Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2009 Sep 11;35(5):551-61.
doi: 10.1016/j.molcel.2009.08.021.

Fine-tuning of the unfolded protein response: Assembling the IRE1alpha interactome

Claudio Hetz  1 , Laurie H Glimcher
Affiliations
Review

Fine-tuning of the unfolded protein response: Assembling the IRE1alpha interactome

Claudio Hetz et al. Mol Cell. .

Abstract

Endoplasmic reticulum (ER) stress is a hallmark feature of secretory cells and many diseases, including cancer, neurodegeneration, and diabetes. Adaptation to protein-folding stress is mediated by the activation of an integrated signal transduction pathway known as the unfolded protein response (UPR). The UPR signals through three distinct stress sensors located at the ER membrane-IRE1alpha, ATF6, and PERK. Although PERK and IRE1alpha share functionally similar ER-luminal sensing domains and both are simultaneously activated in cellular paradigms of ER stress in vitro, they are selectively engaged in vivo by the physiological stress of unfolded proteins. The differences in terms of tissue-specific regulation of the UPR may be explained by the formation of distinct regulatory protein complexes. This concept is supported by the recent identification of adaptor and modulator proteins that directly interact with IRE1alpha. In this Review, we discuss recent evidence supporting a model where IRE1alpha signaling emerges as a highly regulated process, controlled by the formation of a dynamic scaffold onto which many regulatory components assemble.

