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Understanding the Unfolded Protein Response (UPR) Pathway: Insights into Neuropsychiatric Disorders and Therapeutic Potentials

  • Pitna Kim (Department of Cell, Developmental, and Integrative Biology (CDIB), University of Alabama at Birmingham)
  • Received : 2023.10.18
  • Accepted : 2023.12.06
  • Published : 2024.03.01

Abstract

The Unfolded Protein Response (UPR) serves as a critical cellular mechanism dedicated to maintaining protein homeostasis, primarily within the endoplasmic reticulum (ER). This pathway diligently responds to a variety of intracellular indicators of ER stress with the objective of reinstating balance by diminishing the accumulation of unfolded proteins, amplifying the ER's folding capacity, and eliminating slow-folding proteins. Prolonged ER stress and UPR irregularities have been linked to a range of neuropsychiatric disorders, including major depressive disorder, bipolar disorder, and schizophrenia. This review offers a comprehensive overview of the UPR pathway, delineating its activation mechanisms and its role in the pathophysiology of neuropsychiatric disorders. It highlights the intricate interplay within the UPR and its profound influence on brain function, synaptic perturbations, and neural developmental processes. Additionally, it explores evolving therapeutic strategies targeting the UPR within the context of these disorders, underscoring the necessity for precision and further research to effective treatments. The research findings presented in this work underscore the promising potential of UPR-focused therapeutic approaches to address the complex landscape of neuropsychiatric disorders, giving rise to optimism for improving outcomes for individuals facing these complex conditions.

Keywords

References

  1. Acosta-Alvear, D., Zhou, Y., Blais, A., Tsikitis, M., Lents, N. H., Arias, C., Lennon, C. J., Kluger, Y. and Dynlacht, B. D. (2007) XBP1 controls diverse cell type- and condition-specific transcriptional regulatory networks. Mol. Cell 27, 53-66. https://doi.org/10.1016/j.molcel.2007.06.011
  2. Behnke, J., Mann, M. J., Scruggs, F. L., Feige, M. J. and Hendershot, L. M. (2016) Members of the Hsp70 family recognize distinct types of sequences to execute ER quality control. Mol. Cell 63, 739-752. https://doi.org/10.1016/j.molcel.2016.07.012
  3. Bengesser, S. A., Reininghaus, E. Z., Lackner, N., Birner, A., Fellendorf, F. T., Platzer, M., Kainzbauer, N., Tropper, B., Hormanseder, C., Queissner, R., Kapfhammer, H. P., Wallner-Liebmann, S. J., Fuchs, R., Petek, E., Windpassinger, C., Schnalzenberger, M., Reininghaus, B., Evert, B. and Waha, A. (2018) Is the molecular clock ticking differently in bipolar disorder? Methylation analysis of the clock gene ARNTL. World J. Biol. Psychiatry 19, S21-S29. https://doi.org/10.1080/15622975.2016.1231421
  4. Bommiasamy, H., Back, S. H., Fagone, P., Lee, K., Meshinchi, S., Vink, E., Sriburi, R., Frank, M., Jackowski, S., Kaufman, R. J. and Brewer, J. W. (2009) ATF6alpha induces XBP1-independent expansion of the endoplasmic reticulum. J. Cell Sci. 122, 1626-1636. https://doi.org/10.1242/jcs.045625
  5. Bown, C., Wang, J. F., MacQueen, G. and Young, L. T. (2000) Increased temporal cortex ER stress proteins in depressed subjects who died by suicide. Neuropsychopharmacology 22, 327-332. https://doi.org/10.1016/S0893-133X(99)00091-3
  6. Buyukada, E., Bora, E. S., Altuntas, I. and Erbas, O. (2023) Endoplasmic reticulum stress: implications for psychiatric disorders. JEB Med. Sci. 4, 37-44.
