Gene Symbol: Ern1
Description: endoplasmic reticulum (ER) to nucleus signalling 1
Alias: 9030414B18Rik, AI225830, C85377, Ire1a, Ire1alpha, Ire1p, serine/threonine-protein kinase/endoribonuclease IRE1, endoplasmic reticulum-to-nucleus signaling 1, ern1, inositol-requiring 1 alpha, inositol-requiring protein 1, ire1-alpha
Species: mouse
Products:     Ern1

Top Publications

  1. Harding H, Zhang Y, Bertolotti A, Zeng H, Ron D. Perk is essential for translational regulation and cell survival during the unfolded protein response. Mol Cell. 2000;5:897-904 pubmed
    ..PERK thus plays a major role in the ability of cells to adapt to ER stress. ..
  2. Wu J, Rutkowski D, Dubois M, Swathirajan J, Saunders T, Wang J, et al. ATF6alpha optimizes long-term endoplasmic reticulum function to protect cells from chronic stress. Dev Cell. 2007;13:351-64 pubmed
    In vertebrates, three proteins--PERK, IRE1alpha, and ATF6alpha--sense protein-misfolding stress in the ER and initiate ER-to-nucleus signaling cascades to improve cellular function...
  3. Wang X, Harding H, Zhang Y, Jolicoeur E, Kuroda M, Ron D. Cloning of mammalian Ire1 reveals diversity in the ER stress responses. EMBO J. 1998;17:5708-17 pubmed
    ..These results indicate that a single upstream component, Ire1, plays a role in multiple facets of the ER stress-response in mammalian cells. ..
  4. Ghosh R, Lipson K, Sargent K, Mercurio A, Hunt J, Ron D, et al. Transcriptional regulation of VEGF-A by the unfolded protein response pathway. PLoS ONE. 2010;5:e9575 pubmed publisher
    ..b>IRE1alpha, PERK, and ATF6alpha, master regulators of the unfolded protein response (UPR), are activated under these ..
  5. Hu P, Han Z, Couvillon A, Kaufman R, Exton J. Autocrine tumor necrosis factor alpha links endoplasmic reticulum stress to the membrane death receptor pathway through IRE1alpha-mediated NF-kappaB activation and down-regulation of TRAF2 expression. Mol Cell Biol. 2006;26:3071-84 pubmed
    ..Here, we report that, in response to ER stress, IKK forms a complex with IRE1alpha through the adapter protein TRAF2...
  6. Iwawaki T, Akai R, Yamanaka S, Kohno K. Function of IRE1 alpha in the placenta is essential for placental development and embryonic viability. Proc Natl Acad Sci U S A. 2009;106:16657-62 pubmed publisher
    ..This protein is activated during ER stress and induces cellular adaptive responses to the stress. In mice, IRE1alpha inactivation results in widespread developmental defects, leading to embryonic death after 12...
  7. Iwawaki T, Akai R, Kohno K. IRE1? disruption causes histological abnormality of exocrine tissues, increase of blood glucose level, and decrease of serum immunoglobulin level. PLoS ONE. 2010;5:e13052 pubmed publisher
    ..Comparison of this report with previous reports regarding XBP1 conditional knockout mice might provide some clues for the discovery of the novel functions of IRE1? and XBP1. ..
  8. Lee A, Heidtman K, Hotamisligil G, Glimcher L. Dual and opposing roles of the unfolded protein response regulated by IRE1alpha and XBP1 in proinsulin processing and insulin secretion. Proc Natl Acad Sci U S A. 2011;108:8885-90 pubmed publisher
    ..These results demonstrate that IRE1? has dual and opposing roles in ?-cells, and that a precisely regulated feedback circuit involving IRE1? and its product XBP1s is required to achieve optimal insulin secretion and glucose control. ..
  9. Harding H, Zeng H, Zhang Y, Jungries R, Chung P, Plesken H, et al. Diabetes mellitus and exocrine pancreatic dysfunction in perk-/- mice reveals a role for translational control in secretory cell survival. Mol Cell. 2001;7:1153-63 pubmed
    ..Postnatally, ER distention and activation of the ER stress transducer IRE1alpha accompanied increased cell death and led to progressive diabetes mellitus and exocrine pancreatic insufficiency...

More Information


  1. Marciniak S, Yun C, Oyadomari S, Novoa I, Zhang Y, Jungreis R, et al. CHOP induces death by promoting protein synthesis and oxidation in the stressed endoplasmic reticulum. Genes Dev. 2004;18:3066-77 pubmed
    ..CHOP deletion thus protects cells from ER stress by decreasing ER client protein load and changing redox conditions within the organelle. ..
