Alternative titles; symbols
HGNC Approved Gene Symbol: ERN1
Cytogenetic location: 17q23.3 Genomic coordinates (GRCh38) : 17:64,039,142-64,130,144 (from NCBI)
The unfolded protein response (UPR) in eukaryotic cells responds to the presence of unfolded protein in the endoplasmic reticulum (ER) by upregulating the transcription of genes encoding ER protein chaperones, such as BiP (138120). In S. cerevisiae, the ER transmembrane Ire1 (inositol-requiring-1)/Ern1 protein kinase is the UPR proximal sensor that monitors the status of unfolded protein inside the ER lumen. By PCR of fetal liver cDNA with degenerate primers based on a conserved Ire1 domain, Tirasophon et al. (1998) isolated a partial human IRE1 cDNA. They used the partial clone to screen a fetal liver library and recovered additional cDNAs corresponding to the entire IRE1 coding region. The predicted 977-amino acid protein contains a putative N-terminal signal sequence and a transmembrane domain. The C-terminal halves of human and yeast IRE1 are 34% identical and include a ser/thr kinase domain and an RNase L (180435)-like region. When expressed in mammalian cells, IRE1 displayed intrinsic kinase activity and an endoribonuclease activity that cleaved Hac1 mRNA, a yeast Ire1 substrate. Overexpressed IRE1 specifically localized to the ER and activated a reporter gene under the control of the rat BiP promoter. Northern blot analysis of human tissues revealed that the approximately 8-kb IRE1 mRNA is expressed ubiquitously. Tirasophon et al. (1998) concluded that human IRE1 is equivalent to yeast Ire1 and functions as a proximal sensor for the UPR in mammalian cells. Wang et al. (1998) isolated a second mammalian Ire1 homolog, which they designated ERN2 (604034).
Niwa et al. (1999) showed that yeast HAC1 mRNA is correctly spliced in mammalian cells upon UPR induction and that mammalian IRE1 can precisely cleave both splice junctions. Surprisingly, UPR induction led to proteolytic cleavage of IRE1, releasing fragments containing the kinase and nuclease domains that accumulated in the nucleus. Based on their results, Niwa et al. (1999) proposed the following model for activation of mammalian IRE1 during UPR induction: IRE1 resides on the ER membrane with its sensor domain in the lumen of the ER, where it detects accumulation of unfolded proteins via an unidentified mechanism. Activation of IRE1 leads to oligomerization and autophosphorylation. IRE1 is proteolytically cleaved, presumably within the transmembrane domain, releasing the C-terminal cytosolic portion. Activation of IRE1 could either render IRE1 susceptible to cleavage by a constitutively active gamma-secretase or could activate gamma-secretase possibly by phosphorylation. Other proteins might cocluster with IRE1 and be cleaved and/or be substrates for activated gamma-secretase. The resulting IRE1 cleavage product includes the kinase and nuclease domains and is transported into the nucleus, where it may function as a site-specific endoribonuclease. The fate of the severed N-terminal domains was unknown. Niwa et al. (1999) found that nuclear localization and UPR induction were reduced in mouse presenilin-1 (PSEN1; 104311) knockout cells. These results suggested that PSEN1 controls IRE1 proteolysis in mammalian cells.
Malfolded proteins in the endoplasmic reticulum induce cellular stress and activate c-JUN amino-terminal kinases (JNKs). Urano et al. (2000) showed that IRE1 activates chaperone genes in response to stress in the endoplasmic reticulum and also activates JNK (601158). IRE1-alpha -/- fibroblasts were impaired in JNK activation by endoplasmic reticulum stress. Using the yeast 2-hybrid system, Urano et al. (2000) demonstrated that the cytoplasmic part of IRE1 bound TRAF2 (601895), an adaptor protein that couples plasma membrane receptors to JNK activation. The dominant-negative form of TRAF2 inhibited activation of JNK by IRE1. Activation of JNK by endogenous signals initiated in the endoplasmic reticulum proceeds by a pathway similar to that initiated by cell surface receptors in response to extracellular signals.
