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

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 eIF2? (p-eIF2?), a TLR-TRIF-dependent pathway assures that the cells avoid CHOP induction, apoptosis and translational suppression of critical proteins. As p-eIF2? 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-eIF2?. We now show that TLR-TRIF signalling activates eIF2B GEF through PP2A-mediated serine dephosphorylation of the eIF2B ?-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.

SUBMITTER: Woo CW

PROVIDER: S-EPMC3271190 | biostudies-literature | 2012 Jan

REPOSITORIES: biostudies-literature

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

Woo Connie W CW Kutzler Lydia L Kimball Scot R SR Tabas Ira I

Nature cell biology 20120108 2

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 hypothesi ...[more]

PMID: 22231169

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Dataset Information

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

Publications

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

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