  2. Zhang K, Wong H, Song B, Miller C, Scheuner D, Kaufman R. The unfolded protein response sensor IRE1alpha is required at 2 distinct steps in B cell lymphopoiesis. J Clin Invest. 2005;115:268-81 pubmed
    ..Two major proximal sensors of the UPR are inositol-requiring enzyme 1alpha (IRE1alpha), an ER transmembrane protein kinase/endoribonuclease, and ER-resident eukaryotic translation initiation factor ..
  3. Hetz C, Bernasconi P, Fisher J, Lee A, Bassik M, Antonsson B, et al. Proapoptotic BAX and BAK modulate the unfolded protein response by a direct interaction with IRE1alpha. Science. 2006;312:572-6 pubmed
    ..UPR)-mediated by the ER transmembrane protein kinase and endoribonuclease inositol-requiring enzyme-1alpha (IRE1alpha)...
  4. Lipson K, Ghosh R, Urano F. The role of IRE1alpha in the degradation of insulin mRNA in pancreatic beta-cells. PLoS ONE. 2008;3:e1648 pubmed publisher
    ..b>IRE1alpha is a central component of the UPR...
  5. Han D, Upton J, Hagen A, Callahan J, Oakes S, Papa F. A kinase inhibitor activates the IRE1alpha RNase to confer cytoprotection against ER stress. Biochem Biophys Res Commun. 2008;365:777-83 pubmed the endoplasmic reticulum (ER) cause trans-autophosphorylation of the bifunctional transmembrane kinase IRE1alpha, inducing its RNase activity to splice XBP1 mRNA, in turn triggering a transcriptional program in the unfolded ..
  6. Lisbona F, Rojas Rivera D, Thielen P, Zamorano S, Todd D, Martinon F, et al. BAX inhibitor-1 is a negative regulator of the ER stress sensor IRE1alpha. Mol Cell. 2009;33:679-91 pubmed publisher
    ..Here we have investigated the role of BI-1 in the UPR. BI-1 expression suppressed IRE1alpha activity in fly and mouse models of ER stress...
  7. Tohmonda T, Miyauchi Y, Ghosh R, Yoda M, Uchikawa S, Takito J, et al. The IRE1?-XBP1 pathway is essential for osteoblast differentiation through promoting transcription of Osterix. EMBO Rep. 2011;12:451-7 pubmed publisher
    ..The promoter region of the Osx gene encodes two potential binding motifs for XBP1, and we show that XBP1 binds to these regions. Thus, the IRE1?-XBP1 pathway is involved in osteoblast differentiation through promoting Osx transcription. ..
  8. Majumder M, Huang C, Snider M, Komar A, Tanaka J, Kaufman R, et al. A novel feedback loop regulates the response to endoplasmic reticulum stress via the cooperation of cytoplasmic splicing and mRNA translation. Mol Cell Biol. 2012;32:992-1003 pubmed publisher
    ..We propose a model in which eIF2? phosphorylation-mediated control of mRNA turnover is a molecular switch that regulates the stress response transcription program and the ER's capacity for protein folding during stress. ..
  9. Rodriguez D, Zamorano S, Lisbona F, Rojas Rivera D, Urra H, Cubillos Ruiz J, et al. BH3-only proteins are part of a regulatory network that control the sustained signalling of the unfolded protein response sensor IRE1?. EMBO J. 2012;31:2322-35 pubmed publisher
    ..We conclude that a subset of BCL-2 family members participates in a new UPR-regulatory network, thus assuming apoptosis-unrelated functions. ..
  10. Zhang K, Wang S, Malhotra J, Hassler J, Back S, Wang G, et al. The unfolded protein response transducer IRE1? prevents ER stress-induced hepatic steatosis. EMBO J. 2011;30:1357-75 pubmed publisher
    ..The identification of IRE1? as a key regulator to prevent hepatic steatosis provides novel insights into ER stress mechanisms in fatty liver diseases associated with toxic liver injuries. ..
  11. Rutkowski D, Arnold S, Miller C, Wu J, Li J, Gunnison K, et al. Adaptation to ER stress is mediated by differential stabilities of pro-survival and pro-apoptotic mRNAs and proteins. PLoS Biol. 2006;4:e374 pubmed
    ..It underscores the contribution of posttranscriptional and posttranslational mechanisms in influencing this outcome. ..
  12. Lipson K, Fonseca S, Ishigaki S, Nguyen L, Foss E, Bortell R, et al. Regulation of insulin biosynthesis in pancreatic beta cells by an endoplasmic reticulum-resident protein kinase IRE1. Cell Metab. 2006;4:245-54 pubmed
    ..Here, we show that IRE1alpha, an ER-resident protein kinase, has a crucial function in insulin biosynthesis...
