德国欧洲分子生物学实验室Julia Mahamid小组揭示腮腺炎病毒凝聚物中应激诱导再激活的分子机制。这一研究成果发表在2023年4月27日出版的国际学术期刊《细胞》上。

研究人员揭示了细胞压力是如何破坏持续感染中可转移的宿主-病毒平衡，并在腮腺炎病毒的培养模型中诱导病毒复制的。利用细胞生物学、全细胞蛋白质组学和低温电子断层扫描的组合，研究人员表明持久性病毒复制工厂是动态的凝聚物，并确定大部分无序的病毒磷蛋白是其组装的驱动因素。在压力下，磷蛋白与病毒聚合酶相互作用界面上的磷酸化增加与稳定的复制复合物的形成相吻合。

通过获得真实腮腺炎病毒核衣壳的原子模型，研究人员阐明了同时发生的构象变化，使病毒基因组暴露在其复制机器中。这些事件构成了病毒凝聚物内由压力介导的开关，并提供了一个支持病毒复制上调的环境。

据悉，负链RNA病毒可以在人类宿主体内以大型细胞内包涵体的形式建立长期的持续性感染，并引起慢性疾病。

附：英文原文

Title: Molecular mechanisms of stress-induced reactivation in mumps virus condensates

Author: Xiaojie Zhang, Sindhuja Sridharan, Ievgeniia Zagoriy, Christina Eugster Oegema, Cyan Ching, Tim Pflaesterer, Herman K.H. Fung, Isabelle Becher, Ina Poser, Christoph W. Müller, Anthony A. Hyman, Mikhail M. Savitski, Julia Mahamid

Issue&Volume: 2023/04/27

Abstract: Negative-stranded RNA viruses can establish long-term persistent infection in the form of large intracellular inclusions in the human host and cause chronic diseases. Here, we uncover how cellular stress disrupts the metastable host-virus equilibrium in persistent infection and induces viral replication in a culture model of mumps virus. Using a combination of cell biology, whole-cell proteomics, and cryo-electron tomography, we show that persistent viral replication factories are dynamic condensates and identify the largely disordered viral phosphoprotein as a driver of their assembly. Upon stress, increased phosphorylation of the phosphoprotein at its interaction interface with the viral polymerase coincides with the formation of a stable replication complex. By obtaining atomic models for the authentic mumps virus nucleocapsid, we elucidate a concomitant conformational change that exposes the viral genome to its replication machinery. These events constitute a stress-mediated switch within viral condensates that provide an environment to support upregulation of viral replication.

DOI: 10.1016/j.cell.2023.03.015

Source: https://www.cell.com/cell/fulltext/S0092-8674(23)00276-3