【研究前沿】河南农业大学褚贝贝团队发现BRD4在抗病毒天然免疫方面发挥的重要功能|163

3月25日，河南农业大学牧医工程学院的褚贝贝，杨国宇等人在PLOS PATHOGENS上发表关于BRD4在抗病毒天然免疫方面最新研究成果。 BRD4 蛋白是BET家族中最重要的功能蛋白，含两个溴结构域及一个超末端结构域。BRD4通过其溴结构域结合乙酰化的组蛋白，从而招募不同的转录因子来调节靶基因的表达，关于BRD4与抗病毒天然免疫属于首次报道。

染色质表观遗传修饰在维持染色质稳态和基因表达方面发挥重要作用。为了探讨染色质表观遗传修饰在病毒复制过程中发挥的重要功能，作者利用重组伪狂犬病毒PRV-GFP报告基因系统，筛选了10种染色质表观遗传修饰抑制剂。发现三种BRD4抑制剂JQ-1, OTX-015和I-BET 151都能极显著抑制PRV-GFP复制。

进一步研究表明，无论是BRD4抑制剂，还是RNA干扰BRD4表达，均能广谱抑制PRV，herpes simplex virus 1 (HSV1)等病毒。抑制BRD4并不影响上述病毒ORF7基因转录，而是抑制了病毒与宿主细胞的吸附阶段，从而抑制病毒复制。作者进一步研究发现，抑制BRD4还能够激活干扰素调节因子3（Interferon-regulated factor 3, IRF3）依赖的抗病毒天然免疫。

Figure1：BRD4 inhibitors attenuate viral attachment.

这项工作的亮点是首次揭示了抑制BRD4通过DNA损伤依赖的cGAS/STING/TBK1/IRF3通路激活抗病毒天然免疫。此外，该研究还为BRD4抑制剂在基于STING的肿瘤免疫治疗方面提供了参考价值。

Figure2: A schematic model showing BRD4 inhibition in antiviral innate immunity.

附文献信息：

Title:BRD4 inhibition exerts anti-viral activity through DNA damage-dependent innate immune responses.

DOI:10.1371/journal.ppat.1008429

Abstract:Chromatin dynamics regulated by epigenetic modification is crucial in genome stability and gene expression. Various epigenetic mechanisms have been identified in the pathogenesis of human diseases. Here, we examined the effects of ten epigenetic agents on pseudorabies virus (PRV) infection by using GFP-reporter assays. Inhibitors of bromodomain protein 4 (BRD4), which receives much more attention in cancer than viral infection, was found to exhibit substantial anti-viral activity against PRV as well as a range of DNA and RNA viruses. We further demonstrated that BRD4 inhibition boosted a robust innate immune response. BRD4 inhibition also de-compacted chromatin structure and induced the DNA damage response, thereby triggering the activation of cGAS-mediated innate immunity and increasing host resistance to viral infection both in vitro and in vivo. Mechanistically, the inhibitory effect of BRD4 inhibition on viral infection was mainly attributed to the attenuation of viral attachment. Our findings reveal a unique mechanism through which BRD4 inhibition restrains viral infection and points to its potent therapeutic value for viral infectious diseases.