Department of Molecular, Cellular and Developmental Biology, University of California, Santa Barbara, California, USA.
Division of Veterinary Medicine, Paul-Ehrlich-Institute, Langen, Germany.
J Virol. 2024 Sep 17;98(9):e0102024. doi: 10.1128/jvi.01020-24. Epub 2024 Aug 28.
Some negative-sense RNA viruses, including measles virus (MeV), share the characteristic that during their infection cycle, cytoplasmic inclusion bodies (IBs) are formed where components of the viral replication machinery are concentrated. As a foci of viral replication, how IBs act to enhance the efficiency of infection by affecting virus-host interactions remains an important topic of investigation. We previously established that upon MeV infection, the epigenetic host protein, WD repeat-containing protein 5 (WDR5), translocates to cytoplasmic viral IBs and facilitates MeV replication. We now show that WDR5 is recruited to IBs by forming a complex with IB-associated MeV phosphoprotein via a conserved binding motif located on the surface of WDR5. Furthermore, we provide evidence that WDR5 promotes viral replication by suppressing a major innate immune response pathway, the double-stranded RNA-mediated activation of protein kinase R and integrated stress response.
MeV is a pathogen that remains a global concern, with an estimated 9 million measles cases and 128,000 measles deaths in 2022 according to the World Health Organization. A large population of the world still has inadequate access to the effective vaccine against the exceptionally transmissible MeV. Measles disease is characterized by a high morbidity in children and in immunocompromised individuals. An important area of research for negative-sense RNA viruses, including MeV, is the characterization of the complex interactome between virus and host occurring at cytoplasmic IBs where viral replication occurs. Despite the progress made in understanding IB structures, little is known regarding the virus-host interactions within IBs and the role of these interactions in promoting viral replication and antagonizing host innate immunity. Herein we provide evidence suggesting a model by which MeV IBs utilize the host protein WDR5 to suppress the protein kinase R-integrated stress response pathway.
包括麻疹病毒（Measles virus，MeV）在内的一些负义 RNA 病毒具有一个共同特征，即在其感染周期中，细胞质包含体（inclusion bodies，IBs）会形成，病毒复制机制的成分在此处聚集。作为病毒复制的焦点，IBs 如何通过影响病毒-宿主相互作用来提高感染效率仍然是一个重要的研究课题。我们之前的研究表明，在 MeV 感染过程中，表观遗传宿主蛋白 WD 重复蛋白 5（WD repeat-containing protein 5，WDR5）易位到细胞质病毒 IBs 中，促进 MeV 复制。我们现在表明，WDR5 通过与 IB 相关的 MeV 磷酸蛋白形成复合物，利用 WDR5 表面的保守结合基序，被招募到 IBs 中。此外，我们提供的证据表明，WDR5 通过抑制一种主要的先天免疫反应途径，即双链 RNA 介导的蛋白激酶 R 激活和整合应激反应，促进病毒复制。
据世界卫生组织估计，2022 年全球有 900 万麻疹病例和 12.8 万人死于麻疹，麻疹仍然是一个全球性的关注问题。世界上仍有大量人群无法获得针对这种传染性极强的 MeV 的有效疫苗。麻疹疾病的特征是儿童和免疫功能低下者的发病率高。负义 RNA 病毒，包括 MeV，的一个重要研究领域是在细胞质 IBs 中发生的病毒与宿主之间复杂的相互作用组的特征，病毒复制就发生在那里。尽管在理解 IB 结构方面取得了进展，但对于 IBs 内的病毒-宿主相互作用以及这些相互作用在促进病毒复制和拮抗宿主先天免疫方面的作用知之甚少。在此，我们提供的证据表明了一种模型，即 MeV IBs 利用宿主蛋白 WDR5 抑制蛋白激酶 R-整合应激反应途径。