  7. Chakrabarti, A., Chen, A. W. and Varner, J. D. (2011) A review of the mammalian unfolded protein response. Biotechnol. Bioeng. 108, 2777-2793. https://doi.org/10.1002/bit.23282
  8. Chevet, E., Hetz, C. and Samali, A. (2015) Endoplasmic reticulum stress-activated cell reprogramming in oncogenesis. Cancer Discov. 5, 586-597. https://doi.org/10.1158/2159-8290.CD-14-1490
  9. Cho, Y. M., Jang, Y. S., Jang, Y. M., Chung, S. M., Kim, H. S., Lee, J. H., Jeong, S. W., Kim, I. K., Kim, J. J., Kim, K. S. and Kwon, O. J. (2009) Induction of unfolded protein response during neuronal induction of rat bone marrow stromal cells and mouse embryonic stem cells. Exp. Mol. Med. 41, 440-452. https://doi.org/10.3858/emm.2009.41.6.049
  10. Concha, N. O., Smallwood, A., Bonnette, W., Totoritis, R., Zhang, G., Federowicz, K., Yang, J., Qi, H., Chen, S., Campobasso, N., Choudhry, A. E., Shuster, L. E., Evans, K. A., Ralph, J., Sweitzer, S., Heerding, D. A., Buser, C. A., Su, D. S. and DeYoung, M. P. (2015) Long-range inhibitor-induced conformational regulation of human IRE1alpha endoribonuclease activity. Mol. Pharmacol. 88, 1011-1123. https://doi.org/10.1124/mol.115.100917
  11. Costa-Mattioli, M., Gobert, D., Stern, E., Gamache, K., Colina, R., Cuello, C., Sossin, W., Kaufman, R., Pelletier, J., Rosenblum, K., Krnjevic, K., Lacaille, J. C., Nader, K. and Sonenberg, N. (2007) eIF2alpha phosphorylation bidirectionally regulates the switch from short- to long-term synaptic plasticity and memory. Cell 129, 195-206. https://doi.org/10.1016/j.cell.2007.01.050
  12. Delepine, M., Nicolino, M., Barrett, T., Golamaully, M., Lathrop, G. M. and Julier, C. (2000) EIF2AK3, encoding translation initiation factor 2-alpha kinase 3, is mutated in patients with Wolcott-Rallison syndrome. Nat. Genet. 25, 406-409. https://doi.org/10.1038/78085
  13. Edvardson, S., Nicolae, C. M., Noh, G. J., Burton, J. E., Punzi, G., Shaag, A., Bischetsrieder, J., De Grassi, A., Pierri, C. L., Elpeleg, O. and Moldovan, G. L. (2019) Heterozygous RNF13 gain-of-function variants are associated with congenital microcephaly, epileptic encephalopathy, blindness, and failure to thrive. Am. J. Hum. Genet. 104, 179-185. https://doi.org/10.1016/j.ajhg.2018.11.018
  14. Freeman, O. J. and Mallucci, G. R. (2016) The UPR and synaptic dysfunction in neurodegeneration. Brain Res. 1648, 530-537. https://doi.org/10.1016/j.brainres.2016.03.029
  15. Gerakis, Y. and Hetz, C. (2018) Emerging roles of ER stress in the etiology and pathogenesis of Alzheimer's disease. FEBS J. 285, 995-1011. https://doi.org/10.1111/febs.14332
  16. Godin, J. D., Creppe, C., Laguesse, S. and Nguyen, L. (2016) Emerging roles for the unfolded protein response in the developing nervous system. Trends Neurosci. 39, 394-404. https://doi.org/10.1016/j.tins.2016.04.002
  17. Grandjean, J. M. D. and Wiseman, R. L. (2020) Small molecule strategies to harness the unfolded protein response: where do we go from here? J. Biol. Chem. 295, 15692-15711. https://doi.org/10.1074/jbc.REV120.010218
  18. Halliday, M., Hughes, D. and Mallucci, G. R. (2017) Fine-tuning PERK signaling for neuroprotection. J. Neurochem. 142, 812-826. https://doi.org/10.1111/jnc.14112
  19. Halliday, M. and Mallucci, G. R. (2014) Targeting the unfolded protein response in neurodegeneration: a new approach to therapy. Neuropharmacology 76 Pt A, 169-174. https://doi.org/10.1016/j.neuropharm.2013.08.034
  20. Han, J., Back, S. H., Hur, J., Lin, Y. H., Gildersleeve, R., Shan, J., Yuan, C. L., Krokowski, D., Wang, S., Hatzoglou, M., Kilberg, M. S., Sartor, M. A. and Kaufman, R. J. (2013a) ER-stress-induced transcriptional regulation increases protein synthesis leading to cell death. Nat. Cell Biol. 15, 481-490. https://doi.org/10.1038/ncb2738
