The Structure, Activation and Signaling of IRE1 and Its Role in Determining Cell Fate

Sun, 2019, Protein quality control in the secretory pathway, J. Cell Biol., 218, 3171, 10.1083/jcb.201906047

Chino, 2020, ER-Phagy: Quality Control and Turnover of Endoplasmic Reticulum, Trends Cell Biol., 30, 384, 10.1016/j.tcb.2020.02.001

Oakes, 2015, The role of endoplasmic reticulum stress in human pathology, Annu. Rev. Pathol. Mech. Dis., 10, 173, 10.1146/annurev-pathol-012513-104649

Hiramatsu, 2015, Multiple Mechanisms of Unfolded Protein Response-Induced Cell Death, Am. J. Pathol., 185, 1800, 10.1016/j.ajpath.2015.03.009

Lin, J.H., Li, H., Zhang, Y., Ron, D., and Walter, P. (2009). Divergent effects of PERK and IRE1 signaling on cell viability. PLoS ONE, 4.

Tavernier, 2018, Regulation of IRE1 RNase activity by the Ribonuclease inhibitor 1 (RNH1), Cell Cycle, 17, 1901, 10.1080/15384101.2018.1506655

Acosta-Alvear, D., Karagöz, G.E., Fröhlich, F., Li, H., Walther, T.C., and Walter, P. (2018). The unfolded protein response and endoplasmic reticulum protein targeting machineries converge on the stress sensor IRE1. Elife, 7.

Poothong, 2010, Domain compatibility in Ire1 kinase is critical for the unfolded protein response, FEBS Lett., 584, 3203, 10.1016/j.febslet.2010.06.003

Belyy, 2020, Quantitative microscopy reveals dynamics and fate of clustered IRE1α, Proc. Natl. Acad. Sci. USA, 117, 1533, 10.1073/pnas.1915311117

Tavernier, 2017, Regulated IRE1-dependent mRNA decay sets the threshold for dendritic cell survival, Nat. Cell Biol., 19, 698, 10.1038/ncb3518

Sozen, 2020, Cholesterol induced autophagy via IRE1/JNK pathway promotes autophagic cell death in heart tissue, Metabolism, 106, 154205, 10.1016/j.metabol.2020.154205

Szegezdi, 2006, Mediators of endoplasmic reticulum stress-induced apoptosis, EMBO Rep., 7, 880, 10.1038/sj.embor.7400779

Hamanaka, 2005, PERK and GCN2 contribute to eIF2α phosphorylation and cell cycle arrest after activation of the unfolded protein response pathway, Mol. Biol. Cell, 16, 5493, 10.1091/mbc.e05-03-0268

Marciniak, 2006, Activation-dependent substrate recruitment by the eukaryotic translation initiation factor 2 kinase PERK, J. Cell Biol., 172, 201, 10.1083/jcb.200508099

Harding, 2003, An integrated stress response regulates amino acid metabolism and resistance to oxidative stress, Mol. Cell, 11, 619, 10.1016/S1097-2765(03)00105-9

Su, 2008, C/EBP homology protein (CHOP) interacts with activating transcription factor 4 (ATF4) and negatively regulates the stress-dependent induction of the asparagine synthetase gene, J. Biol. Chem., 283, 35106, 10.1074/jbc.M806874200

Ye, 2000, ER stress induces cleavage of membrane-bound ATF6 by the same proteases that process SREBPs, Mol. Cell, 6, 1355, 10.1016/S1097-2765(00)00133-7

Lee, 2003, XBP-1 Regulates a Subset of Endoplasmic Reticulum Resident Chaperone Genes in the Unfolded Protein Response, Mol. Cell. Biol., 23, 7448, 10.1128/MCB.23.21.7448-7459.2003

Huang, 2017, The requirement of IRE1 and XBP1 in resolving physiological stress during Drosophila development, J. Cell Sci., 130, 3040, 10.1242/jcs.203612

Tsuchiya, 2018, IRE1-XBP1 pathway regulates oxidative proinsulin folding in pancreatic β cells, J. Cell Biol., 217, 1287, 10.1083/jcb.201707143

Calfon, 2002, IRE1 couples endoplasmic reticulum load to secretory capacity by processing the XBP-1 mRNA, Nature, 415, 92, 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., and Gutierrez, S. (2019). IRE1α-XBP1 signaling in leukocytes controls prostaglandin biosynthesis and pain. Science, 365.