Calfon et al. (2002) showed that the UPR requires intact Ire1 and Xbp1 (194355) in C. elegans. Both mouse and worm Ire1 splice a small intron from Xbp1 mRNA in response to UPR activation. Immunoblot analysis showed that in the mouse, the processed, but not the unprocessed, 54-kD Xbp1 protein accumulates during the UPR and depends on Ire1. Calfon et al. (2002) proposed that an increased load of proteins in the endoplasmic reticulum activates Xbp1 and triggers the development of an elaborate secretory process, as seen in plasma cells.
Papa et al. (2003) explored the role of the IRE1 kinase domain by sensitizing it through site-directed mutagenesis to the ATP-competitive inhibitor 1NM-PP1. Paradoxically, rather than being inhibited by 1NM-PP1, drug-sensitized IRE1 mutants required 1NM-PP1 as a cofactor for activation. In the presence of 1NM-PP1, drug-sensitized IRE1 bypassed mutations that inactivate its kinase activity and induced a full UPR. Thus, Papa et al. (2003) concluded that rather than through phosphorylation per se, a conformational change in the kinase domain triggered by occupancy of the active site with a ligand leads to activation of all known downstream functions.
Zhang et al. (2005) reconstituted Rag2 (179616)-deficient mice with Ire1-alpha-deficient fetal hemopoietic cells and demonstrated that Ire1 is essential in early lymphocyte development at the pro-B cell stage. Bone marrow cells expressing trans-dominant-negative mutant Ire1-alpha in Rag2-deficient mice showed that Ire1-alpha is also required at a late stage in B-cell lymphopoiesis in which Ire1-alpha-mediated splicing of Xbp1 mRNA is essential for terminal differentiation of B cells into plasma cells. The results suggested that there are specific requirements of the IRE1-alpha-mediated UPR subpathway in the early and late stages of B lymphopoiesis.
In microarray analysis using Drosophila S2 cells, Hollien and Weissman (2006) reported that IRE1 independently mediates the rapid degradation of a specific subset of mRNAs, based both on their localization to the ER membrane and on the amino acid sequence they encode. This response is well suited to complement other UPR mechanisms because it could selectively halt production of proteins that challenge the ER and clear the translocation and folding machinery for the subsequent remodeling process.
The 3 UPR branches, governed by the ER stress sensors IRE1, PERK (604032), and ATF6 (605537), promote cell survival by reducing misfolded protein levels. UPR signaling also promotes apoptotic cell death if ER stress is not alleviated. Lin et al. (2007) found that IRE1 and ATF6 activities were attenuated by persistent ER stress in human cells. By contrast, PERK signaling, including translational inhibition and induction of the proapoptotic transcription regulator CHOP (126337), was maintained. When IRE1 activity was sustained artificially, cell survival was enhanced, suggesting a causal link between the duration of UPR branch signaling and life or death cell fate after ER stress. Key findings from their studies in cell culture were recapitulated in photoreceptors expressing mutant rhodopsin (180380) in animal models of retinitis pigmentosa.
Working in S. cerevisiae, Aragon et al. (2009) demonstrated that, on activation, Ire1 molecules cluster in the ER membrane into discrete foci of higher-order oligomers, to which unspliced Hac1 (the yeast homolog of XBP1, 194355) mRNA is recruited by means of a conserved bipartite targeting element contained in the 3-prime UTR. Disruption of either Ire1 clustering or Hac1 mRNA recruitment impairs UPR signaling. The Hac1 3-prime UTR element is sufficient to target other mRNAs to Ire1 foci, as long as their translation is repressed. Translational repression afforded by the intron fulfills this requirement for Hac1 mRNA. Aragon et al. (2009) concluded that their elucidation of recruitment of mRNA to signaling centers provided a new paradigm for the control of eukaryotic gene expression.
Using yeast 2-hybrid, coimmunoprecipitation, and protein pull-down assays, Nagai et al. (2009) showed that USP14 (607274) interacted with IRE1-alpha in human cell lines and mouse embryonic fibroblasts under nonstressed conditions. The interaction between USP14 and IRE1-alpha was inhibited by ER stress, concomitant with phosphorylation and activation of IRE1-alpha. Mutation analysis revealed that neither the kinase activity of IRE1-alpha nor the deubiquitination activity of USP14 were required for their interaction and for inhibition of ER-associated degradation (ERAD). Knockdown of USP14 in HEK293 cells accelerated ERAD, even under nonstressed conditions. Nagai et al. (2009) concluded that activated IRE1-alpha releases USP14, and that the dissociation accelerates release of unfolded proteins from the ER lumen for their proteasomal degradation.