  21. Han, J., Murthy, R., Wood, B., Song, B., Wang, S., Sun, B., Malhi, H. and Kaufman, R. J. (2013b) ER stress signalling through eIF2alpha and CHOP, but not IRE1alpha, attenuates adipogenesis in mice. Diabetologia 56, 911-924. https://doi.org/10.1007/s00125-012-2809-5
  22. Harding, H. P., Zhang, Y., Bertolotti, A., Zeng, H. and Ron, D. (2000) Perk is essential for translational regulation and cell survival during the unfolded protein response. Mol. Cell 5, 897-904. https://doi.org/10.1016/S1097-2765(00)80330-5
  23. Harding, H. P., Zhang, Y. and Ron, D. (1999) Protein translation and folding are coupled by an endoplasmic-reticulum-resident kinase. Nature 397, 271-274. https://doi.org/10.1038/16729
  24. Harding, H. P., Zhang, Y., Zeng, H., Novoa, I., Lu, P. D., Calfon, M., Sadri, N., Yun, C., Popko, B., Paules, R., Stojdl, D. F., Bell, J. C., Hettmann, T., Leiden, J. M. and Ron, D. (2003) An integrated stress response regulates amino acid metabolism and resistance to oxidative stress. Mol. Cell 11, 619-633. https://doi.org/10.1016/S1097-2765(03)00105-9
  25. Hassler, J. R., Scheuner, D. L., Wang, S., Han, J., Kodali, V. K., Li, P., Nguyen, J., George, J. S., Davis, C., Wu, S. P., Bai, Y., Sartor, M., Cavalcoli, J., Malhi, H., Baudouin, G., Zhang, Y., Yates, J. R., III, Itkin-Ansari, P., Volkmann, N. and Kaufman, R. J. (2015) The IRE1alpha/XBP1s pathway is essential for the glucose response and protection of beta cells. PLoS Biol. 13, e1002277.
  26. Hayashi, A., Kasahara, T., Iwamoto, K., Ishiwata, M., Kametani, M., Kakiuchi, C., Furuichi, T. and Kato, T. (2007) The role of brain-derived neurotrophic factor (BDNF)-induced XBP1 splicing during brain development. J. Biol. Chem. 282, 34525-34534. https://doi.org/10.1074/jbc.M704300200
  27. Hayashi, A., Kasahara, T., Kametani, M., Toyota, T., Yoshikawa, T. and Kato, T. (2009) Aberrant endoplasmic reticulum stress response in lymphoblastoid cells from patients with bipolar disorder. Int. J. Neuropsychopharmacol. 12, 33-43. https://doi.org/10.1017/S1461145708009358
  28. Hetz, C. and Saxena, S. (2017) ER stress and the unfolded protein response in neurodegeneration. Nat. Rev. Neurol. 13, 477-491. https://doi.org/10.1038/nrneurol.2017.99
  29. Hetz, C., Zhang, K. and Kaufman, R. J. (2020) Mechanisms, regulation and functions of the unfolded protein response. Nat. Rev. Mol. Cell Biol. 21, 421-438. https://doi.org/10.1038/s41580-020-0250-z
  30. Hoglinger, G. U., Melhem, N. M., Dickson, D. W., Sleiman, P. M., Wang, L. S., Klei, L., Rademakers, R., de Silva, R., Litvan, I., Riley, D. E., van Swieten, J. C., Heutink, P., Wszolek, Z. K., Uitti, R. J., Vandrovcova, J., Hurtig, H. I., Gross, R. G., Maetzler, W., Goldwurm, S., Tolosa, E., Borroni, B., Pastor, P.; PSP Genetics Study Group; Cantwell, L. B., Han, M. R., Dillman, A., van der Brug, M. P., Gibbs, J. R., Cookson, M. R., Hernandez, D. G., Singleton, A. B., Farrer, M. J., Yu, C. E., Golbe, L. I., Revesz, T., Hardy, J., Lees, A. J., Devlin, B., Hakonarson, H., Muller, U. and Schellenberg, G. D. (2011) Identification of common variants influencing risk of the tauopathy progressive supranuclear palsy. Nat. Genet. 43, 699-705. https://doi.org/10.1038/ng.859
  31. Hollien, J., Lin, J. H., Li, H., Stevens, N., Walter, P. and Weissman, J. S. (2009) Regulated Ire1-dependent decay of messenger RNAs in mammalian cells. J. Cell Biol. 186, 323-331. https://doi.org/10.1083/jcb.200903014
  32. Hollien, J. and Weissman, J. S. (2006) Decay of endoplasmic reticulum-localized mRNAs during the unfolded protein response. Science 313, 104-107. https://doi.org/10.1126/science.1129631
  33. Jan, A. T., Rahman, S., Ahmad, K. and Minakshi, R. (2022) Editorial: unfolded protein response (UPR): an impending target for multiple neurological disorders. Front. Aging Neurosci. 14, 1014450.
