Marek's Disease Virus RLORF4 Inhibits Type I Interferon Production by Antagonizing NF-κB Activation
Marek's Disease Virus RLORF4 Inhibits Type I Interferon Production by Antagonizing NF-κB Activation
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马立克氏病病毒 RLORF4 通过拮抗 NF-κB 激活来抑制 I 型干扰素产生
DOI：
10.1128/jvi.01037-19
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发表时间：
2019-09-01
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：
Liu, Yongzhen;Gao, Li;Wang, Xiaomei
马立克氏病病毒（MDV），导致鸡T细胞淋巴瘤，是经济上重要的，并有助于知识疱疹病毒相关的致癌性。DNA敏感通路诱导针对DNA病毒感染的先天性免疫应答，而核因子-κ B（NF-κ B）信号传导对于先天性免疫的建立至关重要。在这里，我们报告说，RLORF 4，MDV特异性蛋白直接参与病毒减毒，是一种抑制剂的DNA传感途径。结果显示，异位表达的RLORF 4阻断了由环GMP-AMP合酶（cGAS）和干扰素基因刺激因子（STING）诱导的β干扰素（IEN-beta）启动子激活。RLORF 4选择性抑制NF-κ B的活化，但不抑制IFN-调节因子7的活化。发现RLORF 4结合内源性NF-κ B亚基p65和p50，并且它还结合这些亚基的Rel同源结构域。此外，RLORF 4抑制肿瘤坏死因子α和干扰素刺激DNA介导的p65和p50的核转位。最后，从MDV基因组中删除RLORF 4促进了体外和体内IFN-β和白细胞介素-6（IL-6）的产生。在不存在RLORF 4的情况下，在感染鸡期间观察到宿主细胞免疫显著增加，并且病毒滴度降低。我们的研究结果表明，RLORF 4介导的抑制宿主的抗病毒天然免疫可能发挥重要作用，在马立克氏病病毒（MDV）pathogenicity.IMPORTANCE RLORF 4已被证明是直接参与在体外传代后的MDV的减毒，但是，在病毒感染过程中，这种蛋白质的确切功能没有得到很好的表征。该研究表明，RLORF 4通过与NF-κ B亚基p65和p50的Rel同源结构域结合，中断它们向细胞核的易位，从而抑制IFN-β产生，显著抑制cGAS-STING介导的NF-κ B活化。此外，RLORF 4缺陷在MDV感染鸡期间促进IFN-β和下游IFN刺激基因的诱导。我们的研究结果表明，RLORF 4的贡献MDV毒力可能源于其抑制病毒DNA触发的IFN-β反应。
Marek's disease virus (MDV), which causes T cell lymphomas in chickens, is economically important and has contributed to knowledge of herpesvirus-associated oncogenicity. The DNA-sensing pathway induces innate immune responses against DNA virus infection, and nuclear factor kappa B (NF-kappa B) signaling is critical for the establishment of innate immunity. Here, we report that RLORF4, an MDV-specific protein directly involved in viral attenuation, is an inhibitor of the DNA-sensing pathway. The results showed that ectopically expressed RLORF4 blocked beta interferon (IEN-beta) promoter activation induced by cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING). RLORF4 selectively inhibited the activation of NF-kappa B but not IFN-regulatory factor 7. RLORF4 was found to bind the endogenous NF-kappa B subunits p65 and p50, and it also bound to the Rel homology domains of these subunits. Furthermore, RLORF4 suppressed the nuclear translocation of p65 and p50 mediated by tumor necrosis factor alpha and interferon-stimulatory DNA. Finally, deletion of RLORF4 from the MDV genome promoted IFN-beta and interleukin-6 (IL-6) production in vitro and in vivo. In the absence of RLORF4, the host cellular immunity was significantly increased, and reduced viral titers were observed during infection of chickens. Our results suggest that the RLORF4-mediated suppression of the host antiviral innate immunity might play an important role in MDV pathogenesis.IMPORTANCE Marek's disease virus (MDV) RLORF4 has been shown to be directly involved in the attenuation of MDV upon serial passages in vitro; however, the exact function of this protein during viral infection was not well characterized. This study demonstrated that RLORF4 significantly inhibits cGAS-STING-mediated NF-kappa B activation by binding to the Rel homology domains of the NF-kappa B subunits p65 and p50, interrupting their translocation to the nuclei and thereby inhibiting IFN-beta production. Furthermore, RLORF4 deficiency promoted the induction of IFN-beta and downstream IFN-stimulated genes during MDV infection in chickens. Our results suggest that the contribution of RLORF4 to MDV virulence may stem from its inhibition of viral DNA-triggered IFN-beta responses.