Hetz, 2017, ER stress and the unfolded protein response in neurodegeneration, Nat. Rev. Neurol., 13, 477, 10.1038/nrneurol.2017.99

Zhao, 2018, Pharmacological targeting of MYC-regulated IRE1/XBP1 pathway suppresses MYC-driven breast cancer, J. Clin. Investig., 128, 1283, 10.1172/JCI95873

Lin, 2019, Cancer and ER stress: Mutual crosstalk between autophagy, oxidative stress and inflammatory response, Biomed. Pharmacother., 118, 109249, 10.1016/j.biopha.2019.109249

Rozpędek-Kamińska, W., Siwecka, N., Wawrzynkiewicz, A., Wojtczak, R., Pytel, D., Diehl, J.A., and Majsterek, I. (2020). The PERK-Dependent Molecular Mechanisms as a Novel Therapeutic Target for Neurodegenerative Diseases. Int. J. Mol. Sci., 21.

Xiang, 2017, The role of endoplasmic reticulum stress in neurodegenerative disease, Apoptosis, 22, 1, 10.1007/s10495-016-1296-4

Szpigel, 2018, Lipid environment induces ER stress, TXNIP expression and inflammation in immune cells of individuals with type 2 diabetes, Diabetologia, 61, 399, 10.1007/s00125-017-4462-5

Jin, 2019, Development of a Rapid in vivo Assay to Evaluate the Efficacy of IRE1-specific Inhibitors of the Unfolded Protein Response Using Medaka Fish, Cell Struct. Funct., 45, 23, 10.1247/csf.19032

Rosen, D.A., Seki, S.M., Fernández-Castañeda, A., Beiter, R.M., Eccles, J.D., Woodfolk, J.A., and Gaultier, A. (2019). Modulation of the sigma-1 receptor-IRE1 pathway is beneficial in preclinical models of inflammation and sepsis. Sci. Transl. Med., 11.

Tufanli, 2017, Targeting IRE1 with small molecules counteracts progression of atherosclerosis, Proc. Natl. Acad. Sci. USA, 114, E1395, 10.1073/pnas.1621188114

Doultsinos, D., Carlesso, A., Chintha, C., Paton, J.C., Paton, A.W., Samali, A., Chevet, E., and Eriksson, L.A. (2020). Peptidomimetic-based identification of FDA-approved compounds inhibiting IRE1 activity. FEBS J.

Adams, 2019, Structure and molecular mechanism of ER stress signaling by the unfolded protein response signal activator IRE1, Front. Mol. Biosci., 6, 11, 10.3389/fmolb.2019.00011

Wu, 2016, IRE1α signaling pathways involved in mammalian cell fate determination, Cell. Physiol. Biochem., 38, 847, 10.1159/000443039

Shemorry, A., Harnoss, J.M., Guttman, O., Marsters, S.A., Kőműves, L.G., Lawrence, D.A., and Ashkenazi, A. (2019). Caspase-mediated cleavage of IRE1 controls apoptotic cell commitment during endoplasmic reticulum stress. Elife, 8.