  34. Jousse, C., Oyadomari, S., Novoa, I., Lu, P., Zhang, Y., Harding, H. P. and Ron, D. (2003) Inhibition of a constitutive translation initiation factor 2alpha phosphatase, CReP, promotes survival of stressed cells. J. Cell Biol. 163, 767-775. https://doi.org/10.1083/jcb.200308075
  35. Jung, J., Michalak, M. and Agellon, L. B. (2017) Endoplasmic reticulum malfunction in the nervous system. Front. Neurosci. 11, 220.
  36. Kawada, K., Iekumo, T., Saito, R., Kaneko, M., Mimori, S., Nomura, Y. and Okuma, Y. (2014) Aberrant neuronal differentiation and inhibition of dendrite outgrowth resulting from endoplasmic reticulum stress. J. Neurosci. Res. 92, 1122-1133. https://doi.org/10.1002/jnr.23389
  37. Kawada, K. and Mimori, S. (2018) Implication of endoplasmic reticulum stress in autism spectrum disorder. Neurochem. Res. 43, 147-152. https://doi.org/10.1007/s11064-017-2370-1
  38. Kawada, K., Mimori, S., Okuma, Y. and Nomura, Y. (2018) Involvement of endoplasmic reticulum stress and neurite outgrowth in the model mice of autism spectrum disorder. Neurochem. Int. 119, 115-119. https://doi.org/10.1016/j.neuint.2017.07.004
  39. Kim, P., Scott, M. R. and Meador-Woodruff, J. H. (2021) Dysregulation of the unfolded protein response (UPR) in the dorsolateral prefrontal cortex in elderly patients with schizophrenia. Mol. Psychiatry 26, 1321-1331. https://doi.org/10.1038/s41380-019-0537-7
  40. Kowalczyk, M., Kowalczyk, E., Kwiatkowski, P., Lopusiewicz, L., Talarowska, M. and Sienkiewicz, M. (2021) Cellular response to unfolded proteins in depression. Life (Basel) 11, 1376.
  41. Laguesse, S., Creppe, C., Nedialkova, D. D., Prevot, P. P., Borgs, L., Huysseune, S., Franco, B., Duysens, G., Krusy, N., Lee, G., Thelen, N., Thiry, M., Close, P., Chariot, A., Malgrange, B., Leidel, S. A., Godin, J. D. and Nguyen, L. (2015) A dynamic unfolded protein response contributes to the control of cortical neurogenesis. Dev. Cell 35, 553-567. https://doi.org/10.1016/j.devcel.2015.11.005
  42. Lai, E. S. K., Nakayama, H., Miyazaki, T., Nakazawa, T., Tabuchi, K., Hashimoto, K., Watanabe, M. and Kano, M. (2021) An autism-associated neuroligin-3 mutation affects developmental synapse elimination in the cerebellum. Front. Neural Circuits 15, 676891.
  43. Lee, A. S. (2001) The glucose-regulated proteins: stress induction and clinical applications. Trends Biochem. Sci. 26, 504-510. https://doi.org/10.1016/S0968-0004(01)01908-9
  44. Lee, A. S., Delegeane, A. and Scharff, D. (1981) Highly conserved glucose-regulated protein in hamster and chicken cells: preliminary characterization of its cDNA clone. Proc. Natl. Acad. Sci. U. S. A. 78, 4922-4925. https://doi.org/10.1073/pnas.78.8.4922
  45. Lu, M., Lawrence, D. A., Marsters, S., Acosta-Alvear, D., Kimmig, P., Mendez, A. S., Paton, A. W., Paton, J. C., Walter, P. and Ashkenazi, A. (2014) Opposing unfolded-protein-response signals converge on death receptor 5 to control apoptosis. Science 345, 98-101. https://doi.org/10.1126/science.1254312
  46. Momoi, T., Fujita, E., Senoo, H. and Momoi, M. (2009) Genetic factors and epigenetic factors for autism: endoplasmic reticulum stress and impaired synaptic function. Cell Biol. Int. 34, 13-19.