  13. Calfon M, Zeng H, Urano F, Till J, Hubbard S, Harding H, et al. IRE1 couples endoplasmic reticulum load to secretory capacity by processing the XBP-1 mRNA. Nature. 2002;415:92-6 pubmed
    ..Our findings suggest that physiological ER load regulates a developmental decision in higher eukaryotes. ..
  14. Lin J, Li H, Yasumura D, Cohen H, Zhang C, Panning B, et al. IRE1 signaling affects cell fate during the unfolded protein response. Science. 2007;318:944-9 pubmed
    ..Key findings from our studies in cell culture were recapitulated in photoreceptors expressing mutant rhodopsin in animal models of retinitis pigmentosa. ..
  15. Upton J, Wang L, Han D, Wang E, Huskey N, Lim L, et al. IRE1? cleaves select microRNAs during ER stress to derepress translation of proapoptotic Caspase-2. Science. 2012;338:818-22 pubmed publisher
    ..Thus, IRE1? regulates translation of a proapoptotic protein through terminating microRNA biogenesis, and noncoding RNAs are part of the ER stress response. ..
  16. Benosman S, Ravanan P, Correa R, Hou Y, Yu M, Gulen M, et al. Interleukin-1 receptor-associated kinase-2 (IRAK2) is a critical mediator of endoplasmic reticulum (ER) stress signaling. PLoS ONE. 2013;8:e64256 pubmed publisher
    ..These findings demonstrate an unexpected linkage of the innate immunity machinery to UPR signaling, revealing IRAK2 as a novel amplifier of the IRE1 pathway. ..
  17. Lee K, Tirasophon W, Shen X, Michalak M, Prywes R, Okada T, et al. IRE1-mediated unconventional mRNA splicing and S2P-mediated ATF6 cleavage merge to regulate XBP1 in signaling the unfolded protein response. Genes Dev. 2002;16:452-66 pubmed
    ..To elucidate the requirements for IRE1alpha and ATF6 for signaling the mammalian UPR, we identified a UPR reporter gene that was defective for induction in ..
  18. Urano F, Wang X, Bertolotti A, Zhang Y, Chung P, Harding H, et al. Coupling of stress in the ER to activation of JNK protein kinases by transmembrane protein kinase IRE1. Science. 2000;287:664-6 pubmed
    ..homologs of yeast IRE1, which activate chaperone genes in response to ER stress, also activated JNK, and IRE1alpha-/- fibroblasts were impaired in JNK activation by ER stress...
  19. Sha H, He Y, Chen H, Wang C, Zenno A, Shi H, et al. The IRE1alpha-XBP1 pathway of the unfolded protein response is required for adipogenesis. Cell Metab. 2009;9:556-64 pubmed publisher
    ..Here we demonstrate that the IRE1alpha-XBP1 pathway, the most conserved branch of the unfolded protein response (UPR), is indispensable for ..
  20. Wikstrom J, Israeli T, Bachar Wikstrom E, Swisa A, Ariav Y, Waiss M, et al. AMPK regulates ER morphology and function in stressed pancreatic ?-cells via phosphorylation of DRP1. Mol Endocrinol. 2013;27:1706-23 pubmed publisher
    ..DRP1 may thus function as a node integrating signals from stress regulators, such as AMPK, to coordinate organelle shape and function. ..
  21. Li X, Xu C, Yang P. c-Jun NH2-terminal kinase 1/2 and endoplasmic reticulum stress as interdependent and reciprocal causation in diabetic embryopathy. Diabetes. 2013;62:599-608 pubmed publisher
    ..Suppressing JNK1/2 activation by either jnk1 or jnk2 gene deletion prevents ER stress. Thus, our study reveals a reciprocal causation of ER stress and JNK1/2 in mediating the teratogenicity of maternal diabetes. ..
  22. Oikawa D, Iwawaki T. Positive contribution of IRE1?-XBP1 pathway to the expression of placental cathepsins. Biochem Biophys Res Commun. 2013;433:426-31 pubmed publisher
    ..These results indicated that IRE1?-XBP1 pathway function as a specific program supporting the placenta formation by ensuring the moderate expression of specific subset of placental cathepsins. ..
  23. Niederreiter L, Fritz T, Adolph T, Krismer A, Offner F, Tschurtschenthaler M, et al. ER stress transcription factor Xbp1 suppresses intestinal tumorigenesis and directs intestinal stem cells. J Exp Med. 2013;210:2041-56 pubmed publisher
    ..As such, Xbp1 in the intestinal epithelium not only regulates local inflammation but at the same time also determines the propensity of the epithelium to develop tumors. ..