Yoshida, 2001, XBP1 mRNA is induced by ATF6 and spliced by IRE1 in response to ER stress to produce a highly active transcription factor, Cell, 107, 881, 10.1016/S0092-8674(01)00611-0

Tsuru, 2016, Novel mechanism of enhancing IRE1α-XBP1 signalling via the PERK-ATF4 pathway, Sci. Rep., 6, 24217, 10.1038/srep24217

Lee, 2002, IRE1-mediated unconventional mRNA splicing and S2P-mediated ATF6 cleavage merge to regulate XBP1 in signaling the unfolded protein response, Genes Dev., 16, 452, 10.1101/gad.964702

Hampton, 2003, IRE1: A role in UPREgulation of ER degradation, Dev. Cell, 4, 144, 10.1016/S1534-5807(03)00032-7

Walter, 2018, ER stress signaling has an activating transcription factor 6 (ATF6)-dependent “off-switch”, J. Biol. Chem., 293, 18270, 10.1074/jbc.RA118.002121

Saraswat Ohri, S., Howard, R.M., Liu, Y., Andres, K.R., Shepard, C.T., Hetman, M., and Whittemore, S.R. (2020). Oligodendrocyte-specific deletion of Xbp1 exacerbates the endoplasmic reticulum stress response and restricts locomotor recovery after thoracic spinal cord injury. Glia, 69.

Lin, 2007, IRE1 signaling affects cell fate during the unfolded protein response, Science, 318, 944, 10.1126/science.1146361

Chang, 2018, Coordination between Two Branches of the Unfolded Protein Response Determines Apoptotic Cell Fate, Mol. Cell, 71, 629, 10.1016/j.molcel.2018.06.038

Moore, 2015, Ire1-mediated decay in mammalian cells relies on mRNA sequence, structure, and translational status, Mol. Biol. Cell, 26, 2873, 10.1091/mbc.E15-02-0074

Walter, 2015, Imaging of single cell responses to ER stress indicates that the relative dynamics of IRE1/XBP1 and PERK/ATF4 signalling rather than a switch between signalling branches determine cell survival, Cell Death Differ., 22, 1502, 10.1038/cdd.2014.241

Sureda, A., Alizadeh, J., Nabavi, S.F., Berindan-Neagoe, I., Cismaru, C.A., Jeandet, P., Łos, M.J., Clementi, E., Nabavi, S.M., and Ghavami, S. (2020). Endoplasmic reticulum as a potential therapeutic target for covid-19 infection management?. Eur. J. Pharmacol., 882.

Versteeg, 2007, The Coronavirus Spike Protein Induces Endoplasmic Reticulum Stress and Upregulation of Intracellular Chemokine mRNA Concentrations, J. Virol., 81, 10981, 10.1128/JVI.01033-07

Bechill, 2008, Coronavirus Infection Modulates the Unfolded Protein Response and Mediates Sustained Translational Repression, J. Virol., 82, 4492, 10.1128/JVI.00017-08

Chan, 2006, Modulation of the Unfolded Protein Response by the Severe Acute Respiratory Syndrome Coronavirus Spike Protein, J. Virol., 80, 9279, 10.1128/JVI.00659-06

Sicari, 2020, Role of the early secretory pathway in SARS-CoV-2 Infection, J. Cell Biol., 219, e202006005, 10.1083/jcb.202006005

Fung, 2019, The ER stress sensor IRE1 and MAP kinase ERK modulate autophagy induction in cells infected with coronavirus infectious bronchitis virus, Virology, 533, 34, 10.1016/j.virol.2019.05.002

Fung, 2014, The Endoplasmic Reticulum Stress Sensor IRE1 Protects Cells from Apoptosis Induced by the Coronavirus Infectious Bronchitis Virus, J. Virol., 88, 12752, 10.1128/JVI.02138-14

Saunders, 2017, A J-Protein Co-chaperone Recruits BiP to Monomerize IRE1 and Repress the Unfolded Protein Response, Cell, 171, 1625, 10.1016/j.cell.2017.10.040

Neidhardt, 2019, Unstructured regions in IRE1α specify BiP-mediated destabilisation of the luminal domain dimer and repression of the UPR, Elife, 8, e50793, 10.7554/eLife.50793

Walter, P., and Ron, D. (2011). The Unfolded Protein Response: From Stress Pathway to Homeostatic Regulation, American Association for the Advancement of Science.

