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

TitleToll-like receptor activation suppresses ER stress factor CHOP and translation inhibition through activation of eIF2B
Authors
Issue Date2012
Citation
Nature Cell Biology, 2012, v. 14 n. 2, p. 192-200 How to Cite?
AbstractActivation 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 ε-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. © 2012 Macmillan Publishers Limited. All rights reserved.
Persistent Identifierhttp://hdl.handle.net/10722/194342
ISSN
2015 Impact Factor: 18.699
2015 SCImago Journal Rankings: 14.131
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorWoo, CW-
dc.contributor.authorKutzler, L-
dc.contributor.authorKimball, SR-
dc.contributor.authorTabas, I-
dc.date.accessioned2014-01-30T03:32:28Z-
dc.date.available2014-01-30T03:32:28Z-
dc.date.issued2012-
dc.identifier.citationNature Cell Biology, 2012, v. 14 n. 2, p. 192-200-
dc.identifier.issn1465-7392-
dc.identifier.urihttp://hdl.handle.net/10722/194342-
dc.description.abstractActivation 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 ε-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. © 2012 Macmillan Publishers Limited. All rights reserved.-
dc.languageeng-
dc.relation.ispartofNature Cell Biology-
dc.titleToll-like receptor activation suppresses ER stress factor CHOP and translation inhibition through activation of eIF2B-
dc.typeArticle-
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1038/ncb2408-
dc.identifier.pmid22231169-
dc.identifier.scopuseid_2-s2.0-84856487878-
dc.identifier.volume14-
dc.identifier.issue2-
dc.identifier.spage192-
dc.identifier.epage200-
dc.identifier.isiWOS:000300332500014-

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