stark, George R.
中科院分区：
文献类型：
--
作者：
Cheon, HyeonJoo;Holvey-Bates, Elise G.;Schoggins, John W.;Forster, Samuel;Hertzog, Paul;Imanaka, Naoko;Rice, Charles M.;Jackson, Mark W.;Junk, Damian J.;Stark, George R.
关键词：
单次高剂量的干扰素-β（IFNβ）激活强大的细胞应答，其中许多抗病毒、促凋亡和抗增殖蛋白高度表达。由于这些蛋白质中的一些是有害的，细胞迅速下调这种初始反应。然而，许多无害的抗病毒蛋白质的表达是持续的，延长了初始抗病毒反应的相当大一部分，并提供了对DNA损伤的抵抗力。虽然转录因子ISGF 3（IRF 9和酪氨酸磷酸化的STAT 1和2）驱动第一个快速反应阶段，但由IFNβ诱导的高水平IRF 9和STAT 1和2（无酪氨酸磷酸化）形成的相关因子未磷酸化ISGF 3（U-ISGF 3）驱动第二个延长反应阶段。U-ISGF 3诱导的抗病毒基因显示出延长的表达，由不同的IFN刺激的应答元件（ISRE）驱动。细胞持续暴露于低水平的IFNβ（通常见于癌症），导致仅U-ISGF 3依赖性蛋白质的表达稳态增加，而其他IFNβ诱导的蛋白质没有持续增加，并导致对DNA损伤的组成性抗性。
A single high dose of interferon-β (IFNβ) activates powerful cellular responses, in which many anti-viral, pro-apoptotic, and anti-proliferative proteins are highly expressed. Since some of these proteins are deleterious, cells downregulate this initial response rapidly. However, the expression of many anti-viral proteins that do no harm is sustained, prolonging a substantial part of the initial anti-viral response for days and also providing resistance to DNA damage. While the transcription factor ISGF3 (IRF9 and tyrosine-phosphorylated STATs 1 and 2) drives the first rapid response phase, the related factor un-phosphorylated ISGF3 (U-ISGF3), formed by IFNβ-induced high levels of IRF9 and STATs 1 and 2 without tyrosine phosphorylation, drives the second prolonged response. The U-ISGF3-induced anti-viral genes that show prolonged expression are driven by distinct IFN stimulated response elements (ISREs). Continuous exposure of cells to a low level of IFNβ, often seen in cancers, leads to steady-state increased expression of only the U-ISGF3-dependent proteins, with no sustained increase in other IFNβ-induced proteins, and to constitutive resistance to DNA damage.
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