Kopp, 2018, In vitro FRET analysis of IRE1 and BiP association and dissociation upon endoplasmic reticulum stress, Elife, 7, e30257, 10.7554/eLife.30257

Nguyen, 2017, An unfolded protein-induced conformational switch activates mammalian IRE1, Elife, 6, e30700, 10.7554/eLife.30700

Preissler, S., and Ron, D. (2019). Early events in the endoplasmic reticulum unfolded protein response. Cold Spring Harb. Perspect. Biol., 11.

Wang, 2018, The luminal domain of the ER stress sensor protein PERK binds misfolded proteins and thereby triggers PERK oligomerization, J. Biol. Chem., 293, 4110, 10.1074/jbc.RA117.001294

Oikawa, 2009, Activation of mammalian IRE1α upon ER stress depends on dissociation of BiP rather than on direct interaction with unfolded proteins, Exp. Cell Res., 315, 2496, 10.1016/j.yexcr.2009.06.009

Halbleib, 2017, Activation of the Unfolded Protein Response by Lipid Bilayer Stress, Mol. Cell, 67, 673, 10.1016/j.molcel.2017.06.012

Pytel, 2012, PERK Utilizes Intrinsic Lipid Kinase Activity To Generate Phosphatidic Acid, Mediate Akt Activation, and Promote Adipocyte Differentiation, Mol. Cell. Biol., 32, 2268, 10.1128/MCB.00063-12

Nagai, 2009, USP14 inhibits ER-associated degradation via interaction with IRE1α, Biochem. Biophys. Res. Commun., 379, 995, 10.1016/j.bbrc.2008.12.182

Lee, 2008, Structure of the Dual Enzyme Ire1 Reveals the Basis for Catalysis and Regulation in Nonconventional RNA Splicing, Cell, 132, 89, 10.1016/j.cell.2007.10.057

Yang, 2016, Structural Insights into IRE1 Functions in the Unfolded Protein Response, Curr. Med. Chem., 23, 4706, 10.2174/0929867323666160927142349

Joshi, 2015, Molecular mechanisms of human IRE1 activation through dimerization and ligand binding, Oncotarget, 6, 13019, 10.18632/oncotarget.3864

Zhou, 2006, The crystal structure of human IRE1 luminal domain reveals a conserved dimerization interface required for activation of the unfolded protein response, Proc. Natl. Acad. Sci. USA, 103, 14343, 10.1073/pnas.0606480103

Afzal, 2008, Plant receptor-like serine threonine kinases: Roles in signaling and plant defense, Mol. Plant Microbe Interact., 21, 507, 10.1094/MPMI-21-5-0507

Liu, 2002, The protein kinase/endoribonuclease IRE1α that signals the unfolded protein response has a luminal N-terminal ligand-independent dimerization domain, J. Biol. Chem., 277, 18346, 10.1074/jbc.M112454200

Cho, 2019, Intrinsic Structural Features of the Human IRE1α Transmembrane Domain Sense Membrane Lipid Saturation, Cell Rep., 27, 307, 10.1016/j.celrep.2019.03.017

Carlesso, A., Chintha, C., Gorman, A.M., Samali, A., and Eriksson, L.A. (2019). Effect of Kinase Inhibiting RNase Attenuator (KIRA) Compounds on the Formation of Face-to-Face Dimers of Inositol-Requiring Enzyme 1: Insights from Computational Modeling. Int. J. Mol. Sci., 20.

Ali, 2011, Structure of the Ire1 autophosphorylation complex and implications for the unfolded protein response, EMBO J., 30, 894, 10.1038/emboj.2011.18

Liu, 2003, Structure and intermolecular interactions of the luminal dimerization domain of human IRE1α, J. Biol. Chem., 278, 17680, 10.1074/jbc.M300418200

Feldman, 2016, Structural and Functional Analysis of the Allosteric Inhibition of IRE1α with ATP-Competitive Ligands, ACS Chem. Biol., 11, 2195, 10.1021/acschembio.5b00940

Prischi, 2014, Phosphoregulation of Ire1 RNase splicing activity, Nat. Commun., 5, 1

Tirasophon, 2000, The endoribonuclease activity of mammalian IRE1 autoregulates its mRNA and is required for the unfolded protein response, Genes Dev., 14, 2725, 10.1101/gad.839400

Korennykh, 2009, The unfolded protein response signals through high-order assembly of Ire1, Nature, 457, 687, 10.1038/nature07661

Itzhak, D., Bright, M., McAndrew, P., Mirza, A., Newbatt, Y., Strover, J., Widya, M., Thompson, A., Morgan, G., and Collins, I. (2014). Multiple autophosphorylations significantly enhance the endoribonuclease activity of human inositol requiring enzyme 1α. BMC Biochem., 15.

