Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Mechanisms, regulation and functions of the unfolded protein response

Abstract

Cellular stress induced by the abnormal accumulation of unfolded or misfolded proteins at the endoplasmic reticulum (ER) is emerging as a possible driver of human diseases, including cancer, diabetes, obesity and neurodegeneration. ER proteostasis surveillance is mediated by the unfolded protein response (UPR), a signal transduction pathway that senses the fidelity of protein folding in the ER lumen. The UPR transmits information about protein folding status to the nucleus and cytosol to adjust the protein folding capacity of the cell or, in the event of chronic damage, induce apoptotic cell death. Recent advances in the understanding of the regulation of UPR signalling and its implications in the pathophysiology of disease might open new therapeutic avenues.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: The major UPR pathways initiated from the ER.
Fig. 2: Regulation of IRE1α and PERK signalling.
Fig. 3: Regulation of IRE1α signalling through protein–protein interactions and post-translational modifications.
Fig. 4: ER stress-independent functions of the UPR.
Fig. 5: Role of the UPR in physiology and diseases.

Similar content being viewed by others

References

  1. Hebert, D. N. & Molinari, M. In and out of the ER: protein folding, quality control, degradation, and related human diseases. Physiol. Rev. 87, 1377–1408 (2007).

    CAS  PubMed  Google Scholar 

  2. Balch, W. E., Morimoto, R. I., Dillin, A. & Kelly, J. W. Adapting proteostasis for disease intervention. Science 319, 916–919 (2008).

    CAS  PubMed  Google Scholar 

  3. Kaufman, R. J. Orchestrating the unfolded protein response in health and disease. J. Clin. Invest. 110, 1389–1398 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Ron, D. & Walter, P. Signal integration in the endoplasmic reticulum unfolded protein response. Nat. Rev. Mol. Cell Biol. 8, 519–529 (2007).

    CAS  PubMed  Google Scholar 

  5. Dever, T. E. et al. Phosphorylation of initiation factor 2 alpha by protein kinase GCN2 mediates gene-specific translational control of GCN4 in yeast. Cell 68, 585–596 (1992).

    CAS  PubMed  Google Scholar 

  6. Vattem, K. M. & Wek, R. C. Reinitiation involving upstream ORFs regulates ATF4 mRNA translation in mammalian cells. Proc. Natl Acad. Sci. USA 101, 11269–11274 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Lu, P. D., Harding, H. P. & Ron, D. Translation reinitiation at alternative open reading frames regulates gene expression in an integrated stress response. J. Cell Biol. 167, 27–33 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Yaman, I. et al. The zipper model of translational control: a small upstream ORF is the switch that controls structural remodeling of an mRNA leader. Cell 113, 519–531 (2003).

    CAS  PubMed  Google Scholar 

  9. Harding, H. P., Zhang, Y. & Ron, D. Protein translation and folding are coupled by an endoplasmic-reticulum-resident kinase. Nature 397, 271–274 (1999). This study reports the discovery of the consequences of ER stress for protein translation through PERK.

    CAS  PubMed  Google Scholar 

  10. Harding, H. P. et al. An integrated stress response regulates amino acid metabolism and resistance to oxidative stress. Mol. Cell 11, 619–633 (2003).

    CAS  PubMed  Google Scholar 

  11. Han, J. et al. ER-stress-induced transcriptional regulation increases protein synthesis leading to cell death. Nat. Cell Biol. 15, 481–490 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Novoa, I., Zeng, H., Harding, H. P. & Ron, D. Feedback inhibition of the unfolded protein response by GADD34-mediated dephosphorylation of eIF2alpha. J. Cell Biol. 153, 1011–1022 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Jousse, C. et al. Inhibition of a constitutive translation initiation factor 2alpha phosphatase, CReP, promotes survival of stressed cells. J. Cell Biol. 163, 767–775 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Harding, H. P. et al. Ppp1r15 gene knockout reveals an essential role for translation initiation factor 2 alpha (eIF2alpha) dephosphorylation in mammalian development. Proc. Natl Acad. Sci. USA 106, 1832–1837 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Credle, J. J., Finer-Moore, J. S., Papa, F. R., Stroud, R. M. & Walter, P. On the mechanism of sensing unfolded protein in the endoplasmic reticulum. Proc. Natl Acad. Sci. USA 102, 18773–18784 (2005). This study proposes a direct recognition model for sensing ER stress in yeast.