  47. Muneer, A. and Shamsher Khan, R. M. (2019) Endoplasmic reticulum stress: implications for neuropsychiatric disorders. Chonnam Med. J. 55, 8-19. https://doi.org/10.4068/cmj.2019.55.1.8
  48. Nadarajah, B. and Parnavelas, J. G. (2002) Modes of neuronal migration in the developing cerebral cortex. Nat. Rev. Neurosci. 3, 423-432. https://doi.org/10.1038/nrn845
  49. Nemoto, N., Udagawa, T., Ohira, T., Jiang, L., Hirota, K., Wilkinson, C. R., Bahler, J., Jones, N., Ohta, K., Wek, R. C. and Asano, K. (2010) The roles of stress-activated Sty1 and Gcn2 kinases and of the protooncoprotein homologue Int6/eIF3e in responses to endogenous oxidative stress during histidine starvation. J. Mol. Biol. 404, 183-201. https://doi.org/10.1016/j.jmb.2010.09.016
  50. Nevell, L., Zhang, K., Aiello, A. E., Koenen, K., Galea, S., Soliven, R., Zhang, C., Wildman, D. E. and Uddin, M. (2014) Elevated systemic expression of ER stress related genes is associated with stress-related mental disorders in the Detroit Neighborhood Health Study. Psychoneuroendocrinology 43, 62-70. https://doi.org/10.1016/j.psyneuen.2014.01.013
  51. Novoa, I., Zeng, H., Harding, H. P. and Ron, D. (2001) Feedback inhibition of the unfolded protein response by GADD34-mediated dephosphorylation of eIF2alpha. J. Cell Biol. 153, 1011-1022. https://doi.org/10.1083/jcb.153.5.1011
  52. Ounallah-Saad, H., Sharma, V., Edry, E. and Rosenblum, K. (2014) Genetic or pharmacological reduction of PERK enhances cortical-dependent taste learning. J. Neurosci. 34, 14624-14632. https://doi.org/10.1523/JNEUROSCI.2117-14.2014
  53. Pfaffenseller, B., Wollenhaupt-Aguiar, B., Fries, G. R., Colpo, G. D., Burque, R. K., Bristot, G., Ferrari, P., Cereser, K. M., Rosa, A. R., Klamt, F. and Kapczinski, F. (2014) Impaired endoplasmic reticulum stress response in bipolar disorder: cellular evidence of illness progression. Int. J. Neuropsychopharmacol. 17, 1453-1463. https://doi.org/10.1017/S1461145714000443
  54. Rao, R. V., Peel, A., Logvinova, A., del Rio, G., Hermel, E., Yokota, T., Goldsmith, P. C., Ellerby, L. M., Ellerby, H. M. and Bredesen, D. E. (2002) Coupling endoplasmic reticulum stress to the cell death program: role of the ER chaperone GRP78. FEBS Lett. 514, 122-128. https://doi.org/10.1016/S0014-5793(02)02289-5
  55. Read, A. and Schroder, M. (2021) The unfolded protein response: an overview. Biology (Basel) 10, 384.
  56. Reinhardt, S., Schuck, F., Grosgen, S., Riemenschneider, M., Hartmann, T., Postina, R., Grimm, M. and Endres, K. (2014) Unfolded protein response signaling by transcription factor XBP-1 regulates ADAM10 and is affected in Alzheimer's disease. FASEB J. 28, 978-997. https://doi.org/10.1096/fj.13-234864
  57. Remondelli, P. and Renna, M. (2017) The endoplasmic reticulum unfolded protein response in neurodegenerative disorders and its potential therapeutic significance. Front. Mol. Neurosci. 10, 187.
