Human cytomegalovirus UL23 inhibits transcription of interferon-γ stimulated genes and blocks antiviral interferon-γ responses by interacting with human N-myc interactor protein.
Human cytomegalovirus UL23 inhibits transcription of interferon-γ stimulated genes and blocks antiviral interferon-γ responses by interacting with human N-myc interactor protein.
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人巨细胞病毒 UL23 通过与人 N-myc 相互作用蛋白相互作用，抑制干扰素 γ 刺激基因的转录并阻断抗病毒干扰素 γ 反应
DOI：
10.1371/journal.ppat.1006867
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发表时间：
2018-01
期刊：
影响因子：
6.7
通讯作者：
Liu F
中科院分区：
文献类型：
--
作者：
Feng L;Sheng J;Vu GP;Liu Y;Foo C;Wu S;Trang P;Paliza-Carre M;Ran Y;Yang X;Sun X;Deng Z;Zhou T;Lu S;Li H;Liu F
干扰素-γ (IFN-γ)是宿主对抗包括人类疱疹病毒在内的许多人类病毒感染的最重要的先天免疫反应之一。人类N-myc相互作用因子（Nmi）蛋白，已被证明与包括STAT1在内的信号换能器和转录激活因子（STAT）蛋白相互作用，对于激活IFN-γ诱导的许多与IFN-γ免疫应答有关的STAT1依赖性基因的转录非常重要。然而，目前还没有报道疱疹病毒编码的蛋白与Nmi相互作用并抑制Nmi介导的IFN-γ免疫反应的激活，从而实现对IFN-γ反应的免疫逃避。在这项研究中，我们提供了强有力的证据，证明人类巨细胞病毒（HCMV）的UL23蛋白与Nmi特异性相互作用。这种相互作用是通过酵母双杂交筛选和人类细胞的共免疫沉淀来确定的。我们观察到，当Nmi与UL23结合时，与STAT1不相关，这表明UL23结合Nmi破坏了Nmi与STAT1的相互作用。在过表达UL23的细胞中，我们观察到(a)细胞核中Nmi和STAT1的水平显著降低，这些蛋白在这些位点诱导IFN-γ刺激基因的转录，(b)诱导IFN-γ刺激基因的转录水平降低。在IFN-γ处理的细胞中，缺乏UL23的HCMV突变体诱导了IFN-γ刺激基因的更高转录，并且在表达功能性UL23的亲本病毒和对照逆转录病毒中表现出更低的滴度。因此，UL23似乎直接与Nmi相互作用，抑制Nmi及其相关蛋白STAT1的核易位，导致IFN-γ诱导的应答减少，病毒对IFN-γ的抗性增加。我们的研究结果进一步强调了UL23-Nmi相互作用在促进病毒免疫逃避IFN-γ反应和增强病毒对IFN抗病毒作用的抗性中的作用。干扰素-γ (IFN-γ)反应对于宿主对抗包括人类疱疹病毒在内的许多人类病毒感染至关重要。在IFN-γ治疗后，许多负责IFN-γ免疫应答的基因的转录主要由信号换能器和转录激活因子（STAT）蛋白（如STAT1蛋白）激活。人类N-myc相互作用因子（Nmi）蛋白已被证明与STAT1等STAT蛋白相互作用，并激活IFN-γ诱导的STAT依赖性转录。然而，目前还没有报道疱疹病毒编码的蛋白与Nmi相互作用并抑制Nmi介导的IFN-γ免疫反应的激活，从而实现对IFN-γ反应的免疫逃避。在这项研究中，我们提供了强有力的证据，证明人类巨细胞病毒（HCMV）的UL23蛋白与Nmi蛋白特异性相互作用。UL23似乎与Nmi直接相互作用，抑制Nmi及其相关蛋白STAT1的核易位，导致IFN-γ应答减少，病毒对IFN-γ的抗性增加。阻断UL23的表达导致IFN-γ刺激基因的转录增加，并显著抑制感染细胞中的病毒生长。这些结果表明，干扰Nmi功能可能是疱疹病毒阻断Nmi介导的IFN-γ反应并增加病毒对IFN-γ抗性的有效机制。这也为通过阻断病毒蛋白表达调节Nmi活性治疗HCMV感染提供了一种潜在的新治疗策略。
Interferon-γ (IFN-γ) represents one of the most important innate immunity responses in a host to combat infections of many human viruses including human herpesviruses. Human N-myc interactor (Nmi) protein, which has been shown to interact with signal transducer and activator of transcription (STAT) proteins including STAT1, is important for the activation of IFN-γ induced STAT1-dependent transcription of many genes responsible for IFN-γ immune responses. However, no proteins encoded by herpesviruses have been reported to interact with Nmi and inhibit Nmi-mediated activation of IFN-γ immune responses to achieve immune evasion from IFN-γ responses. In this study, we show strong evidence that the UL23 protein of human cytomegalovirus (HCMV), a human herpesvirus, specifically interacts with Nmi. This interaction was identified through a yeast two-hybrid screen and co-immunoprecipitation in human cells. We observed that Nmi, when bound to UL23, was not associated with STAT1, suggesting that UL23 binding of Nmi disrupts the interaction of Nmi with STAT1. In cells overexpressing UL23, we observed (a) significantly reduced levels of Nmi and STAT1 in the nuclei, the sites where these proteins act to induce transcription of IFN-γ stimulated genes, and (b) decreased levels of the induction of the transcription of IFN-γ stimulated genes. UL23-deficient HCMV mutants induced higher transcription of IFN-γ stimulated genes and exhibited lower titers than parental and control revertant viruses expressing functional UL23 in IFN-γ treated cells. Thus, UL23 appears to interact directly with Nmi and inhibit nuclear translocation of Nmi and its associated protein STAT1, leading to a decrease of IFN-γ induced responses and an increase of viral resistance to IFN-γ. Our results further highlight the roles of UL23-Nmi interactions in facilitating viral immune escape from IFN-γ responses and enhancing viral resistance to IFN antiviral effects. Interferon-γ (IFN-γ) responses are vital for a host to combat infections of many human viruses including human herpesviruses. Upon treatment of IFN-γ, transcription of many genes responsible for IFN-γ immune responses is activated primarily by the signal transducer and activator of transcription (STAT) proteins such as STAT1 protein. Human N-myc interactor (Nmi) protein has been shown to interact with STAT proteins including STAT1 and activate IFN-γ induced STAT-dependent transcription. However, no proteins encoded by herpesviruses have been reported to interact with Nmi and inhibit Nmi-mediated activation of IFN-γ immune responses to achieve immune evasion from IFN-γ responses. In this study, we show strong evidence that the UL23 protein of human cytomegalovirus (HCMV), a human herpesvirus, specifically interacts with Nmi protein. UL23 appears to interact directly with Nmi and inhibit nuclear translocation of Nmi and its associated protein STAT1, leading to a decrease of IFN-γ responses and an increase of viral resistance to IFN-γ. Blocking UL23 expression led to higher transcription of IFN-γ stimulated genes and significant inhibition of viral growth in infected cells. These results suggest that interfering with Nmi function may represent an effective mechanism for a herpesvirus to block Nmi-mediated IFN-γ responses and increase viral resistance to IFN-γ. This also provides a potentially new therapeutic strategy to treat HCMV infection by modulating Nmi activity with blocking the expression of a viral protein.
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影响因子：
4.4
作者：
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通讯作者：
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