  24. Klee M, Pallauf K, Alcala S, Fleischer A, Pimentel Muiños F. Mitochondrial apoptosis induced by BH3-only molecules in the exclusive presence of endoplasmic reticular Bak. EMBO J. 2009;28:1757-68 pubmed publisher
    ..We provide evidence that calcium functions coordinately with the ER-stress surveillance machinery IRE1alpha/TRAF2 to transmit apoptotic signals from the reticulum to mitochondria...
  25. Nakato R, Ohkubo Y, Konishi A, Shibata M, Kaneko Y, Iwawaki T, et al. Regulation of the unfolded protein response via S-nitrosylation of sensors of endoplasmic reticulum stress. Sci Rep. 2015;5:14812 pubmed publisher
    ..Importantly, cells overexpressing mutant IRE1α(C931S) were resistant to NO-induced damage. Our findings show that nitrosative stress leads to dysfunctional ER stress signaling, thus contributing to neuronal cell death. ..
  26. Jurczak M, Lee A, Jornayvaz F, Lee H, Birkenfeld A, Guigni B, et al. Dissociation of inositol-requiring enzyme (IRE1?)-mediated c-Jun N-terminal kinase activation from hepatic insulin resistance in conditional X-box-binding protein-1 (XBP1) knock-out mice. J Biol Chem. 2012;287:2558-67 pubmed publisher
  27. He Y, Beatty A, Han X, Ji Y, Ma X, Adelstein R, et al. Nonmuscle myosin IIB links cytoskeleton to IRE1α signaling during ER stress. Dev Cell. 2012;23:1141-52 pubmed publisher
    ..elegans lacking NMIIB exhibit hypersensitivity to ER stress. Thus, optimal IRE1α activation and signaling require concerted coordination between the ER and cytoskeleton. ..
  28. Bailly Maitre B, Belgardt B, Jordan S, Coornaert B, von Freyend M, Kleinridders A, et al. Hepatic Bax inhibitor-1 inhibits IRE1alpha and protects from obesity-associated insulin resistance and glucose intolerance. J Biol Chem. 2010;285:6198-207 pubmed publisher
    ..BI-1 partially inhibits the UPR by interacting with IRE1alpha and inhibiting IRE1alpha endonuclease activity as seen on the splicing of the transcription factor Xbp-1...
  29. Asada R, Kanemoto S, Matsuhisa K, Hino K, Cui M, Cui X, et al. IRE1α-XBP1 is a novel branch in the transcriptional regulation of Ucp1 in brown adipocytes. Sci Rep. 2015;5:16580 pubmed publisher
    ..These data indicate that PKA-dependent IRE1α-XBP1 activation is crucial for the transcriptional induction of Ucp1 in brown adipocytes, and they demonstrate a novel, ER stress -independent role of the UPR during thermogenesis. ..
  30. Wang X, Rao R, Kosakowska Cholody T, Masood M, Southon E, Zhang H, et al. Mitochondrial degeneration and not apoptosis is the primary cause of embryonic lethality in ceramide transfer protein mutant mice. J Cell Biol. 2009;184:143-58 pubmed publisher
    ..Thus, global compromise of ER and mitochondrial integrity caused by ceramide accumulation in CERT mutant mice primarily affects organogenesis rather than causing cell death via apoptotic pathways. ..
  31. Benhamron S, Hadar R, Iwawaky T, So J, Lee A, Tirosh B. Regulated IRE1-dependent decay participates in curtailing immunoglobulin secretion from plasma cells. Eur J Immunol. 2014;44:867-76 pubmed publisher
    ..Interestingly, the IgG1 response is reduced to a similar level in XBP-1 KO, IRE1 KO, and their double knockout animals. Our data demonstrate a specific contribution by RIDD in curtailing immunoglobulin synthesis and secretion. ..
  32. Byrd A, Aragon I, Brewer J. MicroRNA-30c-2* limits expression of proadaptive factor XBP1 in the unfolded protein response. J Cell Biol. 2012;196:689-98 pubmed publisher
  33. Qiu Y, Mao T, Zhang Y, Shao M, You J, Ding Q, et al. A crucial role for RACK1 in the regulation of glucose-stimulated IRE1alpha activation in pancreatic beta cells. Sci Signal. 2010;3:ra7 pubmed publisher
    Autophosphorylation of inositol-requiring enzyme 1alpha (IRE1alpha) is required for its activation, which elicits the cellular unfolded protein response (UPR) and is functionally connected with insulin biosynthesis in pancreatic beta ..
  34. Yang H, Qiu Q, Gao B, Kong S, Lin Z, Fang D. Hrd1-mediated BLIMP-1 ubiquitination promotes dendritic cell MHCII expression for CD4 T cell priming during inflammation. J Exp Med. 2014;211:2467-79 pubmed publisher
    ..We identified Hrd1-mediated BLIMP1 ubiquitination as a previously unknown mechanism in programming DC for CD4(+) T cell activation during inflammation. ..