Gardner and Walter (2011) found that the core ER-lumenal domain (cLD) of yeast Ire1 binds to unfolded proteins in yeast cells and to peptides primarily composed of basic and hydrophobic residues in vitro. Mutation of amino acid side chains exposed in a putative peptide-binding groove of Ire1 cLD impaired peptide binding. Peptide binding caused Ire1 cLD oligomerization in vitro, suggesting that direct binding to unfolded proteins activates the UPR.
Upton et al. (2012) found that sustained IRE1-alpha RNase activation caused rapid decay of select microRNAs (miR17, 609416; miR34a, 611172; miR96, 611606; and miR125b, 610105) that normally repress translation of caspase-2 (600639) mRNA, and thus sharply elevated protein levels of this initiator protease of the mitochondrial apoptotic pathway. In cell-free systems, recombinant IRE1-alpha endonucleolytically cleaved microRNA precursors at sites distinct from DICER (606241). Thus, Upton et al. (2012) concluded that IRE1-alpha regulates translation of a proapoptotic protein through terminating microRNA biogenesis, and noncoding RNAs are a part of the ER stress response.
Maurel et al. (2013) observed that expression of both microRNA-1291 (MIR1291; 615487) and glypican-3 (GPC3; 300037) was upregulated in hepatocellular carcinoma. They found that MIR1291 did not directly bind to GPC3 mRNA, but rather enhanced its stability by binding to and directing degradation of IRE1A. In the absence of MIR1291, IRE1A bound a canonical site in the 3-prime UTR of GPC3 and cleaved the mRNA, causing its degradation via the UPR. Unlike most miRNAs, which typically bind complementary sequences in the 3-prime UTRs of target mRNAs, MIR1291 bound a complementary site in the 5-prime UTR of IRE1A to direct its degradation.
Lu et al. (2014) found that unmitigated ER stress promoted apoptosis through cell-autonomous, UPR-controlled activation of DR5 (603612). ER stressors induced DR5 transcription via the UPR mediator CHOP; however, the UPR sensor IRE1A transiently catalyzed DR5 mRNA decay, which allowed time for adaptation. Persistent ER stress built up intracellular DR5 protein, driving ligand-independent DR5 activation and apoptosis engagement via CASP8 (601763). Thus, DR5 integrates opposing UPR signals to couple ER stress and apoptotic cell fate.
Yang et al. (2015) showed that, in the setting of obesity, inflammatory input through increased inducible nitric oxide synthase (iNOS; 163730) activity causes S-nitrosylation of a key unfolded protein response (UPR) regulator, IRE1-alpha, which leads to a progressive decline in hepatic IRE1-alpha-mediated XBP1 (194355) splicing activity in both genetic (ob/ob) and dietary (high-fat diet-induced) models of obesity. Finally, in obese mice with liver-specific IRE1-alpha deficiency, reconstitution of IRE1-alpha expression with a nitrosylation-resistant variant restored IRE1-alpha-mediated XBP1 splicing and improved glucose homeostasis in vivo. Yang et al. (2015) concluded that their data described a mechanism by which inflammatory pathways compromise UPR function through iNOS-mediated S-nitrosylation of IRE1-alpha, which contributes to defective IRE1-alpha activity, impaired ER function, and prolonged ER stress in obesity.
Song et al. (2018) reported that ovarian cancer induces endoplasmic reticulum stress and activates the IRE1-alpha-XBP1 arm of the unfolded protein response in T cells to control their mitochondrial respiration and antitumor function. In T cells isolated from specimens collected from patients with ovarian cancer, upregulation of XBP1 was associated with decreased infiltration of T cells into tumors and with reduced IFNG mRNA expression. Malignant ascites fluid obtained from patients with ovarian cancer inhibited glucose uptake and caused N-linked protein glycosylation defects in T cells, which triggered IRE1-alpha-XBP1 activation that suppressed mitochondrial activity and IFNG production. Mechanistically, induction of XBP1 regulated the abundance of glutamine carriers and thus limited the influx of glutamine that is necessary to sustain mitochondrial respiration in T cells under glucose-deprived conditions. Restoring N-linked protein glycosylation, abrogating IRE1-alpha-XBP1 activation, or enforcing expression of glutamine transporters enhanced mitochondrial respiration in human T cells exposed to ovarian cancer ascites. XBP1-deficient T cells in the metastatic ovarian cancer milieu exhibited global transcriptional reprogramming and improved effector capacity. Accordingly, mice that bear ovarian cancer and lack XBP1 selectively in T cells demonstrated superior antitumor immunity, delayed malignant progression, and increased overall survival.
