Molecular mechanisms of stress-induced reactivation in mumps virus condensates
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
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.