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

巨细胞病毒被膜蛋白调节 I 型干扰素转录的机制及其对病毒转录的影响

• 批准号: 470667662
• 负责人: Professorin Dr. Melanie Brinkmann
• 金额: --
• 依托单位: Institut für Genetik
• 依托单位国家: 德国
• 项目类别: Research Units
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/470667662?language=en
• 关键词: Mechanistic; insights; into; modulation; type

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.

通过模式识别受体（PRR）检测病毒入侵是诱导快速免疫应答和早期控制感染的关键。PRR感测病毒核酸并激活信号传导级联，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，疱疹病毒进而进化出一系列机制，靶向PRR信号传导的几乎每一步，以克服免疫系统对它们的清除。疱疹病毒甚至可以利用PRR信号为自己的利益，这增加了另一层复杂性的微调疱疹病毒和他们的主机之间的相互作用。与进入的病毒体一起引入感染细胞的病毒被膜蛋白是PRR拮抗剂的主要候选物：它们从一开始就存在，并且可以迅速作用于PRR信号传导。基于我们以前对疱疹病毒PRR拮抗剂的研究，我们将破译巨细胞病毒（CMV）的被膜蛋白M35，UL 35和UL 82如何干扰细胞核内I型IFN诱导的分子机制，以及这如何影响细胞和病毒的转录。人CMV（HCMV）的被膜蛋白UL 35和UL 82在感染早期共定位于非常接近早幼粒细胞白血病核体（PML-NB）。UL 82与PML-NB客户端DAXX相互作用，导致ATRX蛋白从PML-NB中脱位，随后导致DAXX降解。特异性PML亚型已经与IFNB 1的转录相关，但它们在HCMV感染或其他DNA病毒感染中的作用尚不清楚。因此，我们将阐明不同PML亚型以及PML组分ATRX和DAXX在HCMV感染后对IFNB 1转录的贡献，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。该项目将加深我们对CMV逃避先天免疫反应的多方面的了解，从而为IFNB 1转录和感染进展的重要细胞决定因素提供新的见解。