Inhibition of DNA-Sensing Pathway by Marek's Disease Virus VP23 Protein through Suppression of Interferon Regulatory Factor 7 Activation
Inhibition of DNA-Sensing Pathway by Marek's Disease Virus VP23 Protein through Suppression of Interferon Regulatory Factor 7 Activation
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马立克氏病病毒 VP23 蛋白通过抑制干扰素调节因子 7 激活来抑制 DNA 传感途径。
DOI：
10.1128/jvi.01934-18
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发表时间：
2019-02-01
影响因子：
5.4
通讯作者：
Wang, Xiaomei
中科院分区：
文献类型：
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作者：
Gao, Li;Li, Kai;Wang, Xiaomei
I型干扰素（IFN）应答是宿主对病毒感染的先天免疫防御的第一线;然而，病毒已经开发了多种策略来拮抗宿主IFN应答以进行有效的感染和复制。在这里，我们报告马立克氏病病毒（MDV），一种致癌疱疹病毒，编码VP 23蛋白作为一种新的免疫调节剂，以阻止β干扰素（IFN-β）激活诱导的环GMP-AMP合成酶（cGAS）和干扰素基因（STING）在鸡成纤维细胞和巨噬细胞。VP 23过表达显著降低病毒DNA触发的IFN-β产生并促进病毒复制，而MDV感染期间VP 23的敲低增强IFN-β应答并抑制病毒复制。VP 23选择性抑制IFN调节因子7（IRF 7）而非核因子κ B（NF-κ B）活化。此外，我们发现VP 23与IRF 7相互作用并阻断其与TANK结合激酶1（TBK 1）的结合，从而抑制IRF 7磷酸化和核转位，导致IFN-β产生减少。这些研究结果扩大了我们的知识，在鸡的DNA传感器，并揭示了一种机制，通过该机制，MDV拮抗宿主IFN response.IMPORTANCE尽管广泛接种疫苗，马立克氏病（MD）继续为全球家禽业带来重大挑战。MDV在鸡中引起免疫抑制和致命的淋巴瘤，表明这种病毒已经发展出成功的免疫逃避策略。然而，关于MDV感染期间宿主先天免疫应答的启动和调节知之甚少。该研究表明，cGAS-STING DNA传感途径对于诱导鸡成纤维细胞和巨噬细胞中针对MDV感染的IFN-β应答至关重要。发现MDV蛋白VP 23有效抑制cGAS-STING途径。VP 23选择性抑制IRF 7而非NF-κ B活化。VP 23与IRF 7相互作用并阻断其与TBK 1的结合，从而抑制IRF 7活化并导致DNA传感途径的抑制。这些发现扩展了我们对鸡DNA传感的认识，并揭示了MDV拮抗宿主IFN应答的机制。
The type I interferon (IFN) response is the first line of host innate immune defense against viral infection; however, viruses have developed multiple strategies to antagonize host IFN responses for efficient infection and replication. Here, we report that Marek's disease virus (MDV), an oncogenic herpesvirus, encodes VP23 protein as a novel immune modulator to block the beta interferon (IFN-beta) activation induced by cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING) in chicken fibroblasts and macrophages. VP23 overexpression markedly reduces viral DNA-triggered IFN-beta production and promotes viral replication, while knockdown of VP23 during MDV infection enhances the IFN-beta response and suppresses viral replication. VP23 selectively inhibits IFN regulatory factor 7 (IRF7) but not nuclear factor kappa B (NF-kappa B) activation. Furthermore, we found that VP23 interacts with IRF7 and blocks its binding to TANK-binding kinase 1 (TBK1), thereby inhibiting IRF7 phosphorylation and nuclear translocation, resulting in reduced IFN-beta production. These findings expand our knowledge of DNA sensing in chickens and reveal a mechanism through which MDV antagonizes the host IFN response.IMPORTANCE Despite widespread vaccination, Marek's disease (MD) continues to pose major challenges for the poultry industry worldwide. MDV causes immunosuppression and deadly lymphomas in chickens, suggesting that this virus has developed a successful immune evasion strategy. However, little is known regarding the initiation and modulation of the host innate immune response during MDV infection. This study demonstrates that the cGAS-STING DNA-sensing pathway is critical for the induction of the IFN-beta response against MDV infection in chicken fibroblasts and macrophages. An MDV protein, VP23, was found to efficiently inhibit the cGAS-STING pathway. VP23 selectively inhibits IRF7 but not NF-kappa B activation. VP23 interacts with IRF7 and blocks its binding to TBK1, thereby suppressing IRF7 activation and resulting in inhibition of the DNA-sensing pathway. These findings expand our knowledge of DNA sensing in chickens and reveal a mechanism through which MDV antagonizes the host IFN response.