Schiattarella et al. (2019) reported that concomitant metabolic and hypertensive stress in mice, elicited by a combination of high-fat diet and inhibition of constitutive nitric oxide synthase (NOS) using N-nitro-L-arginine methyl ester (L-NAME), recapitulates the numerous systemic and cardiovascular features of heart failure with preserved ejection fraction in humans. Expression of one of the unfolded protein response effectors, the spliced form of XBP1, was reduced in the myocardium of the rodent model and in humans with heart failure with preserved ejection fraction. Mechanistically, the decrease in spliced XBP1 resulted from increased activity of inducible NOS (INOS) and S-nitrosylation of the endonuclease IRE1A, culminating in defective XBP1 splicing. Pharmacologic or genetic suppression of INOS, or cardiomyocyte-restricted overexpression of spliced XBP1, each ameliorated the heart failure with preserved ejection fraction phenotype. Schiattarella et al. (2019) concluded that INOS-driven dysregulation of the IRE1A-XBP1 pathway is a crucial mechanism of cardiomyocyte dysfunction in heart failure with preserved ejection fraction.
Chopra et al. (2019) found that induction of prostaglandin-endoperoxide synthase-2 (PTGS2; 600262) and prostaglandin E synthase (PTGES; 605172) was compromised in IRE1-alpha-deficient myeloid cells undergoing ER stress or stimulated through pattern recognition receptors. inducible biosynthesis of prostaglandins, including the proalgesic mediator prostaglandin E2 (PGE2), was decreased in myeloid cells that lack IRE1-alpha or XBP1 (194535) but not other ER stress sensors. Functional XBP1 transactivated the human PTGS2 and PTGES genes to enable optimal PGE2 production. Mice that lacked IRE1a-XBP1 in leukocytes, or that were treated with IRE1-alpha inhibitors, demonstrated reduced pain behaviors in PGE2-dependent models of pain. Thus, Chopra et al. (2019) concluded that IRE1-alpha-XBP1 is a mediator of prostaglandin biosynthesis and a potential target to control pain.
Crystal Structure
Korennykh et al. (2009) showed that oligomerization is central to IRE1 function and is an intrinsic attribute of its cytosolic domains. Korennykh et al. (2009) obtained a 3.2-angstrom crystal structure of the oligomer of the IRE1 cytosolic domains in complex with a kinase inhibitor that acts as a potent activator of the IRE1 RNase. The structure revealed a rod-shaped assembly that had no known precedence among kinases. This assembly positions the kinase domain for trans-autophosphorylation, orders the RNase domain, and creates an interaction surface for binding of the mRNA substrate. Korennykh et al. (2009) concluded that activation of Ire1 through oligomerization expands the mechanistic repertoire of kinase-based signaling receptors.
Zhang et al. (2005) reported that homozygous inactivation of Ire1-alpha in mice resulted in widespread developmental defects and embryonic lethality after 12.5 days gestation.
Iwawaki et al. (2009) found that embryonic lethality in Ire1-alpha -/- mice was due to severe placental defects. Ire1-alpha -/- placentas showed normal spongiotrophoblast and decidua layers, but the labyrinth layer was severely disrupted relative to normal controls, with reduced internal space for fetal and maternal blood vessels. Ire1-alpha -/- placentas also showed reduced Vegfa (192240) expression. The reduction in blood space in Ire1-alpha -/- labyrinth suggested that embryonic lethality was due to restricted nutrient and/or oxygen exchange between mother and developing embryos. Conditional Ire1-alpha knockout in embryos, but not in trophoblasts, produced viable pups at near mendelian ratios. Iwawaki et al. (2009) concluded that IRE1-alpha has a critical function in extraembryonic cells that is essential for fetal viability.
The article by Hetz et al. (2006) regarding the unfolded protein response signaling events in mice in the absence of proapoptotic BCL2 family members Bax and Bak (600516) was retracted.