Li, 2010, Mammalian endoplasmic reticulum stress sensor IRE1 signals by dynamic clustering, Proc. Natl. Acad. Sci. USA, 107, 16113, 10.1073/pnas.1010580107

Tam, 2014, Ire1 has distinct catalytic mechanisms for XBP1/HAC1 splicing and RIDD, Cell Rep., 9, 850, 10.1016/j.celrep.2014.09.016

Ricci, 2019, Clustering of IRE1α depends on sensing ER stress but not on its RNase activity, FASEB J., 33, 9811, 10.1096/fj.201801240RR

Zhang, L., Zhang, C., and Wang, A. (2016). Divergence and Conservation of the Major UPR Branch IRE1-bZIP Signaling Pathway across Eukaryotes. Sci. Rep., 6.

Yoshida, 2006, pXBP1(U) encoded in XBP1 pre-mRNA negatively regulates unfolded protein response activator pXBP1(S) in mammalian ER stress response, J. Cell Biol., 172, 565, 10.1083/jcb.200508145

Kanemoto, 2005, XBP1 activates the transcription of its target genes via an ACGT core sequence under ER stress, Biochem. Biophys. Res. Commun., 331, 1146, 10.1016/j.bbrc.2005.04.039

Yoshida, 2007, Unconventional splicing of XBP-1 mRNA in the unfolded protein response, Antioxid. Redox Signal., 9, 2323, 10.1089/ars.2007.1800

Coelho, D.S., Gaspar, C.J., and Domingos, P.M. (2014). Ire1 mediated mRNA splicing in a C-terminus deletion mutant of drosophila Xbp1. PLoS ONE, 9.

Sung, 2006, Cytoplasmic IRE1α-mediated XBP1 mRNA splicing in the absence of nuclear processing and endoplasmic reticulum stress, J. Biol. Chem., 281, 18691, 10.1074/jbc.M602030200

Iwawaki, 2006, Analysis of the XBP1 splicing mechanism using endoplasmic reticulum stress-indicators, Biochem. Biophys. Res. Commun., 350, 709, 10.1016/j.bbrc.2006.09.100

Wang, 2015, Acute endoplasmic reticulum stress-independent unconventional splicing of XBP1 mRNA in the nucleus of mammalian cells, Int. J. Mol. Sci., 16, 13302, 10.3390/ijms160613302

Hollien, 2009, Regulated Ire1-dependent decay of messenger RNAs in mammalian cells, J. Cell Biol., 186, 323, 10.1083/jcb.200903014

Maurel, 2014, Getting RIDD of RNA: IRE1 in cell fate regulation, Trends Biochem. Sci., 39, 245, 10.1016/j.tibs.2014.02.008

Oikawa, 2010, Identification of a consensus element recognized and cleaved by IRE1α, Nucleic Acids Res., 38, 6265, 10.1093/nar/gkq452

Coelho, D.S., and Domingos, P.M. (2014). Physiological roles of regulated Ire1 dependent decay. Front. Genet., 5.