  58. Ron, D. and Walter, P. (2007) Signal integration in the endoplasmic reticulum unfolded protein response. Nat. Rev. Mol. Cell Biol. 8, 519-529. https://doi.org/10.1038/nrm2199
  59. Scheper, W. and Hoozemans, J. J. (2015) The unfolded protein response in neurodegenerative diseases: a neuropathological perspective. Acta Neuropathol. 130, 315-331. https://doi.org/10.1007/s00401-015-1462-8
  60. Sharma, V., Ounallah-Saad, H., Chakraborty, D., Hleihil, M., Sood, R., Barrera, I., Edry, E., Kolatt Chandran, S., Ben Tabou de Leon, S., Kaphzan, H. and Rosenblum, K. (2018) Local inhibition of PERK enhances memory and reverses age-related deterioration of cognitive and neuronal properties. J. Neurosci. 38, 648-658. https://doi.org/10.1523/JNEUROSCI.0628-17.2017
  61. Shim, J., Umemura, T., Nothstein, E. and Rongo, C. (2004) The unfolded protein response regulates glutamate receptor export from the endoplasmic reticulum. Mol. Biol. Cell 15, 4818-4828. https://doi.org/10.1091/mbc.e04-02-0108
  62. Shoulders, M. D., Ryno, L. M., Genereux, J. C., Moresco, J. J., Tu, P. G., Wu, C., Yates, J. R., 3rd, Su, A. I., Kelly, J. W. and Wiseman, R. L. (2013) Stress-independent activation of XBP1s and/or ATF6 reveals three functionally diverse ER proteostasis environments. Cell Rep. 3, 1279-1292. https://doi.org/10.1016/j.celrep.2013.03.024
  63. Sidhom, E., O'Brien, J. T., Butcher, A. J., Smith, H. L., Mallucci, G. R. and Underwood, B. R. (2022) Targeting the unfolded protein response as a disease-modifying pathway in dementia. Int. J. Mol. Sci. 23, 2021.
  64. Smith, H. L. and Mallucci, G. R. (2016) The unfolded protein response: mechanisms and therapy of neurodegeneration. Brain 139, 2113-2121. https://doi.org/10.1093/brain/aww101
  65. Snapp, E. L. (2012) Unfolded protein responses with or without unfolded proteins? Cells 1, 926-950. https://doi.org/10.3390/cells1040926
  66. So, J., Warsh, J. J. and Li, P. P. (2007) Impaired endoplasmic reticulum stress response in B-lymphoblasts from patients with bipolar-I disorder. Biol. Psychiatry 62, 141-147. https://doi.org/10.1016/j.biopsych.2006.10.014
  67. Stutzbach, L. D., Xie, S. X., Naj, A. C., Albin, R., Gilman, S.; PSP Genetics Study Group; Lee, V. M., Trojanowski, J. Q., Devlin, B. and Schellenberg, G. D. (2013) The unfolded protein response is activated in disease-affected brain regions in progressive supranuclear palsy and Alzheimer's disease. Acta Neuropathol. Commun. 1, 31.
  68. Taverna, E., Gotz, M. and Huttner, W. B. (2014) The cell biology of neurogenesis: toward an understanding of the development and evolution of the neocortex. Annu. Rev. Cell Dev. Biol. 30, 465-502. https://doi.org/10.1146/annurev-cellbio-101011-155801
  69. Timberlake, M. A., 2nd and Dwivedi, Y. (2015) Altered expression of endoplasmic reticulum stress associated genes in hippocampus of learned helpless rats: relevance to depression pathophysiology. Front. Pharmacol. 6, 319.
  70. Trobiani, L., Favaloro, F. L., Di Castro, M. A., Di Mattia, M., Cariello, M., Miranda, E., Canterini, S., De Stefano, M. E., Comoletti, D., Limatola, C. and De Jaco, A. (2018) UPR activation specifically modulates glutamate neurotransmission in the cerebellum of a mouse model of autism. Neurobiol. Dis. 120, 139-150. https://doi.org/10.1016/j.nbd.2018.08.026
  71. Ulbrich, L., Favaloro, F. L., Trobiani, L., Marchetti, V., Patel, V., Pascucci, T., Comoletti, D., Marciniak, S. J. and De Jaco, A. (2016) Autism-associated R451C mutation in neuroligin3 leads to activation of the unfolded protein response in a PC12 Tet-On inducible system. Biochem. J. 473, 423-434. https://doi.org/10.1042/BJ20150274
  72. 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. and Oakes, S. A. (2012) IRE1alpha cleaves select microRNAs during ER stress to derepress translation of proapoptotic Caspase-2. Science 338, 818-822. https://doi.org/10.1126/science.1226191
  73. Urra, H., Henriquez, D. R., Canovas, J., Villarroel-Campos, D., Carreras-Sureda, A., Pulgar, E., Molina, E., Hazari, Y. M., Limia, C. M., Alvarez-Rojas, S., Figueroa, R., Vidal, R. L., Rodriguez, D. A., Rivera, C. A., Court, F. A., Couve, A., Qi, L., Chevet, E., Akai, R., Iwawaki, T., Concha, M. L., Glavic, A., Gonzalez-Billault, C. and Hetz, C. (2018) IRE1alpha governs cytoskeleton remodelling and cell migration through a direct interaction with filamin A. Nat. Cell Biol. 20, 942-953.
