Abstract
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
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Vesicular Transport / deficiency*
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Adaptor Proteins, Vesicular Transport / genetics
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Animals
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Cells, Cultured
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Embryo, Mammalian / cytology
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Endoplasmic Reticulum Stress / drug effects
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Eukaryotic Initiation Factor-2B / genetics
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Eukaryotic Initiation Factor-2B / metabolism*
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Fibroblasts / cytology
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Fibroblasts / drug effects
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Fibroblasts / metabolism
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Immunoblotting
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Lipopolysaccharides / pharmacology
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Macrophages / cytology
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Macrophages / drug effects
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Macrophages / metabolism
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Mutation
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Phosphorylation / drug effects
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Protein Biosynthesis / drug effects
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Protein Phosphatase 2 / metabolism
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RNA Interference
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Serine / metabolism
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Signal Transduction / drug effects
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Toll-Like Receptor 4 / genetics
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Toll-Like Receptor 4 / metabolism*
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Transcription Factor CHOP / genetics
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Transcription Factor CHOP / metabolism*
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Tunicamycin / pharmacology
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Unfolded Protein Response / drug effects
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src-Family Kinases / metabolism
Substances
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Adaptor Proteins, Vesicular Transport
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Eukaryotic Initiation Factor-2B
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Lipopolysaccharides
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TICAM-1 protein, mouse
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Toll-Like Receptor 4
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Tunicamycin
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Transcription Factor CHOP
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Serine
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src-Family Kinases
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Protein Phosphatase 2