Chen, 2013, IRE1: ER stress sensor and cell fate executor, Trends Cell Biol., 23, 547, 10.1016/j.tcb.2013.06.005

Iurlaro, 2016, Cell death induced by endoplasmic reticulum stress, FEBS J., 283, 2640, 10.1111/febs.13598

Urano, 2000, Coupling of stress in the ER to activation of JNK protein kinases by transmembrane protein kinase IRE1, Science, 287, 664, 10.1126/science.287.5453.664

Saveljeva, 2015, Endoplasmic reticulum stress induces ligand-independent TNFR1-mediated necroptosis in L929 cells, Cell Death Dis., 6, e1587, 10.1038/cddis.2014.548

Sano, 2013, ER stress-induced cell death mechanisms, Biochim. Biophys. Acta Mol. Cell Res., 1833, 3460, 10.1016/j.bbamcr.2013.06.028

Kanekura, 2015, IRE1 prevents endoplasmic reticulum membrane permeabilization and cell death under pathological conditions, Sci. Signal., 8, ra62, 10.1126/scisignal.aaa0341

Brown, 2016, An initial phase of JNK activation inhibits cell death early in the endoplasmic reticulum stress response, J. Cell Sci., 129, 2317, 10.1242/jcs.179127

Treiber, 2013, Ins and outs of kinase DFG motifs, Chem. Biol., 20, 745, 10.1016/j.chembiol.2013.06.001

Grandjean, 2020, Small molecule strategies to harness the unfolded protein response: Where do we go from here?, J. Biol. Chem., 295, 15692, 10.1074/jbc.REV120.010218

Wang, 2012, Divergent allosteric control of the IRE1α endoribonuclease using kinase inhibitors, Nat. Chem. Biol., 8, 982, 10.1038/nchembio.1094

Tomasio, 2013, Selective inhibition of the unfolded protein response: Targeting catalytic sites for Schiff base modification, Mol. Biosyst., 9, 2408, 10.1039/c3mb70234k

Medinas, D.B., González, J.V., Falcon, P., and Hetz, C. (2017). Fine-tuning ER stress signal transducers to treat amyotrophic lateral sclerosis. Front. Mol. Neurosci., 10.

Thakur, 2018, Inhibition of endoplasmic-reticulum-stress-mediated autophagy enhances the effectiveness of chemotherapeutics on pancreatic cancer, J. Transl. Med., 16, 190, 10.1186/s12967-018-1562-z

Mendez, 2015, Endoplasmic reticulum stress-independent activation of unfolded protein response kinases by a small molecule ATP-mimic, Elife, 4, e05434, 10.7554/eLife.05434

Feldman, 2019, Development of a Chemical Toolset for Studying the Paralog-Specific Function of IRE1, ACS Chem. Biol., 14, 2595, 10.1021/acschembio.9b00482

Ghosh, 2014, Allosteric inhibition of the IRE1α RNase preserves cell viability and function during endoplasmic reticulum stress, Cell, 158, 534, 10.1016/j.cell.2014.07.002

Kolpikova, E.P., Tronco, A.R., Den Hartigh, A.B., Jackson, K.J., Iwawaki, T., and Fink, S.L. (2020). IRE1α promotes zika virus infection via XBP1. Viruses, 12.

Chang, 2018, Phosphorylation of IRE1 at S729 regulates RIDD in B cells and antibody production after immunization, J. Cell Biol., 217, 1739, 10.1083/jcb.201709137

Mahameed, M., Wilhelm, T., Darawshi, O., Obiedat, A., Tommy, W.S., Chintha, C., Schubert, T., Samali, A., Chevet, E., and Eriksson, L.A. (2019). The unfolded protein response modulators GSK2606414 and KIRA6 are potent KIT inhibitors. Cell Death Dis., 10.

Thamsen, M., Ghosh, R., Auyeung, V.C., Brumwell, A., Chapman, H.A., Backes, B.J., Perara, G., Maly, D.J., Sheppard, D., and Papa, F.R. (2019). Small molecule inhibition of IRE1α kinase/ RNase has anti-fibrotic effects in the lung. PLoS ONE, 14.

