Interferon regulatory factor 7 is activated by a viral oncoprotein through RIP-dependent ubiquitination
Interferon regulatory factor 7 is activated by a viral oncoprotein through RIP-dependent ubiquitination
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DOI：
10.1128/mcb.02256-06
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发表时间：
2007-04-01
影响因子：
5.3
通讯作者：
Pagano, Joseph S.
中科院分区：
文献类型：
--
作者：
Huye, Leslie E.;Ning, Shunbin;Pagano, Joseph S.
作为I型干扰素（IFN）（IFN-α/β）应答的关键介质，IFN调节因子7（IRF 7）对于宿主免疫防御是必需的。IRF 7的激活通常需要病毒诱导的C-末端磷酸化，这导致其核积累和靶基因的激活。在这里，我们使用EB病毒（EBV）癌蛋白LMP 1，它激活IRF 7，以确定参与IRF 7激活的因素。我们首次证明RIP激活IRF 7，RIP和IRF 7在EBV阳性伯基特淋巴瘤细胞的生理条件下相互作用。我们提供的证据表明，RIP和IRF 7在这些细胞中是泛素化的，并且IRF 7优先与泛素化的RIP相互作用。RIP是LMP 1完全激活IRF 7所必需的，LMP 1刺激RIP的泛素化及其与IRF 7的相互作用。此外，LMP 1刺激RIP依赖性K63连接的IRF 7泛素化，其调节蛋白质功能而不是蛋白酶体降解蛋白质。我们认为RIP可能是IRF 7的一个通用激活因子，响应并传递来自各种刺激的信号，并且泛素化可能是增强IRF 7活性的一个通用机制。
As a key mediator of type I interferon (IFN) (IFN-alpha/beta) responses, IFN regulatory factor 7 (IRF7) is essential to host immune defenses. Activation of IRF7 generally requires virus-induced C-terminal phosphorylation, which leads to its nuclear accumulation and activation of target genes. Here we use the Epstein-Barr virus (EBV) oncoprotein LMP1, which activates IRF7, to identify factors involved in IRF7 activation. We demonstrate for the first time that RIP activates IRF7 and that RIP and IRF7 interact under physiological conditions in EBV-positive Burkitt's lymphoma cells. We provide evidence that both RIP and IRF7 are ubiquitinated in these cells and that IRF7 preferentially interacts with ubiquitinated RIP. RIP is required for full activation of IRF7 by LMP1, with LMP1 stimulating the ubiquitination of RIP and its interaction with IRF7. Moreover, LMP1 stimulates RIP-dependent K63-linked ubiquitination of IRF7, which regulates protein function rather than proteasomal degradation of proteins. We suggest that RIP may serve as a general activator of IRF7, responding to and transmitting the signals from various stimuli, and that ubiquitination may be a general mechanism for enhancing the activity of IRF7.