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A Primary Neuron Culture System for the Study of Herpes Simplex Virus Latency and Reactivation
Published on: April 2, 2012
Molecular mechanisms of stress-induced reactivation in mumps virus condensates
Xiaojie Zhang1, Sindhuja Sridharan2, Ievgeniia Zagoriy1
1Structural and Computational Biology Unit, European Molecular Biology Laboratory (EMBL), Meyerhofstraße 1, 69117 Heidelberg, Germany.
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.
Insights
Cellular stress can reactivate persistent mumps virus infections. This study reveals how stress triggers viral replication by altering viral protein dynamics and genome accessibility within cellular condensates.
Area of Science:
- Virology
- Cell Biology
- Structural Biology
Background:
- Negative-stranded RNA viruses establish persistent infections, causing chronic diseases via intracellular inclusions.
- The equilibrium between host and virus in persistent infections is delicate and can be disrupted.
Purpose of the Study:
- To investigate how cellular stress disrupts host-virus equilibrium and induces viral replication in mumps virus.
- To understand the molecular mechanisms underlying stress-induced viral reactivation.
Main Methods:
- Employed cell biology, whole-cell proteomics, and cryo-electron tomography.
- Developed atomic models of the mumps virus nucleocapsid.
Main Results:
- Persistent viral replication factories are dynamic protein-RNA condensates driven by the viral phosphoprotein.
- Cellular stress increases phosphoprotein phosphorylation, stabilizing the viral replication complex.
- This stabilization induces a conformational change in the nucleocapsid, exposing the viral genome.
Conclusions:
- Cellular stress acts as a switch, modulating viral condensates to upregulate replication of persistent mumps virus.
- The viral phosphoprotein is a key regulator in stress-mediated viral reactivation.
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