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

Connie W. Woo, Lydia Kutzler, Scot Kimball, Ira Tabas

Research output: Contribution to journalArticle

74 Citations (Scopus)

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 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.

Original languageEnglish (US)
Pages (from-to)192-200
Number of pages9
JournalNature Cell Biology
Volume14
Issue number2
DOIs
StatePublished - Feb 1 2012

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Endoplasmic Reticulum Stress
Toll-Like Receptors
Guanine Nucleotide Exchange Factors
Unfolded Protein Response
Endoplasmic Reticulum
Apoptosis
src-Family Kinases
Protein Biosynthesis
Serine
Catalytic Domain
Proteins
Phosphorylation

All Science Journal Classification (ASJC) codes

  • Cell Biology

Cite this

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Toll-like receptor activation suppresses ER stress factor CHOP and translation inhibition through activation of eIF2B. / Woo, Connie W.; Kutzler, Lydia; Kimball, Scot; Tabas, Ira.

In: Nature Cell Biology, Vol. 14, No. 2, 01.02.2012, p. 192-200.

Research output: Contribution to journalArticle

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