Mechanistic insights into modulation of type I interferon transcription by tegument proteins of cytomegalovirus and its impact on viral transcription

通过模式识别受体(PRR)检测病毒入侵是诱导快速免疫反应和早期控制感染的关键。PRR感知病毒核酸并激活信号级联，最终导致I型干扰素(IFN)和促炎细胞因子的转录。由于这种有效的抗病毒免疫反应限制了病毒的传播，疱疹病毒反过来又进化出一系列机制，几乎针对PRR信号的每一步，以克服免疫系统对它们的清除。疱疹病毒甚至可以为自己的利益使用PRR信号，这为疱疹病毒和它们的宿主之间的微调相互作用增加了另一层复杂性。与病毒粒子一起进入感染细胞的病毒被蛋白是PRR拮抗剂的主要候选者：它们从一开始就存在，并能迅速对PRR信号起作用。基于我们以前在疱疹病毒PRR拮抗剂方面的工作，我们将破译巨细胞病毒被膜蛋白M35、UL35和UL82如何干扰细胞核内I型干扰素的诱导，以及这如何影响细胞和病毒转录的分子机制(S)。人巨细胞病毒(HCMV)被膜蛋白UL35和UL82在感染早期与早幼粒细胞白血病核体(PML-NBS)共定位。UL82与PML-NB客户端DAXX相互作用，导致ATRX蛋白从PML-NBS脱位，进而降解DAXX。特定的PML亚型已经与IFNB1的转录相关，但它们在HCMV感染或与其他DNA病毒感染过程中的作用尚不清楚。因此，我们将阐明不同的PML亚型以及PML组分ATRX和DAXX对IFNB1转录在HCMV感染中的作用，并将这一重点扩展到腺病毒、多瘤病毒和进一步的疱疹病毒。这个项目将加深我们对CMV逃避先天性免疫反应的多方面的了解，从而为IFNB1转录和感染进展中重要的细胞决定因素提供新的见解。

Detection of viral invasion by pattern recognition receptors (PRR) is key for the induction of a rapid immune response and early control of infection. PRR sense viral nucleic acids and activate signaling cascades culminating in the transcription of type I interferons (IFN) and proinflammatory cytokines. Since this potent antiviral immune response restricts viral propagation, herpesviruses have in turn evolved a range of mechanisms targeting virtually every step of PRR signaling to overcome their clearance by the immune system. Herpesviruses can even use PRR signaling for their own benefit, which adds another layer of complexity to the fine-tuned interplay between herpesviruses and their host. Viral tegument proteins that are introduced into the infected cell with the incoming virions are prime candidates for PRR antagonists: they are present from the beginning and can act promptly on PRR signaling. Based on our previous work on herpesviral PRR antagonists, we will decipher the molecular mechanism(s) how the tegument proteins M35, UL35, and UL82 of cytomegalovirus (CMV) interfere with type I IFN induction within the nucleus, and how this affects cellular and viral transcription. The tegument proteins of human CMV (HCMV), UL35 and UL82, co-localize in close proximity to promyelocytic leukemia nuclear bodies (PML-NBs) early in infection. UL82 interacts with the PML-NB client DAXX, which leads to dislocation of the ATRX protein from PML-NBs and subsequent degradation of DAXX. Specific PML isoforms were already associated with transcription of IFNB1, but their role during HCMV infection or infection with other DNA viruses is not known. Hence, we will clarify the contribution of different PML isoforms as well as PML components ATRX and DAXX for IFNB1 transcription upon HCMV infection, and will expand this focus to adenoviruses, polyomaviruses, and further herpesviruses. This project will deepen our knowledge about the manifold facets of CMV evasion of the innate immune response, and thereby provide novel insights into cellular determinants important for IFNB1 transcription and progression of infection.