G3BP1, G3BP2 and CAPRIN1 are required for translation of interferon stimulated mRNAs and are targeted by a dengue virus non-coding RNA

PLoS Pathog. 2014 Jul 3;10(7):e1004242. doi: 10.1371/journal.ppat.1004242. eCollection 2014 Jul.

Abstract

Viral RNA-host protein interactions are critical for replication of flaviviruses, a genus of positive-strand RNA viruses comprising major vector-borne human pathogens including dengue viruses (DENV). We examined three conserved host RNA-binding proteins (RBPs) G3BP1, G3BP2 and CAPRIN1 in dengue virus (DENV-2) infection and found them to be novel regulators of the interferon (IFN) response against DENV-2. The three RBPs were required for the accumulation of the protein products of several interferon stimulated genes (ISGs), and for efficient translation of PKR and IFITM2 mRNAs. This identifies G3BP1, G3BP2 and CAPRIN1 as novel regulators of the antiviral state. Their antiviral activity was antagonized by the abundant DENV-2 non-coding subgenomic flaviviral RNA (sfRNA), which bound to G3BP1, G3BP2 and CAPRIN1, inhibited their activity and lead to profound inhibition of ISG mRNA translation. This work describes a new and unexpected level of regulation for interferon stimulated gene expression and presents the first mechanism of action for an sfRNA as a molecular sponge of anti-viral effectors in human cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Base Sequence
  • Carrier Proteins / genetics
  • Carrier Proteins / immunology*
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / immunology*
  • Cricetinae
  • DNA Helicases
  • Dengue Virus / immunology*
  • Humans
  • Membrane Proteins / genetics
  • Membrane Proteins / immunology
  • Molecular Sequence Data
  • Poly-ADP-Ribose Binding Proteins
  • Protein Biosynthesis / immunology*
  • RNA Helicases
  • RNA Recognition Motif Proteins
  • RNA, Messenger / genetics
  • RNA, Messenger / immunology*
  • RNA, Untranslated / genetics
  • RNA, Untranslated / immunology*
  • RNA, Viral / genetics
  • RNA, Viral / immunology*
  • eIF-2 Kinase / genetics
  • eIF-2 Kinase / immunology

Substances

  • CAPRIN1 protein, human
  • Carrier Proteins
  • Cell Cycle Proteins
  • G3BP2 protein, human
  • IFITM2 protein, human
  • Membrane Proteins
  • Poly-ADP-Ribose Binding Proteins
  • RNA Recognition Motif Proteins
  • RNA, Messenger
  • RNA, Untranslated
  • RNA, Viral
  • eIF-2 Kinase
  • DNA Helicases
  • G3BP1 protein, human
  • RNA Helicases

Associated data

  • GENBANK/AF038463
  • GENBANK/EU081177
  • GENBANK/EU081222
  • GENBANK/GQ398283
  • GENBANK/GQ398308
  • GENBANK/X03700
  • RefSeq/NM_002046
  • RefSeq/NM_002759
  • RefSeq/NM_005101
  • RefSeq/NM_005347
  • RefSeq/NM_005754
  • RefSeq/NM_005898
  • RefSeq/NM_006435
  • RefSeq/NM_007315
  • RefSeq/NM_01144925
  • RefSeq/NM_014314
  • RefSeq/NM_201999
  • RefSeq/NM_203505

Grant support

This work was supported by the Duke-NUS Signature Research Program funded by the Agency for Science, Technology and Research (A*STAR), Singapore, the Ministry of Health, Singapore and a grant from the National Medical Research Council, Singapore (NMRC/1267/2010). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.