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The Sec61 translocon limits IRE1? signaling during the unfolded protein response.

ABSTRACT: IRE1? is an endoplasmic reticulum (ER) localized endonuclease activated by misfolded proteins in the ER. Previously, we demonstrated that IRE1? forms a complex with the Sec61 translocon, to which its substrate XBP1u mRNA is recruited for cleavage during ER stress (Plumb et al., 2015). Here, we probe IRE1? complexes in cells with blue native PAGE immunoblotting. We find that IRE1? forms a hetero-oligomeric complex with the Sec61 translocon that is activated upon ER stress with little change in the complex. In addition, IRE1? oligomerization, activation, and inactivation during ER stress are regulated by Sec61. Loss of the IRE1?-Sec61 translocon interaction as well as severe ER stress conditions causes IRE1? to form higher-order oligomers that exhibit continuous activation and extended cleavage of XBP1u mRNA. Thus, we propose that the Sec61-IRE1? complex defines the extent of IRE1? activity and may determine cell fate decisions during ER stress conditions.

SUBMITTER: Sundaram A

PROVIDER: S-EPMC5449187 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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The Sec61 translocon limits IRE1α signaling during the unfolded protein response.

Sundaram Arunkumar A Plumb Rachel R Appathurai Suhila S Mariappan Malaiyalam M

eLife 20170515

IRE1α is an endoplasmic reticulum (ER) localized endonuclease activated by misfolded proteins in the ER. Previously, we demonstrated that IRE1α forms a complex with the Sec61 translocon, to which its substrate XBP1u mRNA is recruited for cleavage during ER stress (Plumb et al., 2015). Here, we probe IRE1α complexes in cells with blue native PAGE immunoblotting. We find that IRE1α forms a hetero-oligomeric complex with the Sec61 translocon that is activated upon ER stress with little change in th ...[more]

PMID: 28504640

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IRE1 signaling affects cell fate during the unfolded protein response.

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Unfolded protein response in wildtype, ire1, gcn4, gcn2

Project description:We measured steady-state mRNA levels by microarray hybridization, comparing WT, (delta)ire1, (delta)gcn4, and (delta)gcn2 cells treated with 2 mM DTT for 30 min (by which time the UPR is qualitatively complete) to untreated samples of the same genotype. WT cells were taken as a positive control for UPR induction, and (delta)ire1 cells as a negative control. Fold change in expression of a given gene was computed as the ratio of mRNA level in the treated sample to the level in an untreated sample of the same genotype. Values reported here are the log2 fold change. Keywords = unfolded protein response Keywords = UPR Keywords = ire1 Keywords = gcn4 Keywords = gcn2 Keywords: parallel sample

2004-08-19 | GSE1688 | GEO

Structure and Molecular Mechanism of ER Stress Signaling by the Unfolded Protein Response Signal Activator IRE1.

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Unfolded protein response in wildtype, ire1, gcn4, gcn2

2010-06-06 | E-GEOD-1688 | biostudies-arrayexpress

IRE1?/XBP1-mediated branch of the unfolded protein response regulates osteoclastogenesis.

Project description:The unfolded protein response (UPR) is a cellular adaptive mechanism that is activated in response to the accumulation of unfolded proteins in the endoplasmic reticulum. The inositol-requiring protein-1?/X-box-binding protein-mediated (IRE1?/XBP1-mediated) branch of the UPR is highly conserved and has also been shown to regulate various cell-fate decisions. Herein, we have demonstrated a crucial role for the IRE?/XBP1-mediated arm of the UPR in osteoclast differentiation. Using murine models, we found that the conditional abrogation of IRE1? in bone marrow cells increases bone mass as the result of defective osteoclastic bone resorption. In osteoclast precursors, IRE1? was transiently activated during osteoclastogenesis, and suppression of the IRE1?/XBP1 pathway in these cells substantially inhibited the formation of multinucleated osteoclasts in vitro. We determined that XBP1 directly binds the promoter and induces transcription of the gene encoding the master regulator of osteoclastogenesis nuclear factor of activated T cells cytoplasmic 1 (NFATc1). Moreover, activation of IRE1? was partially dependent on Ca2+ oscillation mediated by inositol 1,4,5-trisphosphate receptors 2 and 3 (ITPR2 and ITPR3) in the endoplasmic reticulum, as pharmacological inhibition or deletion of these receptors markedly decreased Xbp1 mRNA processing. The present study thus reveals an intracellular pathway that integrates the UPR and osteoclast differentiation through activation of the IRE1?/XBP1 pathway.

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