PubMed Disclaimer

Figures

Figure 1
Figure 1. Essential components of the Unfolded Protein Response
(A) UPR signaling. Accumulation of misfolded protein inside the endoplasmic reticulum (ER) lumen triggers a stress response known as UPR. There are at least three main stress sensors at the ER membrane, IRE1α, PERK, and ATF6. In cells undergoing ER stress, IRE1α auto-phosphorylates, leading to the activation of its endoribonuclease domain. This activity mediates the processing of the mRNA encoding XBP1, which is a transcriptional factor that upregulates many essential UPR genes involved in folding and protein quality control and regulates ER/Golgi biogenesis. Active IRE1α binds the adaptor protein TRAF2, triggering JNK activation, which may participate in the regulation of autophagy and apoptosis. Alternatively, activated PERK phosphorylates and inhibits translation initiator factor eIF2α, decreasing the synthesis of proteins and the overload of misfolded proteins at the ER. In addition, this event leads to the specific translation of ATF4, a transcription factor that induces the expression of genes that function in amino acid metabolism, the antioxidant response and apoptosis regulators including CHOP. A third UPR pathway is initiated by ATF6, a type II ER transmembrane protein encoding a bZIP transcriptional factor in its cytosolic domain and localized in the ER in unstressed cells. Upon ER stress induction, ATF6 is processed, increasing the expression of some ER chaperones, and ERAD-related genes. At the bottom, the cellular functions affected by each UPR-signaling branch are indicated. (B) XBP1 splicing. Schematic representation of the unspliced and spliced forms of XBP1 (XBP1u and XBP1s, respectively). Numbers indicate amino acid positions with the initiation methionine set at 1. ORF1 and ORF2 for the C-terminal domain as well as the basic and leucine zipper (ZIP) domains are indicated. Putative hydrophobic region of XBP-1u related to targeting is also indicated. (C) IRE1 structure. A schematic representation of the primary structure of IRE1p is presented indicating the kinase and RNAse domains. BiP-binding domain (BBD), the MHC-like domain, linker region, tramsmembrane region ™ and kinase and RNAse domains are indicated. In the bottom panel, the crystal structure of the ER luminal domain groove (MHC-I like structure) of yeast IRE1p is shown (Credle et al., 2005). The dimer interface is indicated with a white line. This structural domain of IRE1p is proposed to bind misfolded proteins to stabilize the oligomeric conformation. In addition, the three dimensional structure of the cytosolic domain of IRE1p is presented highlighting the two lobes of the kinase domain (Lee et al., 2008b). The ADP and the kinase domain are indicated with a white arrow. The KEN domain containing the RNAse activity is also shown where a red arrow indicates the putative RNAse active site (Lee et al., 2008b).
Figure 2
Figure 2. Mechanism of IRE1 activation in yeast and mammals
(A) A direct recognition model proposes that unfolded proteins bind directly to the luminal domains of IRE1p, facilitating the assembly of highly ordered IRE1p clusters exemplified by the parenthesis and “n” IREp units). This may orient the cytosolic region of the dimer to form the ribonuclease active site and generation of an mRNA docking region. BiP dissociation from IRE1p may play an indirect role in unfolded-peptide loading. Oligomerization of IRE1p is essential for its auto-transphosphorylation between dimers (as indicated with arrows). IRE1p clusters recruit untranslated HAC1 mRNA contained in ribosomes (inhibited by the secondary structure of the HAC1 intron), an association which depends on structural motifs in IRE1p and the HAC1 mRNA including a bipartite element at the 3′ end (3′BE). (B) In mammalian cells, IRE1α is maintained in a repressed state through an association with BiP. Upon ER stress BiP dissociates, leading to partial IRE1 phosphorylation and IRE1 dimerization mediated by the N-terminal ER luminal region. Dimerization triggers further phosphorylation events (auto-transphosphorylation, indicated with arrows) and activation of the RNAse domain of IRE1α. The unspliced XBP1 mRNA is translated in mammals and a hydrophobic region (HR) on the nascent peptide targets the translated XBP-1 mRNA to the ER membrane, enhancing its processing by active IRE1α. XBP-1 mRNA targeting to the ER membrane does not depend on the expression of IRE1α. In (i) and (ii) splicing sites on the XBP1 and HAC1 mRNA are indicated with an arrowhead.
Figure 3
Figure 3. The IRE1α interactome
Mammalian IRE1α signaling is initiated by the formation of a complex protein platform at the ER membrane termed the UPRosome where multiple factors assemble and modulate its activity. For example, activation of IRE1α requires the binding of accessory proteins, such as BAX, BAK, AIP1, and possibly BH3-only proteins such as PUMA and BIM (upstream of BAX/BAK), in addition to the activity of the ER-located phosphatase PTP-1B. Under chronic or prolonged ER stress, IRE1α signaling is down regulated and the ER located protein BI-1 is involved in the inactivation of IRE1α, whereas HSP90 binding decreases its turnover. In addition, active IRE1α initiates a variety of signaling responses through the binding of TRAF2 and possibly other adaptor proteins. These events trigger the activation of ASK1/JNK, ERK and p38 kinases which may regulate apoptosis and autophagy. Sequestration of IKK by IRE1α induces NF-κB signaling. In addition, a non specific RNAse activity has been described for IRE1α in flies to degrade the mRNA of proteins that have a high tendency to misfold under ER stress conditions. Inactive IRE1α interacts with components of the ERAD machinery and may regulate this process and modulators of ERK such as NCK. For simplicity, the figure separates the components that control IRE1α activation/inactivation in relation to XBP1 mRNA splicing activity [i], and the components related to the regulation of other signaling branches [ii], and this graphical separation of the complexes does not reflect a temporal dissociation between i and ii. Proteins that bids to inactive IRE1α (resting condition) are shown in gray scale colors, that regulates its activation and XBP- mRNA splicing in blue and that controls other signaling pathways in brown.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Acosta-Alvear D, Zhou Y, Blais A, Tsikitis M, Lents NH, Arias C, Lennon CJ, Kluger Y, Dynlacht BD. XBP1 Controls Diverse Cell Type- and Condition-Specific Transcriptional Regulatory Networks. Mol Cell. 2007;27:53–66. - PubMed
    1. Aragon T, van AE, Pincus D, Serafimova IM, Korennykh AV, Rubio CA, Walter P. Messenger RNA targeting to endoplasmic reticulum stress signalling sites. Nature. 2009;457:736–740. - PMC - PubMed
    1. Arsham AM, Neufeld TP. A genetic screen in Drosophila reveals novel cytoprotective functions of the autophagy-lysosome pathway. PLoS One. 2009;4:e6068. - PMC - PubMed
    1. Bailly-Maitre B, Fondevila C, Kaldas F, Droin N, Luciano F, Ricci JE, Croxton R, Krajewska M, Zapata JM, Kupiec-Weglinski JW, Farmer D, Reed JC. Cytoprotective gene bi-1 is required for intrinsic protection from endoplasmic reticulum stress and ischemia-reperfusion injury. Proc Natl Acad Sci U S A. 2006;103:2809–2814. - PMC - PubMed
    1. Bertolotti A, Zhang Y, Hendershot LM, Harding HP, Ron D. Dynamic interaction of BiP and ER stress transducers in the unfolded-protein response. Nat Cell Biol. 2000;2:326–332. - PubMed

Publication types

MeSH terms

LinkOut - more resources