Harrington, 2015, Unfolded protein response in cancer: IRE1α inhibition by selective kinase ligands does not impair tumor cell viability, ACS Med. Chem. Lett., 6, 68, 10.1021/ml500315b

Harnoss, 2019, Disruption of IRE1α through its kinase domain attenuates multiple myeloma, Proc. Natl. Acad. Sci. USA, 116, 16420, 10.1073/pnas.1906999116

Volkmann, 2011, Potent and selective inhibitors of the inositol-requiring enzyme 1 endoribonuclease, J. Biol. Chem., 286, 12743, 10.1074/jbc.M110.199737

Chien, 2014, Selective inhibition of unfolded protein response induces apoptosis in pancreatic cancer cells, Oncotarget, 5, 4881, 10.18632/oncotarget.2051

Cross, B.C.S., Bond, P.J., Sadowski, P.G., Jha, B.K., Zak, J., Goodman, J.M., Silverman, R.H., Neubert, T.A., Baxendale, I.R., and Ron, D. (2012). The molecular basis for selective inhibition of unconventional mRNA splicing by an IRE1-binding small molecule. Proc. Natl. Acad. Sci. USA, 109.

Stewart, 2017, Regulation of IRE1α by the small molecule inhibitor 4μ8c in hepatoma cells, Endoplasmic Reticulum Stress Dis., 4, 1, 10.1515/ersc-2017-0001

Zhang, 2020, The UPR Transducer IRE1 Promotes Breast Cancer Malignancy by Degrading Tumor Suppressor microRNAs, iScience, 23, 101503, 10.1016/j.isci.2020.101503

Zhang, L., Nosak, C., Sollazzo, P., Odisho, T., and Volchuk, A. (2014). IRE1 inhibition perturbs the unfolded protein response in a pancreatic β-cell line expressing mutant proinsulin, but does not sensitize the cells to apoptosis. BMC Cell Biol., 15.

Chan, 2018, The inositol-requiring enzyme 1 (IRE1α) RNAse inhibitor, 4m8C, is also a potent cellular antioxidant, Biochem. J., 475, 923, 10.1042/BCJ20170678

Masouleh, B.K., Geng, H., Hurtz, C., Chan, L.N., Logan, A.C., Chang, M.S., Huang, C., Swaminathan, S., Sun, H., and Paietta, E. (2014). Mechanistic rationale for targeting the unfolded protein response in pre-B acute lymphoblastic leukemia. Proc. Natl. Acad. Sci. USA, 111.

Sun, 2016, Inhibition of IRE1α-driven pro-survival pathways is a promising therapeutic application in acute myeloid leukemia, Oncotarget, 7, 18736, 10.18632/oncotarget.7702

Papandreou, 2011, Identification of an Ire1alpha endonuclease specific inhibitor with cytotoxic activity against human multiple myeloma, Blood, 117, 1311, 10.1182/blood-2010-08-303099

Deck, 2020, Testing Inhibitory Drugs of the Human UPR Sensor IRE1 on Aspergillus fumigatus, FASEB J., 34, 1, 10.1096/fasebj.2020.34.s1.01911

Ri, M., Tashiro, E., Oikawa, D., Shinjo, S., Tokuda, M., Yokouchi, Y., Narita, T., Masaki, A., Ito, A., and Ding, J. (2012). Identification of Toyocamycin, an agent cytotoxic for multiple myeloma cells, as a potent inhibitor of ER stress-induced XBP1 mRNA splicing. Blood Cancer, J., 2.

Park, 2017, Toyocamycin induces apoptosis via the crosstalk between reactive oxygen species and p38/ERK MAPKs signaling pathway in human prostate cancer PC-3 cells, Pharmacol. Rep., 69, 90, 10.1016/j.pharep.2016.10.014

Bodeau, 2017, Targeting the unfolded protein response as a potential therapeutic strategy in renal carcinoma cells exposed to cyclosporine a, Anticancer Res., 37, 1049, 10.21873/anticanres.11416

Li, 2019, Gut microbiota dependent anti-tumor immunity restricts melanoma growth in Rnf5 −/− mice, Nat. Commun., 10, 1492, 10.1038/s41467-019-09525-y

Cawley, K., Logue, S.E., Gorman, A.M., Zeng, Q., Patterson, J., Gupta, S., and Samali, A. (2013). Disruption of microRNA biogenesis confers resistance to ER stress-induced cell death upstream of the mitochondrion. PLoS ONE, 8.

