Norovirus infection results in eIF2α independent host translation shut-off and remodels the G3BP1 interactome evading stress granule formation

Viral infections impose major stress on the host cell. In response, stress pathways can rapidly deploy defence mechanisms by shutting off the protein synthesis machinery and triggering the accumulation of mRNAs into stress granules to limit the use of energy and nutrients. Because this threatens viral gene expression, viruses need to evade these pathways to propagate. Human norovirus is responsible for gastroenteritis outbreaks worldwide. Here we examined how norovirus interacts with the eIF2α signaling axis controlling translation and stress granules. While norovirus infection represses host cell translation, our mechanistic analyses revealed that eIF2α signaling mediated by the stress kinase GCN2 is uncoupled from translational stalling. Moreover, infection results in a redistribution of the RNA-binding protein G3BP1 to replication complexes and remodelling of its interacting partners, allowing the avoidance from canonical stress granules. These results define novel strategies by which norovirus undergo efficient replication whilst avoiding the host stress response and manipulating the G3BP1 interactome.
Author summary Viruses have evolved elegant strategies to evade host responses that restrict viral propagation by targeting the protein synthesis machinery and stress granules, which are membrane-less RNA granules with antiviral properties. Previous studies have unravelled how viruses, including norovirus the leading cause of gastroenteritis, regulate the activity of translation factors to affect the antiviral response. Furthermore, stress granules evasion strategies have been linked to targeting the scaffolding protein G3BP1. Here we dissect how murine norovirus, the main model for norovirus, evades the cellular stress responses. Our work challenges the dogma that translational control during infection is mainly mediated by eIF2α and demonstrate that norovirus evades this stress pathway. We further show that norovirus evades the stress granule response in a novel way by isolating and characterising the G3BP1 interactome for the first time in the context of a viral infection. We conclude that norovirus infection results in a redistribution of G3BP1 and its cellular partners to replication complexes, thereby preventing the assembly of stress granules. Overall, we define a novel evasion strategy by which norovirus escapes stress granule formation by rewiring the G3BP1 interactome.