Journal article
Endoplasmic reticulum stress impairs IL-4/IL-13 signaling through C/EBPβ-mediated transcriptional suppression
Journal of cell science, Vol.126(17), pp.4026-4036
09/01/2013
DOI: 10.1242/jcs.130757
PMCID: PMC3757336
PMID: 23813955
Abstract
Activation of the unfolded protein response (UPR) by endoplasmic reticulum (ER) stress culminates in extensive gene regulation, with transcriptional upregulation of genes that improve the protein folding capacity of the organelle. However, a substantial number of genes are downregulated by ER stress, and the mechanisms that lead to this downregulation and its consequences on cellular function are poorly understood. We found that ER stress led to coordinated transcriptional suppression of diverse cellular processes, including those involved in cytokine signaling. Using expression of the IL-4/IL-13 receptor subunit
Il4ra
as a sentinel, we sought to understand the mechanism behind this suppression and its impact on inflammatory signaling. We found that reinitiation of global protein synthesis by GADD34-mediated dephosphorylation of eIF2α resulted in preferential expression of the inhibitory LIP isoform of the transcription factor C/EBPβ. This regulation was in turn required for the suppression of
Il4ra
and related inflammatory genes. Suppression of
Il4ra
was lost in
Cebpb
−/−
cells but could be induced by LIP overexpression. As a consequence of
Il4ra
suppression, ER stress impaired IL-4/IL-13 signaling. Strikingly,
Cebpb
−/−
cells lacking
Il4ra
downregulation were protected from this signaling impairment. This work identifies a novel role for C/EBPβ in regulating transcriptional suppression and inflammatory signaling during ER stress.
Details
- Title: Subtitle
- Endoplasmic reticulum stress impairs IL-4/IL-13 signaling through C/EBPβ-mediated transcriptional suppression
- Creators
- Angela M Arensdorf - Department of Anatomy and Cell Biology, University of Iowa Carver College of MedicineD Thomas Rutkowski - Department of Anatomy and Cell Biology, University of Iowa Carver College of Medicine
- Resource Type
- Journal article
- Publication Details
- Journal of cell science, Vol.126(17), pp.4026-4036
- Publisher
- The Company of Biologists
- DOI
- 10.1242/jcs.130757
- PMID
- 23813955
- PMCID
- PMC3757336
- ISSN
- 0021-9533
- eISSN
- 1477-9137
- Language
- English
- Date published
- 09/01/2013
- Academic Unit
- Anatomy and Cell Biology; Internal Medicine
- Record Identifier
- 9984094405602771
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