  35. Murakami T, Hino S, Saito A, Imaizumi K. Endoplasmic reticulum stress response in dendrites of cultured primary neurons. Neuroscience. 2007;146:1-8 pubmed
    ..These results indicate that the ER in dendrites could respond to ER stress and retain the capacity of protein quality control. ..
  36. Li X, Zhang H, Xu Y, Zhang R, Chen Y, Fan L, et al. Knockdown of IRE1α inhibits colonic tumorigenesis through decreasing β-catenin and IRE1α targeting suppresses colon cancer cells. Oncogene. 2017;36:6738-6746 pubmed publisher
    ..We found that the IRE1a-specific inhibitor 4μ8C could suppress the production of β-catenin, inhibited the proliferation of colon ..
  37. Margariti A, Li H, Chen T, Martin D, Vizcay Barrena G, Alam S, et al. XBP1 mRNA splicing triggers an autophagic response in endothelial cells through BECLIN-1 transcriptional activation. J Biol Chem. 2013;288:859-72 pubmed publisher
    ..These results suggest that XBP1 mRNA splicing triggers an autophagic signal pathway through transcriptional regulation of BECLIN-1. ..
  38. Pierre N, Barbé C, Gilson H, Deldicque L, Raymackers J, Francaux M. Activation of ER stress by hydrogen peroxide in C2C12 myotubes. Biochem Biophys Res Commun. 2014;450:459-63 pubmed publisher
    ..The mechanisms by which the three branches of UPR can be specifically regulated by oxidative stress are currently unresolved and need further investigations. ..
  39. Zhang H, Chen Y, Fan L, Xi Q, Wu G, Li X, et al. The Endoplasmic Reticulum Stress Sensor IRE1α in Intestinal Epithelial Cells Is Essential for Protecting against Colitis. J Biol Chem. 2015;290:15327-36 pubmed publisher
    ..These results suggest that IRE1α functions to maintain the intestinal epithelial homeostasis and plays an important role in defending against inflammation bowel diseases. ..
  40. Yan D, Wang H, Bowman R, Joyce J. STAT3 and STAT6 Signaling Pathways Synergize to Promote Cathepsin Secretion from Macrophages via IRE1? Activation. Cell Rep. 2016;16:2914-2927 pubmed publisher
    ..Together, these findings demonstrate that cytokine-activated STAT3 and STAT6 cooperate in macrophages to promote a secretory phenotype that enhances tumor progression in a cathepsin-dependent manner. ..
  41. Auf G, Jabouille A, Guérit S, Pineau R, Delugin M, Bouchecareilh M, et al. Inositol-requiring enzyme 1alpha is a key regulator of angiogenesis and invasion in malignant glioma. Proc Natl Acad Sci U S A. 2010;107:15553-8 pubmed publisher
    ..In a human glioma model, inhibition of IRE1alpha correlated with down-regulation of prevalent proangiogenic factors such as VEGF-A, IL-1beta, IL-6, and IL-8...
  42. Fedeles S, So J, Shrikhande A, Lee S, Gallagher A, Barkauskas C, et al. Sec63 and Xbp1 regulate IRE1α activity and polycystic disease severity. J Clin Invest. 2015;125:1955-67 pubmed publisher
  43. Bujisic B, de Gassart A, Tallant R, Demaria O, Zaffalon L, Chelbi S, et al. Impairment of both IRE1 expression and XBP1 activation is a hallmark of GCB DLBCL and contributes to tumor growth. Blood. 2017;129:2420-2428 pubmed publisher
    ..These findings indicate that IRE1-XBP1 downregulation distinguishes GCB DLBCL from other DLBCL subtypes and contributes to tumor growth. ..
  44. Adolph T, Tomczak M, Niederreiter L, Ko H, Böck J, Martínez Naves E, et al. Paneth cells as a site of origin for intestinal inflammation. Nature. 2013;503:272-6 pubmed publisher
  45. Kitai Y, Ariyama H, Kono N, Oikawa D, Iwawaki T, Arai H. Membrane lipid saturation activates IRE1? without inducing clustering. Genes Cells. 2013;18:798-809 pubmed publisher
    ..Together, these results suggest membrane lipid saturation, and unfolded proteins activate the UPR through different mechanisms. ..
  46. Stan R, Silva R, de Camargo M. Human GRP78 affinity towards its signaling partners Ire1? and PERK is differently modulated by an unfolded protein client. Biochem Biophys Res Commun. 2017;487:375-380 pubmed publisher
    ..These results imply a gated UPR mechanism that tunes the overall cellular behavior to the accumulation of unfolded proteins. ..