  74. van Ziel, A. M. and Scheper, W. (2020) The UPR in neurodegenerative disease: not just an inside job. Biomolecules 10, 1090.
  75. Vandenberghe, W., Nicoll, R. A. and Bredt, D. S. (2005) Interaction with the unfolded protein response reveals a role for stargazin in biosynthetic ampa receptor transport. J. Neurosci. 25, 1095-1102. https://doi.org/10.1523/JNEUROSCI.3568-04.2005
  76. Vasquez, G. E., Medinas, D. B., Urra, H. and Hetz, C. (2022) Emerging roles of endoplasmic reticulum proteostasis in brain development. Cells Dev. 170, 203781.
  77. Vattem, K. M. and Wek, R. C. (2004) Reinitiation involving upstream ORFs regulates ATF4 mRNA translation in mammalian cells. Proc. Natl. Acad. Sci. U. S. A. 101, 11269-11274. https://doi.org/10.1073/pnas.0400541101
  78. Vidal, R. L. and Hetz, C. (2012) Crosstalk between the UPR and autophagy pathway contributes to handling cellular stress in neurodegenerative disease. Autophagy 8, 970-972. https://doi.org/10.4161/auto.20139
  79. Wang, J. M., Qiu, Y., Yang, Z. Q., Li, L. and Zhang, K. (2017) Inositol-requiring enzyme 1 facilitates diabetic wound healing through modulating microRNAs. Diabetes 66, 177-192. https://doi.org/10.2337/db16-0052
  80. Wang, M. and Kaufman, R. J. (2014) The impact of the endoplasmic reticulum protein-folding environment on cancer development. Nat. Rev. Cancer 14, 581-597. https://doi.org/10.1038/nrc3800
  81. Wang, S. and Kaufman, R. J. (2012) The impact of the unfolded protein response on human disease. J. Cell Biol. 197, 857-867. https://doi.org/10.1083/jcb.201110131
  82. Xue, X., Wu, X., Liu, L., Liu, L. and Zhu, F. (2023) ERVW-1 activates ATF6-mediated unfolded protein response by decreasing GANAB in recent-onset schizophrenia. Viruses 15, 1298.
  83. Yang, J., Liu, H., Li, L., Liu, H., Shi, W., Yuan, X. and Wu, L. (2016) Structural insights into IRE1 functions in the unfolded protein response. Curr. Med. Chem. 23, 4706-4716. https://doi.org/10.2174/0929867323666160927142349
  84. Yoshino, Y. and Dwivedi, Y. (2020) Elevated expression of unfolded protein response genes in the prefrontal cortex of depressed subjects: effect of suicide. J. Affect. Disord. 262, 229-236. https://doi.org/10.1016/j.jad.2019.11.001
  85. Zhang, L. H. and Zhang, X. (2010) Roles of GRP78 in physiology and cancer. J. Cell. Biochem. 110, 1299-305. https://doi.org/10.1002/jcb.22679
  86. Zhang, Y., Liu, R., Ni, M., Gill, P. and Lee, A. S. (2010) Cell surface relocalization of the endoplasmic reticulum chaperone and unfolded protein response regulator GRP78/BiP. J. Biol. Chem. 285, 15065-15075. https://doi.org/10.1074/jbc.M109.087445
  87. Zhao, F., Li, B., Yang, W., Ge, T. and Cui, R. (2022) Brain-immune interaction mechanisms: implications for cognitive dysfunction in psychiatric disorders. Cell Prolif. 55, e13295.
  88. Zinszner, H., Kuroda, M., Wang, X., Batchvarova, N., Lightfoot, R. T., Remotti, H., Stevens, J. L. and Ron, D. (1998) CHOP is implicated in programmed cell death in response to impaired function of the endoplasmic reticulum. Genes Dev. 12, 982-995. https://doi.org/10.1101/gad.12.7.982