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Zhou, J. et al. 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, 14343–14348 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Yoshida, H., Matsui, T., Yamamoto, A., Okada, T. & Mori, K. XBP1 mRNA is induced by ATF6 and spliced by IRE1 in response to ER stress to produce a highly active transcription factor. Cell 107, 881–891 (2001). This article is one of the first reports identifying XBP1 as a downstream target of IRE1α.

    CAS  PubMed  Google Scholar 

  18. Calfon, M. et al. IRE1 couples endoplasmic reticulum load to secretory capacity by processing the XBP-1 mRNA. Nature 415, 92–96 (2002). Yoshida et al. (2001) and Calfon et al. (2002) identify XBP1 as a downstream target of IRE1α.

    CAS  PubMed  Google Scholar 

  19. Shen, X. et al. Complementary signaling pathways regulate the unfolded protein response and are required for C. elegans development. Cell 107, 893–903 (2001). This article is one of the first reports identifying XBP1 as a downstream target of IRE1α.

    CAS  PubMed  Google Scholar 

  20. Hollien, J. et al. Regulated Ire1-dependent decay of messenger RNAs in mammalian cells. J. Cell Biol. 186, 323–331 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Hollien, J. & Weissman, J. S. Decay of endoplasmic reticulum-localized mRNAs during the unfolded protein response. Science 313, 104–107 (2006). In this study, the process known as regulated IRE1-dependent decay (RIDD) is discovered.

    CAS  PubMed  Google Scholar 

  22. Upton, J. P. et al. IRE1alpha cleaves select microRNAs during ER stress to derepress translation of proapoptotic caspase-2. Science 338, 818–822 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Wang, J. M., Qiu, Y., Yang, Z. Q., Li, L. & Zhang, K. Inositol-requiring enzyme 1 facilitates diabetic wound healing through modulating microRNAs. Diabetes 66, 177–192 (2017).

    PubMed  Google Scholar 

  24. Han, D. et al. IRE1alpha kinase activation modes control alternate endoribonuclease outputs to determine divergent cell fates. Cell 138, 562–575 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Hassler, J. R. et al. The IRE1alpha/XBP1s pathway is essential for the glucose response and protection of beta cells. PLoS Biol. 13, e1002277 (2015).

    PubMed  PubMed Central  Google Scholar 

  26. Acosta-Alvear, D. et al. The unfolded protein response and endoplasmic reticulum protein targeting machineries converge on the stress sensor IRE1. eLife 7, e43036 (2018).

    PubMed  PubMed Central  Google Scholar 

  27. Hetz, C. & Papa, F. R. The unfolded protein response and cell fate control. Mol. Cell 69, 169–181 (2018).

    CAS  PubMed  Google Scholar 

  28. Haze, K., Yoshida, H., Yanagi, H., Yura, T. & Mori, K. Mammalian transcription factor ATF6 is synthesized as a transmembrane protein and activated by proteolysis in response to endoplasmic reticulum stress. Mol. Biol. Cell 10, 3787–3799 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Ye, J. et al. ER stress induces cleavage of membrane-bound ATF6 by the same proteases that process SREBPs. Mol. Cell 6, 1355–1364 (2000).

    CAS  PubMed  Google Scholar 

  30. Wu, J. et al. ATF6alpha optimizes long-term endoplasmic reticulum function to protect cells from chronic stress. Dev. Cell 13, 351–364 (2007).