  47. Tohmonda T, Yoda M, Mizuochi H, Morioka H, Matsumoto M, Urano F, et al. The IRE1?-XBP1 pathway positively regulates parathyroid hormone (PTH)/PTH-related peptide receptor expression and is involved in pth-induced osteoclastogenesis. J Biol Chem. 2013;288:1691-5 pubmed publisher
    ..Thus, the present study reveals potential involvement of the IRE1?-XBP1 pathway in PTH-induced osteoclastogenesis through the regulation of PTH1R expression. ..
  48. Shum E, Jones S, Shao A, Dumdie J, Krause M, Chan W, et al. The Antagonistic Gene Paralogs Upf3a and Upf3b Govern Nonsense-Mediated RNA Decay. Cell. 2016;165:382-95 pubmed publisher
    ..Mice conditionally lacking UPF3A exhibit "hyper" NMD and display defects in embryogenesis and gametogenesis. Our results support a model in which UPF3A serves as a molecular rheostat that directs developmental events. ..
  49. Hassler J, Scheuner D, Wang S, Han J, Kodali V, Li P, et al. The IRE1α/XBP1s Pathway Is Essential for the Glucose Response and Protection of β Cells. PLoS Biol. 2015;13:e1002277 pubmed publisher
    ..The results demonstrate that glucose activates IRE1α-mediated Xbp1 splicing to expand the secretory capacity of the β cell for increased proinsulin synthesis and to limit oxidative stress that leads to β cell failure. ..
  50. Pierre N, Fernández Verdejo R, Regnier P, Vanmechelen S, Demeulder B, Francaux M. IRE1α and TRB3 do not contribute to the disruption of proximal insulin signaling caused by palmitate in C2C12 myotubes. Cell Biol Int. 2016;40:91-9 pubmed publisher
    ..Knocking down TRB3 or IRE1α did not prevent the inhibitory effect of palmitate on Akt phosphorylation. Our results support the idea that ER stress is not responsible for lipid-induced IR in C2C12 myotubes. ..
  51. Homma T, Fujii J. Heat stress promotes the down-regulation of IRE1? in cells: An atypical modulation of the UPR pathway. Exp Cell Res. 2016;349:128-138 pubmed publisher
    ..These collective results suggest that heat stress simultaneously activates both the UPR and autophagy, followed by the activation of a negative feedback system in UPR by modulating the responses related to the IRE1?-XBP-1 axis. ..
  52. Xiao Y, Xia T, Yu J, Deng Y, Liu H, Liu B, et al. Knockout of inositol-requiring enzyme 1? in pro-opiomelanocortin neurons decreases fat mass via increasing energy expenditure. Open Biol. 2016;6: pubmed publisher
    ..Our results also suggest that IRE1? is not only an endoplasmic reticulum stress sensor, but also a new potential therapeutic target for obesity and obesity-related metabolic diseases. ..
  53. Yang Q, Kim Y, Lin Y, Lewis J, Neckers L, Liu Z. Tumour necrosis factor receptor 1 mediates endoplasmic reticulum stress-induced activation of the MAP kinase JNK. EMBO Rep. 2006;7:622-7 pubmed
    ..We also found that TNFR1 functions downstream of IRE1 and that IRE1 is present in the same complex with TNFR1 under ER stress condition. Therefore, our study shows a novel role of TNFR1 in mediating ER stress-induced JNK activation. ..
  54. Shan B, Wang X, Wu Y, Xu C, Xia Z, Dai J, et al. The metabolic ER stress sensor IRE1α suppresses alternative activation of macrophages and impairs energy expenditure in obesity. Nat Immunol. 2017;18:519-529 pubmed publisher
    ..Myeloid-specific IRE1α abrogation in Ern1f/f; Lyz2-Cre mice largely reversed high-fat diet (HFD)-induced M1-M2 imbalance in white adipose tissue (..
  55. Mao T, Shao M, Qiu Y, Huang J, Zhang Y, Song B, et al. PKA phosphorylation couples hepatic inositol-requiring enzyme 1alpha to glucagon signaling in glucose metabolism. Proc Natl Acad Sci U S A. 2011;108:15852-7 pubmed publisher
    ..Hence, these results suggest that IRE1? integrates signals from both the ER lumen and the cytoplasm in the liver and is coupled to the glucagon signaling in the regulation of glucose metabolism. ..
  56. Mann M, Pereira E, Liao N, Hendershot L. UPR-induced resistance to etoposide is downstream of PERK and independent of changes in topoisomerase II? levels. PLoS ONE. 2012;7:e47931 pubmed publisher
  57. Luo D, He Y, Zhang H, Yu L, Chen H, Xu Z, et al. AIP1 is critical in transducing IRE1-mediated endoplasmic reticulum stress response. J Biol Chem. 2008;283:11905-12 pubmed publisher
    ..More importantly, AIP1-KO mice show impaired ER stress-induced IRE1-dependent signaling in vivo. We conclude that AIP1 is essential for transducing the IRE1-mediated ER stress response. ..
