Dengue virus modulates the unfolded protein response in a time-dependent manner

J Biol Chem. 2011 Apr 22;286(16):14226-36. doi: 10.1074/jbc.M111.222703. Epub 2011 Mar 8.

Abstract

Flaviviruses, such as dengue virus (DENV), depend on the host endoplasmic reticulum for translation, replication, and packaging of their genomes. Here we report that DENV-2 infection modulates the unfolded protein response in a time-dependent manner. We show that early DENV-2 infection triggers and then suppresses PERK-mediated eIF2α phosphorylation and that in mid and late DENV-2 infection, the IRE1-XBP1 and ATF6 pathways are activated, respectively. Activation of IRE1-XBP1 correlated with induction of downstream targets GRP78, CHOP, and GADD34. Furthermore, induction of CHOP did not induce apoptotic markers, such as suppression of anti-apoptotic protein Bcl-2, activation of caspase-9 or caspase-3, and cleavage of poly(ADP-ribose) polymerase. Finally, we show that DENV-2 replication is affected in PERK(-/-) and IRE1(-/-) mouse embryo fibroblasts when compared with wild-type mouse embryo fibroblasts. These results demonstrate that time-dependent activation of the unfolded protein response by DENV-2 can override inhibition of translation, prevent apoptosis, and prolong the viral life cycle.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Apoptosis
  • Caspase 3 / metabolism
  • Caspase 9 / metabolism
  • Dengue Virus / metabolism*
  • Endoplasmic Reticulum / enzymology
  • Eukaryotic Initiation Factor-2 / metabolism
  • Heat-Shock Proteins / metabolism
  • Humans
  • Mice
  • Protein Phosphatase 1 / metabolism
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Time Factors
  • Transcription Factor CHOP / metabolism
  • Unfolded Protein Response*
  • eIF-2 Kinase / metabolism

Substances

  • DDIT3 protein, human
  • Ddit3 protein, mouse
  • Eukaryotic Initiation Factor-2
  • Heat-Shock Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • Transcription Factor CHOP
  • PERK kinase
  • eIF-2 Kinase
  • PPP1R15A protein, human
  • Protein Phosphatase 1
  • Caspase 3
  • Caspase 9
  • molecular chaperone GRP78