title: Dynamic oscillation of translation and stress granule formation mark the cellular response to virus infection.
abstract: Virus infection-induced global protein synthesis suppression is linked to assembly of stress granules (SGs), cytosolic aggregates of stalled translation preinitiation complexes. To study long-term stress responses, we developed an imaging approach for extended observation and analysis of SG dynamics during persistent hepatitis C virus (HCV) infection. In combination with type 1 interferon, HCV infection induces highly dynamic assembly/disassembly of cytoplasmic SGs, concomitant with phases of active and stalled translation, delayed cell division, and prolonged cell survival. Double-stranded RNA (dsRNA), independent of viral replication, is sufficient to trigger these oscillations. Translation initiation factor eIF2α phosphorylation by protein kinase R mediates SG formation and translation arrest. This is antagonized by the upregulation of GADD34, the regulatory subunit of protein phosphatase 1 dephosphorylating eIF2α. Stress response oscillation is a general mechanism to prevent long-lasting translation repression and a conserved host cell reaction to multiple RNA viruses, which HCV may exploit to establish persistence.
authors: Department of Infectious Diseases, Molecular Virology, University of Heidelberg, Germany.
authors: Alessia
authors: A
authors: Ruggieri
authors: Eva
authors: E
authors: Dazert
authors: Philippe
authors: P
authors: Metz
authors: Sarah
authors: S
authors: Hofmann
authors: Jan-Philip
authors: JP
authors: Bergeest
authors: Johanna
authors: J
authors: Mazur
authors: Peter
authors: P
authors: Bankhead
authors: Marie-Sophie
authors: MS
authors: Hiet
authors: Stephanie
authors: S
authors: Kallis
authors: Gualtiero
authors: G
authors: Alvisi
authors: Charles E
authors: CE
authors: Samuel
authors: Volker
authors: V
authors: Lohmann
authors: Lars
authors: L
authors: Kaderali
authors: Karl
authors: K
authors: Rohr
authors: Michael
authors: M
authors: Frese
authors: Georg
authors: G
authors: Stoecklin
authors: Ralf
authors: R
authors: Bartenschlager
mesh_terms: D002455:Cell Division; D002460:Cell Line; D003594:Cytoplasmic Granules / Q000187:drug effects / Q000378:metabolism*; D015852:Eukaryotic Initiation Factor-2 / Q000235:genetics / Q000378:metabolism; D016174:Hepacivirus / Q000472:pathogenicity*; D006526:Hepatitis C / Q000235:genetics / Q000378:metabolism / Q000473:pathology* / Q000821:virology; D054884:Host-Pathogen Interactions; D006801:Humans; D016898:Interferon-alpha / Q000378:metabolism / Q000494:pharmacology; D008099:Liver / Q000166:cytology / Q000821:virology; D014176:Protein Biosynthesis; D054645:Protein Phosphatase 1 / Q000378:metabolism; D012330:RNA, Double-Stranded / Q000378:metabolism; D014779:Virus Replication / Q000235:genetics; D019892:eIF-2 Kinase / Q000378:metabolism
chemical_list: D015852:Eukaryotic Initiation Factor-2; D016898:Interferon-alpha; D012330:RNA, Double-Stranded; D019892:eIF-2 Kinase; C087519:PPP1R15A protein, human; D054645:Protein Phosphatase 1