  58. Qiu Q, Zheng Z, Chang L, Zhao Y, Tan C, Dandekar A, et al. Toll-like receptor-mediated IRE1? activation as a therapeutic target for inflammatory arthritis. EMBO J. 2013;32:2477-90 pubmed publisher
  59. Xue Z, He Y, Ye K, Gu Z, Mao Y, Qi L. A conserved structural determinant located at the interdomain region of mammalian inositol-requiring enzyme 1alpha. J Biol Chem. 2011;286:30859-66 pubmed publisher
    ..Our finding may facilitate the identification of small molecules to compromise IRE1? function specifically. ..
  60. Wang J, Qiu Y, Yang Z, Li L, Zhang K. Inositol-Requiring Enzyme 1 Facilitates Diabetic Wound Healing Through Modulating MicroRNAs. Diabetes. 2017;66:177-192 pubmed publisher
    ..In conclusion, our studies revealed a novel mechanistic basis for rescuing angiogenesis and tissue repair in diabetic wound treatments. ..
  61. So J, Cho S, Min S, Kimball S, Lee A. IRE1α-Dependent Decay of CReP/Ppp1r15b mRNA Increases Eukaryotic Initiation Factor 2α Phosphorylation and Suppresses Protein Synthesis. Mol Cell Biol. 2015;35:2761-70 pubmed publisher
    ..Taken together, the results of our study reveal a novel function of IRE1α in the regulation of eIF2α phosphorylation and the translational control. ..
  62. Yao T, Deng Z, Gao Y, Sun J, Kong X, Huang Y, et al. Ire1α in Pomc Neurons Is Required for Thermogenesis and Glycemia. Diabetes. 2017;66:663-673 pubmed publisher
    ..Together, the current studies extend and confirm conclusions that Ire1α-Xbp1s and associated molecular targets link ER stress in arcuate Pomc neurons to aspects of normal energy and glucose homeostasis. ..
  63. Mendez A, Alfaro J, Morales Soto M, Dar A, McCullagh E, Gotthardt K, et al. Endoplasmic reticulum stress-independent activation of unfolded protein response kinases by a small molecule ATP-mimic. elife. 2015;4: pubmed publisher
    ..The mechanism by which partial occupancy with an inhibitor can activate kinases may be wide-spread and carries major implications for design and therapeutic application of kinase inhibitors. ..
  64. Hiramatsu N, Chiang W, Kurt T, Sigurdson C, Lin J. Multiple Mechanisms of Unfolded Protein Response-Induced Cell Death. Am J Pathol. 2015;185:1800-8 pubmed publisher
    ..In mammalian cells, three ER transmembrane proteins, inositol-requiring enzyme-1 (IRE1; official name ERN1), PKR-like ER kinase (PERK; official name EIF2AK3), and activating transcription factor-6, control the UPR...
  65. Sun S, Shi G, Sha H, Ji Y, Han X, Shu X, et al. IRE1α is an endogenous substrate of endoplasmic-reticulum-associated degradation. Nat Cell Biol. 2015;17:1546-55 pubmed publisher
    ..Hence, Sel1L-Hrd1 ERAD serves a distinct, essential function in restraint of IRE1α signalling in vivo by managing its protein turnover. ..
  66. Pena J, Harris E. Dengue virus modulates the unfolded protein response in a time-dependent manner. J Biol Chem. 2011;286:14226-36 pubmed publisher
    ..These results demonstrate that time-dependent activation of the unfolded protein response by DENV-2 can override inhibition of translation, prevent apoptosis, and prolong the viral life cycle. ..
  67. Sanches M, Duffy N, Talukdar M, Thevakumaran N, Chiovitti D, Canny M, et al. Structure and mechanism of action of the hydroxy-aryl-aldehyde class of IRE1 endoribonuclease inhibitors. Nat Commun. 2014;5:4202 pubmed publisher
    ..These studies lay the foundation for understanding both the biochemical and cellular functions of IRE1α using small molecule inhibitors and suggest new avenues for inhibitor design. ..
  68. Gomez J, Rutkowski D. Experimental reconstitution of chronic ER stress in the liver reveals feedback suppression of BiP mRNA expression. elife. 2016;5: pubmed publisher
  69. Yang L, Xue Z, He Y, Sun S, Chen H, Qi L. A Phos-tag-based approach reveals the extent of physiological endoplasmic reticulum stress. PLoS ONE. 2010;5:e11621 pubmed publisher
    ..Our study may pave the foundation for future studies on physiological UPR, aid in the diagnosis of ER-associated diseases and improve and facilitate therapeutic strategies targeting UPR in vivo. ..
