Olanubi Oladunni, Frost Jasmine Rae, Radko Sandi, Pelka Peter
Department of Microbiology, University of Manitoba, Winnipeg, MB, Canada.
Department of Microbiology, University of Manitoba, Winnipeg, MB, Canada
J Virol. 2017 Mar 29;91(8). doi: 10.1128/JVI.02484-16. Print 2017 Apr 15.
Suppression of interferon signaling is of paramount importance to a virus. Interferon signaling significantly reduces or halts the ability of a virus to replicate; therefore, viruses have evolved sophisticated mechanisms that suppress activation of the interferon pathway or responsiveness of the infected cell to interferon. Adenovirus has multiple modes of inhibiting the cellular response to interferon. Here, we report that E1A, previously shown to regulate interferon signaling in multiple ways, inhibits interferon-stimulated gene expression by modulating RuvBL1 function. RuvBL1 was previously shown to affect type I interferon signaling. E1A binds to RuvBL1 and is recruited to RuvBL1-regulated promoters in an interferon-dependent manner, preventing their activation. Depletion of RuvBL1 impairs adenovirus growth but does not appear to significantly affect viral protein expression. Although RuvBL1 has been shown to play a role in cell growth, its depletion had no effect on the ability of the virus to replicate its genome or to drive cells into S phase. E1A was found to bind to RuvBL1 via the C terminus of E1A, and this interaction was important for suppression of interferon-stimulated gene transcriptional activation and recruitment of E1A to interferon-regulated promoters. Here, we report the identification of RuvBL1 as a new target for adenovirus in its quest to suppress the interferon response. For most viruses, suppression of the interferon signaling pathway is crucial to ensure a successful replicative cycle. Human adenovirus has evolved several different mechanisms that prevent activation of interferon or the ability of the cell to respond to interferon. The viral immediate-early gene was previously shown to affect interferon signaling in several different ways. Here, we report a novel mechanism reliant on RuvBL1 that E1A uses to prevent activation of interferon-stimulated gene expression following infection or interferon treatment. This adds to the growing knowledge of how viruses are able to inhibit interferon and identifies a novel target used by adenovirus for modulation of the cellular interferon pathway.
抑制干扰素信号传导对病毒至关重要。干扰素信号传导会显著降低或阻止病毒复制的能力；因此，病毒已经进化出复杂的机制来抑制干扰素途径的激活或受感染细胞对干扰素的反应。腺病毒有多种抑制细胞对干扰素反应的模式。在此，我们报告，先前已显示以多种方式调节干扰素信号传导的E1A，通过调节RuvBL1功能来抑制干扰素刺激的基因表达。先前已表明RuvBL1会影响I型干扰素信号传导。E1A与RuvBL1结合，并以干扰素依赖的方式被招募到RuvBL1调节的启动子上，从而阻止它们的激活。RuvBL1的缺失会损害腺病毒的生长，但似乎不会显著影响病毒蛋白的表达。尽管已表明RuvBL1在细胞生长中起作用，但其缺失对病毒复制基因组或驱动细胞进入S期的能力没有影响。发现E1A通过E1A的C末端与RuvBL1结合，这种相互作用对于抑制干扰素刺激的基因转录激活以及将E1A招募到干扰素调节的启动子至关重要。在此，我们报告鉴定出RuvBL1是腺病毒在抑制干扰素反应过程中的一个新靶点。对于大多数病毒来说，抑制干扰素信号通路对于确保成功的复制周期至关重要。人类腺病毒已经进化出几种不同的机制来阻止干扰素的激活或细胞对干扰素的反应能力。病毒立即早期基因先前已显示以几种不同方式影响干扰素信号传导。在此，我们报告一种依赖RuvBL1的新机制，E1A利用该机制在感染或干扰素处理后阻止干扰素刺激的基因表达的激活。这增加了我们对病毒如何抑制干扰素的认识，并确定了腺病毒用于调节细胞干扰素途径的一个新靶点。
