RT Journal Article
SR Electronic
T1 Mouse Norovirus infection arrests host cell translation uncoupled from the stress granule-PKR-eIF2α axis
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 536052
DO 10.1101/536052
A1 Svenja Fritzlar
A1 Turgut E. Aktepe
A1 Yi-Wei Chao
A1 Michael R. McAllaster
A1 Craig B. Wilen
A1 Peter A. White
A1 Jason M. Mackenzie
YR 2019
UL http://biorxiv.org/content/early/2019/01/31/536052.abstract
AB The integrated stress response (ISR) is a cellular response system activated upon different types of stresses, including viral infection, to restore cellular homeostasis. However, many viruses manipulate this response for their own advantage. In this study we investigated the association between murine norovirus (MNV) infection and the ISR and demonstrate that MNV regulates the ISR by activating and recruiting key ISR host factors. We observed that during MNV infection, there is a progressive increase in phosphorylated eukaryotic initiation factor 2 alpha (p-eIF2α) resulting in the suppression of host translation, yet MNV translation still progresses under these conditions. Interestingly, the shutoff of host translation also impacts the translation of key signalling cytokines such as IFNβ, IL-6 and TNFα. Our subsequent analyses revealed that the phosphorylation of eIF2α was mediated via Protein kinase-R (PKR), but further investigation revealed that PKR activation, phosphorylation of eIF2α and translational arrest were uncoupled during infection. We further observed that stress granules (SGs) are not induced during MNV infection, and MNV has the capacity to restrict SG nucleation and formation. We observed that MNV recruited the key SG nucleating protein G3BP1 to its replication sites and intriguingly the silencing of G3BP1 negatively impacts MNV replication. Thus, it appears, MNV utilises G3BP1 to enhance replication, but equally to prevent SG formation, intimating an anti-MNV property of SGs. Overall, thus study highlights MNV manipulation of SGs, PKR and translational control to regulate cytokine translation and to promote viral replication.Importance Viruses hijack host machinery and regulate cellular homeostasis to actively replicate their genome, propagate and cause disease. In retaliation, cells possess various defence mechanisms to detect, destroy and clear infecting viruses as well as signal to neighbouring cells to inform them of the imminent threat. In this study, we demonstrate that the murine norovirus (MNV) infection stalls host protein translation and the production of antiviral and pro-inflammatory cytokines. However, virus replication and protein translation still ensues. We show that MNV further prevents the formation of cytoplasmic RNA granules, called stress granules (SG), by recruiting the key host protein G3BP1 to the MNV replication complex; a recruitment that is crucial to establishing and maintaining virus replication. Thus MNV promotes immune evasion of the virus by altering protein translation. Together, this evasion strategy delays innate immune responses to MNV infection and accelerates disease onset.