Aragon, T., van Anken, E., Pincus, D., Serafimova, I. M., Korennykh, A. V., Rubio, C. A., Walter, P. Messenger RNA targeting to endoplasmic reticulum stress signalling sites. Nature 457: 736-740, 2009. [PubMed: 19079237] [Full Text: https://doi.org/10.1038/nature07641]
Calfon, M., Zeng, H., Urano, F., Till, J. H., Hubbard, S. R., Harding, H. P., Clark, S. G., Ron, D. IRE1 couples endoplasmic reticulum load to secretory capacity by processing the XBP-1 mRNA. Nature 415: 92-96, 2002. Note: Erratum: Nature 420: 202 only, 2002. [PubMed: 11780124] [Full Text: https://doi.org/10.1038/415092a]
Chopra, S., Giovanelli, P., Alvarado-Vazquez, P. A., Alonso, S., Song, M., Sandoval, T. A., Chae, C.-S., Tan, C., Fonseca, M. M., Gutierrez, S., Jimenez, L., Subbaramaiah, K., and 9 others. IRE1-alpha-XBP1 signaling in leukocytes controls prostaglandin biosynthesis and pain. Science 365: eaau6499, 2019. Note: Electronic Article. [PubMed: 31320508] [Full Text: https://doi.org/10.1126/science.aau6499]
Gardner, B. M., Walter, P. Unfolded proteins are Ire1-activating ligands that directly induce the unfolded protein response. Science 333: 1891-1894, 2011. [PubMed: 21852455] [Full Text: https://doi.org/10.1126/science.1209126]
Hetz, C., Bernasconi, P., Fisher, J., Lee, A.-H., Bassik, M. C., Antonsson, B., Brandt, G. S., Iwakoshi, N. N., Schinzel, A., Glimcher, L. H., Korsmeyer, S. J. Proapoptotic BAX and BAK modulate the unfolded protein response by a direct interaction with IRE1-alpha. Science 312: 572-576, 2006. Note: Retraction: Science 384: 280 only, 2024. [PubMed: 16645094] [Full Text: https://doi.org/10.1126/science.1123480]
Hollien, J., Weissman, J. S. Decay of endoplasmic reticulum-localized mRNAs during the unfolded protein response. Science 313: 104-107, 2006. [PubMed: 16825573] [Full Text: https://doi.org/10.1126/science.1129631]
Iwawaki, T., Akai, R., Yamanaka, S., Kohno, K. Function of IRE1 alpha in the placenta is essential for placental development and embryonic viability. Proc. Nat. Acad. Sci. 106: 16657-16662, 2009. [PubMed: 19805353] [Full Text: https://doi.org/10.1073/pnas.0903775106]
Korennykh, A. V., Egea, P. F., Korostelev, A. A., Finer-Moore, J., Zhang, C., Shokat, K. M., Stroud, R. M., Walter, P. The unfolded protein response signals through high-order assembly of Ire1. Nature 457: 687-693, 2009. [PubMed: 19079236] [Full Text: https://doi.org/10.1038/nature07661]
Lin, J. H., Li, H., Yasumura, D., Cohen, H. R., Zhang, C., Panning, B., Shokat, K. M., LaVail, M. M., Walter, P. IRE1 signaling affects cell fate during the unfolded protein response. Science 318: 944-949, 2007. [PubMed: 17991856] [Full Text: https://doi.org/10.1126/science.1146361]
Lu, M., Lawrence, D. A., Marsters, S., Acosta-Alvear, D., Kimmig, P., Mendez, A. S., Paton, A. W., Paton, J. C., Walter, P., Ashkenazi, A. Opposing unfolded-protein-response signals converge on death receptor 5 to control apoptosis. Science 345: 98-101, 2014. [PubMed: 24994655] [Full Text: https://doi.org/10.1126/science.1254312]
Maurel, M., Dejeans, N., Taouji, S., Chevet, E., Grosset, C. F. MicroRNA-1291-mediated silencing of IRE1-alpha enhances glypican-3 expression. RNA 19: 778-788, 2013. [PubMed: 23598528] [Full Text: https://doi.org/10.1261/rna.036483.112]
