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Article: Adaptive suppression of the ATF4-CHOP branch of the unfolded protein response by toll-like receptor signalling

TitleAdaptive suppression of the ATF4-CHOP branch of the unfolded protein response by toll-like receptor signalling
Authors
Issue Date2009
Citation
Nature Cell Biology, 2009, v. 11 n. 12, p. 1473-1480 How to Cite?
AbstractThe endoplasmic reticulum (ER) unfolded protein response (UPR) restores equilibrium to the ER, but prolonged expression of the UPR effector CHOP (GADD153) is cytotoxic. We found that CHOP expression induced by ER stress was suppressed by prior engagement of toll-like receptor (TLR) 3 or 4 through a TRIF-dependent pathway. TLR engagement did not suppress phosphorylation of PERK or eIF-2α, which are upstream of CHOP, but phospho-eIF-2α failed to promote translation of the CHOP activator ATF4. In mice subjected to systemic ER stress, pretreatment with low dose lipopolysaccharide (LPS), a TLR4 ligand, suppressed CHOP expression and apoptosis in splenic macrophages, renal tubule cells and hepatocytes, and prevented renal dysfunction and hepatosteatosis. This protective effect of LPS did not occur in Trif -/- mice or in wild-type mice in which CHOP expression was genetically restored. Thus, TRIF-mediated signals from TLRs selectively attenuate translational activation of ATF4 and its downstream target gene CHOP. We speculate that this mechanism evolved to promote survival of TLR-expressing cells that experience prolonged levels of physiological ER stress in the course of the host response to invading pathogens. © 2009 Macmillan Publishers Limited. All rights reserved.
Persistent Identifierhttp://hdl.handle.net/10722/194259
ISSN
2015 Impact Factor: 18.699
2015 SCImago Journal Rankings: 14.131
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorWoo, CW-
dc.contributor.authorCui, D-
dc.contributor.authorArellano, J-
dc.contributor.authorDorweiler, B-
dc.contributor.authorHarding, H-
dc.contributor.authorFitzgerald, KA-
dc.contributor.authorRon, D-
dc.contributor.authorTabas, I-
dc.date.accessioned2014-01-30T03:32:22Z-
dc.date.available2014-01-30T03:32:22Z-
dc.date.issued2009-
dc.identifier.citationNature Cell Biology, 2009, v. 11 n. 12, p. 1473-1480-
dc.identifier.issn1465-7392-
dc.identifier.urihttp://hdl.handle.net/10722/194259-
dc.description.abstractThe endoplasmic reticulum (ER) unfolded protein response (UPR) restores equilibrium to the ER, but prolonged expression of the UPR effector CHOP (GADD153) is cytotoxic. We found that CHOP expression induced by ER stress was suppressed by prior engagement of toll-like receptor (TLR) 3 or 4 through a TRIF-dependent pathway. TLR engagement did not suppress phosphorylation of PERK or eIF-2α, which are upstream of CHOP, but phospho-eIF-2α failed to promote translation of the CHOP activator ATF4. In mice subjected to systemic ER stress, pretreatment with low dose lipopolysaccharide (LPS), a TLR4 ligand, suppressed CHOP expression and apoptosis in splenic macrophages, renal tubule cells and hepatocytes, and prevented renal dysfunction and hepatosteatosis. This protective effect of LPS did not occur in Trif -/- mice or in wild-type mice in which CHOP expression was genetically restored. Thus, TRIF-mediated signals from TLRs selectively attenuate translational activation of ATF4 and its downstream target gene CHOP. We speculate that this mechanism evolved to promote survival of TLR-expressing cells that experience prolonged levels of physiological ER stress in the course of the host response to invading pathogens. © 2009 Macmillan Publishers Limited. All rights reserved.-
dc.languageeng-
dc.relation.ispartofNature Cell Biology-
dc.titleAdaptive suppression of the ATF4-CHOP branch of the unfolded protein response by toll-like receptor signalling-
dc.typeArticle-
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1038/ncb1996-
dc.identifier.pmid19855386-
dc.identifier.scopuseid_2-s2.0-73349141743-
dc.identifier.volume11-
dc.identifier.issue12-
dc.identifier.spage1473-
dc.identifier.epage1480-
dc.identifier.isiWOS:000272251300015-

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