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Review
. 2013 Nov;23(11):547-55.
doi: 10.1016/j.tcb.2013.06.005. Epub 2013 Jul 21.

IRE1: ER stress sensor and cell fate executor

Yani Chen  1 , Federica Brandizzi
Affiliations
Review

IRE1: ER stress sensor and cell fate executor

Yani Chen et al. Trends Cell Biol. 2013 Nov.

Abstract

Cells operate a signaling network termed the unfolded protein response (UPR) to monitor protein-folding capacity in the endoplasmic reticulum (ER). Inositol-requiring enzyme 1 (IRE1) is an ER transmembrane sensor that activates the UPR to maintain the ER and cellular function. Although mammalian IRE1 promotes cell survival, it can initiate apoptosis via decay of antiapoptotic miRNAs. Convergent and divergent IRE1 characteristics between plants and animals underscore its significance in cellular homeostasis. This review provides an updated scenario of the IRE1 signaling model, discusses emerging IRE1 sensing mechanisms, compares IRE1 features among species, and outlines exciting future directions in UPR research.

Keywords: ER stress; IRE1; cell fate; membrane trafficking system; protein quality control; unfolded protein response.

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Figures

Figure 1
Figure 1. Overview of UPR arms in eukaryotes
The IRE1 arm is conserved in eukaryotes. IRE1 unconventionally splices bZIP transcription factors, Xbp-1, bZIP60, and Hac1 mRNA in mammals, plants, and yeast respectively. The spliced bZIP transcription factor enters into the nucleus to regulate UPR target genes. In addition, two distinct arms mediated by PERK and ATF6 regulate mammalian UPR. ATF6 is an ER transmembrane transcription factor. ER stress triggers the relocation of ATF6 from the ER to the Golgi apparatus where it is undergone proteolytic cleavage. Subsequently, the transcription factor domain of ATF6 enters into the nucleus to modulate transcription of UPR target genes. Two functional homologues of ATF6, bZIP17 and bZIP28, exist in plants. PERK, an ER transmembrane protein kinase is identified only in animals. Upon ER stress, PERK phosphorylates eukaryotic initiation factor 2 (elF2α), which leads to a transient inhibition of general protein translation and selective translation of the transcription factor ATF4. Under irremediable ER stress, PERK-elF2α-ATF4-CHOP and IRE1-JNK initiate apoptosis in mammals. Moreover, the beta subunit of the heterotrimeric G protein complex, AGB1, is essential for the plant UPR. Although the G protein complex is conserved in eukaryotes, its significance in UPR is unclear in other eukaryotic organisms. Color code: blue - eukaryotes; black - mammals; green - plants; red - yeast.
Figure 2
Figure 2. IRE1α regulatory mechanisms during ER stress
Mammalian IRE1α is repressed through a physical interaction with BiP when demand and capacity of protein folding is balanced in the ER. A dissociation of IRE1α from BiP due to an elevated level of unfolded protein in the ER leads to activation of IRE1α. The IRE1α activating processes include its auto-phosphorylation, conformational change, and higher order assembly. IRE1α directs cell fate decision through unconventional splicing and Regulated IRE1-Dependent Decay (RIDD). To prevent increasing demand of ER protein folding, IRE1α conducts RIDD to degrade the transcripts of ER-translocating proteins. In parallel, IRE1α unconventionally splices the transcript of Xbp-1 transcription factor. The spliced XBP-1 enters into the nucleus to transcriptionally reprogram UPR target genes, including ER chaperones. Under irremediable ER stress, IRE1α ceases to splice Xbp-1 mRNA. Instead, IRE1α operates RIDD on selective UPR target genes including BiP to enhance the ER stress intensity. Once the ER stress intensity reaches its threshold, IRE1α represses anti-Casp2 microRNA, miR-17, miR-34a, miR-96, and miR-125b through RIDD. IRE1α-mediated degradation of anti-Casp2 microRNAs leads to activation of apoptotic initiator Casp2 and subsequently triggers the mitochondrion-dependent apoptosis.
Figure 3
Figure 3. Updated model of IRE1α and PERK signaling in cell fate determination during ER stress
The UPR signaling aimed for cell survival is considered an adaptive response during ER stress. Under irremediable ER stress, UPR represses the adaptive response and triggers an apoptotic response. IRE1α and PERK are two ER stress sensors that decrease ER protein folding demand through mRNA decay and translational inhibition, respectively. Both PERK and IRE1α signaling appear to persist throughout ER stress. IRE1α differentially triggers diverse UPR according to need. In the adaptive phase, to increase protein folding capcity, IRE1α-mediated Xbp-1 mRNA splicing is activated for transcriptional regulation of UPR target genes. In a transition phase between the adaptive and apoptotic responses, the signaling mediated by IRE1α-Xbp-1 is attenuated. In parallel, IRE1α incrases ER stress intensity through mRNA decay of selective UPR target genes including ER chaperones. During the apoptotic phase, IRE1α-Casp2 signaling is activated to initate cell death.
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