Nagai, A., Kadowaki, H., Maruyama, T., Takeda, K., Nishitoh, H., Ichijo, H. USP14 inhibits ER-associated degradation via interaction with IRE1-alpha. Biochem. Biophys. Res. Commun. 379: 995-1000, 2009. [PubMed: 19135427] [Full Text: https://doi.org/10.1016/j.bbrc.2008.12.182]
Niwa, M., Sidrauski, C., Kaufman, R. J., Walter, P. A role for presenilin-1 in nuclear accumulation of Ire1 fragments and induction of the mammalian unfolded protein response. Cell 99: 691-702, 1999. [PubMed: 10619423] [Full Text: https://doi.org/10.1016/s0092-8674(00)81667-0]
Papa, F. R., Zhang, C., Shokat, K., Walter, P. Bypassing a kinase activity with an ATP-competitive drug. Science 302: 1533-1537, 2003. [PubMed: 14564015] [Full Text: https://doi.org/10.1126/science.1090031]
Schiattarella, G. G., Altamirano, F., Tong, D., French, K. M., Villalobos, E., Kim, S. Y., Luo, X., Jiang, N., May, H. I., Wang, Z. V., Hill, T. M., Mammen, P. P. A., Huang, J., Lee, D. I., Hahn, V. S., Sharma, K., Kass, D. A., Lavandero, S., Gillette, T. G., Hill, J. A. Nitrosative stress drives heart failure with preserved ejection fraction. Nature 568: 351-356, 2019. [PubMed: 30971818] [Full Text: https://doi.org/10.1038/s41586-019-1100-z]
Song, M., Sandoval, T. A., Chae, C. S., Chopra, S., Tan, C., Rutkowski, M. R., Raundhal, M., Chaurio, R. A., Payne, K. K., Konrad, C., Bettigole, S. E., Shin, H. R., and 13 others. IRE1-alpha-XBP1 controls T cell function in ovarian cancer by regulating mitochondrial activity. Nature 562: 423-428, 2018. [PubMed: 30305738] [Full Text: https://doi.org/10.1038/s41586-018-0597-x]
Tirasophon, W., Welihinda, A. A., Kaufman, R. J. A stress response pathway from the endoplasmic reticulum to the nucleus requires a novel bifunctional protein kinase/endoribonuclease (Ire1p) in mammalian cells. Genes Dev. 12: 1812-1824, 1998. [PubMed: 9637683] [Full Text: https://doi.org/10.1101/gad.12.12.1812]
Upton, J.-P., Wang, L., Han, D., Wang, E. S., Huskey, N. E., Lim, L., Truitt, M., McManus, M. T., Ruggero, D., Goga, A., Papa, F. R., Oakes, S. A. IRE1-alpha cleaves select microRNAs during ER stress to derepress translation of proapoptotic caspase-2. Science 338: 818-822, 2012. [PubMed: 23042294] [Full Text: https://doi.org/10.1126/science.1226191]
Urano, F., Wang, X., Bertolotti, A., Zhang, Y., Chung, P., Harding, H. P., Ron, D. Coupling of stress in the ER to activation of JNK protein kinases by transmembrane protein kinase IRE1. Science 287: 664-666, 2000. [PubMed: 10650002] [Full Text: https://doi.org/10.1126/science.287.5453.664]
Wang, X.-Z., Harding, H. P., Zhang, Y., Jolicoeur, E. M., Kuroda, M., Ron, D. Cloning of mammalian Ire1 reveals diversity in the ER stress responses. EMBO J. 17: 5708-5717, 1998. [PubMed: 9755171] [Full Text: https://doi.org/10.1093/emboj/17.19.5708]
Yang, L., Calay, E. S., Fan, J., Arduini, A., Kunz, R. C., Gygi, S. P., Yalcin, A., Fu, S., Hotamisligil, G. S. S-nitrosylation links obesity-associated inflammation to endoplasmic reticulum dysfunction. Science 349: 500-506, 2015. [PubMed: 26228140] [Full Text: https://doi.org/10.1126/science.aaa0079]
Zhang, K., Wong, H. N., Song, B., Miller, C. N., Scheuner, D., Kaufman, R. J. The unfolded protein response sensor IRE1-alpha is required at 2 distinct steps in B cell lymphopoiesis. J. Clin. Invest. 115: 268-281, 2005. [PubMed: 15690081] [Full Text: https://doi.org/10.1172/JCI21848]