title: Mammalian orthoreovirus escape from host translational shutoff correlates with stress granule disruption and is independent of eIF2alpha phosphorylation and PKR.
abstract: In response to mammalian orthoreovirus (MRV) infection, cells initiate a stress response that includes eIF2α phosphorylation and protein synthesis inhibition. We have previously shown that early in infection, MRV activation of eIF2α phosphorylation results in the formation of cellular stress granules (SGs). In this work, we show that as infection proceeds, MRV disrupts SGs despite sustained levels of phosphorylated eIF2α and, further, interferes with the induction of SGs by other stress inducers. MRV interference with SG formation occurs downstream of eIF2α phosphorylation, suggesting the virus uncouples the cellular stress signaling machinery from SG formation. We additionally examined mRNA translation in the presence of SGs induced by eIF2α phosphorylation-dependent and -independent mechanisms. We found that irrespective of eIF2α phosphorylation status, the presence of SGs in cells correlated with inhibition of viral and cellular translation. In contrast, MRV disruption of SGs correlated with the release of viral mRNAs from translational inhibition, even in the presence of phosphorylated eIF2α. Viral mRNAs were also translated in the presence of phosphorylated eIF2α in PKR(-/-) cells. These results suggest that MRV escape from host cell translational shutoff correlates with virus-induced SG disruption and occurs in the presence of phosphorylated eIF2α in a PKR-independent manner.
authors.affiliation: Department of Veterinary Microbiology and Preventive Medicine, College of Veterinary Medicine, Iowa State University, 1802 University Boulevard, VMRI Building 3, Ames, IA 50011, USA.
authors.forename: Qingsong
authors.initials: Q
authors.lastname: Qin
authors.forename: Kate
authors.initials: K
authors.lastname: Carroll
authors.forename: Craig
authors.initials: C
authors.lastname: Hastings
authors.forename: Cathy L
authors.initials: CL
authors.lastname: Miller
mesh_terms: D002460:Cell Line; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism*; D054884:Host-Pathogen Interactions; D006801:Humans; D030102:Orthoreovirus, Mammalian / Q000502:physiology*; D010766:Phosphorylation; D014176:Protein Biosynthesis; D012333:RNA, Messenger / Q000378:metabolism; D012367:RNA, Viral / Q000378:metabolism; D014764:Viral Proteins / Q000096:biosynthesis*; D014779:Virus Replication; D019892:eIF-2 Kinase / Q000378:metabolism*
chemical_list: D015852:Eukaryotic Initiation Factor-2; D012333:RNA, Messenger; D012367:RNA, Viral; D014764:Viral Proteins; D019892:eIF-2 Kinase