  70. Oikawa D, Akai R, Iwawaki T. Positive contribution of the IRE1alpha-XBP1 pathway to placental expression of CEA family genes. FEBS Lett. 2010;584:1066-70 pubmed publisher
    Inositol requiring enzyme-1alpha (IRE1alpha) is an ER-located transmembrane RNase whose activation leads to the production of the transcription factor X-box binding protein 1 (XBP1)...
  71. Qi Y, Wang W, Chen J, Dai L, Kaczorowski D, Gao X, et al. Sphingosine Kinase 1 Protects Hepatocytes from Lipotoxicity via Down-regulation of IRE1α Protein Expression. J Biol Chem. 2015;290:23282-90 pubmed publisher
    ..Therefore, this study provides new insights into the role of SphK1 in hepatocyte survival and uncovers a novel mechanism for protection against ER stress-mediated cell death. ..
  72. Tohmonda T, Yoda M, Iwawaki T, Matsumoto M, Nakamura M, Mikoshiba K, et al. IRE1α/XBP1-mediated branch of the unfolded protein response regulates osteoclastogenesis. J Clin Invest. 2015;125:3269-79 pubmed publisher
    ..The present study thus reveals an intracellular pathway that integrates the UPR and osteoclast differentiation through activation of the IRE1α/XBP1 pathway. ..
  73. Kanekura K, Ma X, Murphy J, Zhu L, Diwan A, Urano F. IRE1 prevents endoplasmic reticulum membrane permeabilization and cell death under pathological conditions. Sci Signal. 2015;8:ra62 pubmed publisher
    ..Our results reveal a role for IRE1 in preventing a cell death-initializing step that emanates from the ER and provide a potential target for treating diseases characterized by ER stress, including diabetes and Wolfram syndrome. ..
  74. Cunha D, Igoillo Esteve M, Gurzov E, Germano C, Naamane N, Marhfour I, et al. Death protein 5 and p53-upregulated modulator of apoptosis mediate the endoplasmic reticulum stress-mitochondrial dialog triggering lipotoxic rodent and human β-cell apoptosis. Diabetes. 2012;61:2763-75 pubmed publisher
    ..This study elucidates the crosstalk between lipotoxic ER stress and the mitochondrial pathway of apoptosis that causes β-cell death in diabetes. ..
  75. Binet F, Mawambo G, Sitaras N, Tétreault N, Lapalme E, Favret S, et al. Neuronal ER stress impedes myeloid-cell-induced vascular regeneration through IRE1? degradation of netrin-1. Cell Metab. 2013;17:353-71 pubmed publisher
    ..Degradation of netrin-1, by persistent neuronal ER stress, thereby hinders vascular regeneration. These data identify a neuronal-immune mechanism that directly regulates reparative angiogenesis. ..
  76. Li F, Guo Y, Sun S, Jiang X, Tang B, Wang Q, et al. Free cholesterol-induced macrophage apoptosis is mediated by inositol-requiring enzyme 1 alpha-regulated activation of Jun N-terminal kinase. Acta Biochim Biophys Sin (Shanghai). 2008;40:226-34 pubmed
    ..Inositol-requiring enzyme 1 alpha (IRE1alpha) is an integral membrane protein of the ER that is a key signaling step in cholesterol-induced apoptosis in ..
  77. Kim S, Joe Y, Kim H, Kim Y, Jeong S, Pae H, et al. Endoplasmic reticulum stress-induced IRE1α activation mediates cross-talk of GSK-3β and XBP-1 to regulate inflammatory cytokine production. J Immunol. 2015;194:4498-506 pubmed publisher
    ..These results have important implications in the regulation of inflammatory pathways during ER stress, and they suggest novel therapeutic targets for diseases in which meta-inflammation plays a key role. ..
  78. Osorio F, Tavernier S, Hoffmann E, Saeys Y, Martens L, Vetters J, et al. The unfolded-protein-response sensor IRE-1? regulates the function of CD8?+ dendritic cells. Nat Immunol. 2014;15:248-57 pubmed publisher
    ..Thus, a precisely regulated feedback circuit involving IRE-1? and XBP-1 controls the homeostasis of CD8?+ conventional DCs. ..
  79. Han J, Murthy R, Wood B, Song B, Wang S, Sun B, et al. ER stress signalling through eIF2? and CHOP, but not IRE1?, attenuates adipogenesis in mice. Diabetologia. 2013;56:911-24 pubmed publisher
    ..In contrast to the eIF2?-CHOP pathway, activation or deletion of Ire1a (also known as Ern1) did not alter adipocyte differentiation in 3T3-L1 cells...