Dynamic Oscillation of Translation and Stress Granule Formation Mark the Cellular Response to Virus Infection

Cell Host Microbe. 2012 Jul 19;12(1):71-85. doi: 10.1016/j.chom.2012.05.013.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Division
  • Cell Line
  • Cytoplasmic Granules / drug effects
  • Cytoplasmic Granules / metabolism*
  • Eukaryotic Initiation Factor-2 / genetics
  • Eukaryotic Initiation Factor-2 / metabolism
  • Hepacivirus / pathogenicity*
  • Hepatitis C / genetics
  • Hepatitis C / metabolism
  • Hepatitis C / pathology*
  • Hepatitis C / virology
  • Host-Pathogen Interactions*
  • Humans
  • Interferon-alpha / metabolism
  • Interferon-alpha / pharmacology
  • Liver / cytology
  • Liver / virology
  • Protein Biosynthesis*
  • Protein Phosphatase 1 / metabolism
  • RNA, Double-Stranded / metabolism
  • Virus Replication / genetics
  • eIF-2 Kinase / metabolism

Substances

  • Eukaryotic Initiation Factor-2
  • Interferon-alpha
  • RNA, Double-Stranded
  • eIF-2 Kinase
  • PPP1R15A protein, human
  • Protein Phosphatase 1