Pineau, 2020, Local intracerebral inhibition of IRE1 by MKC8866 sensitizes glioblastoma to irradiation/chemotherapy in vivo, Cancer Lett., 494, 73, 10.1016/j.canlet.2020.08.028

Logue, S.E., McGrath, E.P., Cleary, P., Greene, S., Mnich, K., Almanza, A., Chevet, E., Dwyer, R.M., Oommen, A., and Legembre, P. (2018). Inhibition of IRE1 RNase activity modulates the tumor cell secretome and enhances response to chemotherapy. Nat. Commun., 9.

Vieri, 2018, Synergistic Dual Inhibition of BCR-ABL1 and the Unfolded Protein Response Causes p38 MAPK-Mediated Cell Death and Sensitizes BCR-ABL1+ Acute Lymphoblastic Leukemia to Dexamethasone, Blood, 132, 4674, 10.1182/blood-2018-99-110967

Sheng, 2019, IRE1α-XBP1s pathway promotes prostate cancer by activating c-MYC signaling, Nat. Commun., 10, 323, 10.1038/s41467-018-08152-3

McCarthy, 2020, The IRE1 and PERK arms of the unfolded protein response promote survival of rhabdomyosarcoma cells, Cancer Lett., 490, 76, 10.1016/j.canlet.2020.07.009

Mimura, 2012, Blockade of XBP1 splicing by inhibition of IRE1α is a promising therapeutic option in multiple myeloma, Blood, 119, 5772, 10.1182/blood-2011-07-366633

Jiang, 2016, Acridine derivatives as inhibitors of the IRE1α-XBP1 pathway are cytotoxic to human multiple myeloma, Mol. Cancer Ther., 15, 2055, 10.1158/1535-7163.MCT-15-1023

Sanches, M., Duffy, N.M., Talukdar, M., Thevakumaran, N., Chiovitti, D., Canny, M.D., Lee, K., Kurinov, I., Uehling, D., and Al-Awar, R. (2014). Structure and mechanism of action of the hydroxy-aryl-aldehyde class of IRE1 endoribonuclease inhibitors. Nat. Commun., 5.

Tang, 2014, Inhibition of ER stress-associated IRE-1/XBP-1 pathway reduces leukemic cell survival, J. Clin. Investig., 124, 2585, 10.1172/JCI73448

Xie, 2018, IRE1α RNase-dependent lipid homeostasis promotes survival in Myc-transformed cancers, J. Clin. Investig., 128, 1300, 10.1172/JCI95864

Zhang, T., Li, N., Sun, C., Jin, Y., and Sheng, X. (2020). MYC and the unfolded protein response in cancer: Synthetic lethal partners in crime?. EMBO Mol. Med., 12.

Wiseman, 2010, Flavonol Activation Defines an Unanticipated Ligand-Binding Site in the Kinase-RNase Domain of IRE1, Mol. Cell, 38, 291, 10.1016/j.molcel.2010.04.001

Papa, 2003, Bypassing a Kinase Activity with an ATP-Competitive Drug, Science, 302, 1533, 10.1126/science.1090031

Han, 2009, IRE1α Kinase Activation Modes Control Alternate Endoribonuclease Outputs to Determine Divergent Cell Fates, Cell, 138, 562, 10.1016/j.cell.2009.07.017

Ferri, E., Le Thomas, A., Wallweber, H.A., Day, E.S., Walters, B.T., Kaufman, S.E., Braun, M.G., Clark, K.R., Beresini, M.H., and Mortara, K. (2020). Activation of the IRE1 RNase through remodeling of the kinase front pocket by ATP-competitive ligands. Nat. Commun., 11.

Grandjean, 2020, Pharmacologic IRE1/XBP1s activation confers targeted ER proteostasis reprogramming, Nat. Chem. Biol., 16, 1052, 10.1038/s41589-020-0584-z