Condensate-mediated reactivation of mumps virus infection under stress

Viruses can establish both acute and persistent chronic infections, and some viruses have developed the ability to switch between the two. However, the molecular mechanisms that trigger a transition from a benign chronic infection into pathogenesis remain unknown. Here we investigated the role of the cellular stress response in provoking a chronic-to-acute transition in viral replication in a model of mumps virus infection. Using a combination of cell biology, whole-cell proteomics and cryo-electron tomography we show that stress induces phosphorylation of the disordered viral Phosphoprotein, which we suggest facilitates partitioning of the viral polymerase into preformed viral condensates, constituting the core components of the viral replication machinery. This occurs concomitantly with a conformational change in the viral nucleocapsids that exposes the viral genome and can further facilitate its replication. These changes in the viral condensate upon exogenous stress, accompanied by down-regulation of the host antiviral response, provide an environment that supports up-regulation of viral replication and virion release. Thus, we elucidate molecular and structural mechanisms of a stress-mediated switch that disrupts the equilibrium between the virome and the host in chronic infection. ### Competing Interest Statement A.A.H. is a founder and scientific advisory board member of Dewpoint Therapeutics and a founder of Caraway Therapeutics. All authors declare no competing interests.