Molecular mechanisms of stress-induced reactivation in mumps virus condensates

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 disor-dered 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 upre-gulation of viral replication.

Automated summary

Researchers have discovered that cellular stress can disrupt the equilibrium of persistent infection and induce replication of the mumps virus. They found that persistent viral replication factories are dynamic condensates and identified the viral phosphoprotein as a key driver in their assembly. Under stress, phosphorylation of the phosphoprotein at its interaction interface with the viral polymerase increases, leading to the formation of a stable replication complex. By obtaining atomic models for the authentic mumps virus nucleocapsid, the researchers elucidated a concomitant conformational change that exposes the viral genome to its replication machinery. These events represent a stress-mediated switch within viral condensates that support increased viral replication.