Toll-like receptor activation suppresses ER stress factor CHOP and translation inhibition through activation of eIF2B

Nat Cell Biol. 2012 Jan 8;14(2):192-200. doi: 10.1038/ncb2408.


Activation of Toll-like receptors (TLRs) induces the endoplasmic reticulum (ER) unfolded protein response (UPR) to accommodate essential protein translation. However, despite increased levels of phosphorylated eIF2α (p-eIF2α), a TLR-TRIF-dependent pathway assures that the cells avoid CHOP induction, apoptosis and translational suppression of critical proteins. As p-eIF2α decreases the functional interaction of eIF2 with eIF2B, a guanine nucleotide exchange factor (GEF), we explored the hypothesis that TLR-TRIF signalling activates eIF2B GEF activity to counteract the effects of p-eIF2α. We now show that TLR-TRIF signalling activates eIF2B GEF through PP2A-mediated serine dephosphorylation of the eIF2B ɛ-subunit. PP2A itself is activated by decreased Src-family-kinase-induced tyrosine phosphorylation of its catalytic subunit. Each of these processes is required for TLR-TRIF-mediated CHOP suppression in ER-stressed cells in vitro and in vivo. Thus, in the setting of prolonged, physiologic ER stress, a unique TLR-TRIF-dependent translational control pathway enables cells to carry out essential protein synthesis and avoid CHOP-induced apoptosis while still benefiting from the protective arms of the UPR.

Publication types

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

MeSH terms

  • Adaptor Proteins, Vesicular Transport / deficiency*
  • Adaptor Proteins, Vesicular Transport / genetics
  • Animals
  • Cells, Cultured
  • Embryo, Mammalian / cytology
  • Endoplasmic Reticulum Stress / drug effects
  • Eukaryotic Initiation Factor-2B / genetics
  • Eukaryotic Initiation Factor-2B / metabolism*
  • Fibroblasts / cytology
  • Fibroblasts / drug effects
  • Fibroblasts / metabolism
  • Immunoblotting
  • Lipopolysaccharides / pharmacology
  • Macrophages / cytology
  • Macrophages / drug effects
  • Macrophages / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mutation
  • Phosphorylation / drug effects
  • Protein Biosynthesis / drug effects
  • Protein Phosphatase 2 / metabolism
  • RNA Interference
  • Serine / metabolism
  • Signal Transduction / drug effects
  • Toll-Like Receptor 4 / genetics
  • Toll-Like Receptor 4 / metabolism*
  • Transcription Factor CHOP / genetics
  • Transcription Factor CHOP / metabolism*
  • Tunicamycin / pharmacology
  • Unfolded Protein Response / drug effects
  • src-Family Kinases / metabolism


  • Adaptor Proteins, Vesicular Transport
  • Eukaryotic Initiation Factor-2B
  • Lipopolysaccharides
  • TICAM-1 protein, mouse
  • Toll-Like Receptor 4
  • Tunicamycin
  • Transcription Factor CHOP
  • Serine
  • src-Family Kinases
  • Protein Phosphatase 2