    CAS  PubMed  Google Scholar 

  31. Shoulders, M. D. et al. Stress-independent activation of XBP1s and/or ATF6 reveals three functionally diverse ER proteostasis environments. Cell Rep. 3, 1279–1292 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Bommiasamy, H. et al. ATF6alpha induces XBP1-independent expansion of the endoplasmic reticulum. J. Cell Sci. 122, 1626–1636 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Sriburi, R., Jackowski, S., Mori, K. & Brewer, J. W. XBP1: a link between the unfolded protein response, lipid biosynthesis, and biogenesis of the endoplasmic reticulum. J. Cell Biol. 167, 35–41 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Shaffer, A. L. et al. XBP1, downstream of Blimp-1, expands the secretory apparatus and other organelles, and increases protein synthesis in plasma cell differentiation. Immunity 21, 81–93 (2004).

    CAS  PubMed  Google Scholar 

  35. Hetz, C. et al. Proapoptotic BAX and BAK modulate the unfolded protein response by a direct interaction with IRE1alpha. Science 312, 572–576 (2006).

    CAS  PubMed  Google Scholar 

  36. Wei, M. C. et al. Proapoptotic BAX and BAK: a requisite gateway to mitochondrial dysfunction and death. Science 292, 727–730 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Pihan, P., Carreras-Sureda, A. & Hetz, C. BCL-2 family: integrating stress responses at the ER to control cell demise. Cell Death Differ. 24, 1478–1487 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Singh, R., Letai, A. & Sarosiek, K. Regulation of apoptosis in health and disease: the balancing act of BCL-2 family proteins. Nat. Rev. Mol. Cell Biol. 20, 175–193 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Puthalakath, H. et al. ER stress triggers apoptosis by activating BH3-only protein Bim. Cell 129, 1337–1349 (2007).

    CAS  PubMed  Google Scholar 

  40. McCullough, K. D., Martindale, J. L., Klotz, L. O., Aw, T. Y. & Holbrook, N. J. Gadd153 sensitizes cells to endoplasmic reticulum stress by down-regulating Bcl2 and perturbing the cellular redox state. Mol. Cell Biol. 21, 1249–1259 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Marciniak, S. J. et al. CHOP induces death by promoting protein synthesis and oxidation in the stressed endoplasmic reticulum. Genes Dev. 18, 3066–3077 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Rutkowski, D. T. et al. Adaptation to ER stress is mediated by differential stabilities of pro-survival and pro-apoptotic mRNAs and proteins. PLoS Biol. 4, e374 (2006).

    PubMed  PubMed Central  Google Scholar 

  43. Pedraza, J. M. & van Oudenaarden, A. Noise propagation in gene networks. Science 307, 1965–1969 (2005).

    CAS  PubMed  Google Scholar 

  44. Schinzel, R. T. et al. The hyaluronidase, TMEM2, promotes ER homeostasis and longevity independent of the UPR(ER). Cell 179, 1306–1318 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Lerner, A. G. et al. IRE1alpha induces thioredoxin-interacting protein to activate the NLRP3 inflammasome and promote programmed cell death under irremediable ER stress. Cell Metab. 16, 250–264 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Bronner, D. N. et al. Endoplasmic reticulum stress activates the inflammasome via NLRP3- and caspase-2-driven mitochondrial damage. Immunity 43, 451–462 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Oslowski, C. M. et al. Thioredoxin-interacting protein mediates ER stress-induced beta cell death through initiation of the inflammasome. Cell Metab. 16, 265–273 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Lin, J. H. et al. IRE1 signaling affects cell fate during the unfolded protein response. Science 318, 944–949 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Lam, M., Lawrence, D. A., Ashkenazi, A. & Walter, P. Confirming a critical role for death receptor 5 and caspase-8 in apoptosis induction by endoplasmic reticulum stress. Cell Death Differ. 25, 1530–1531 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Munoz-Pinedo, C. & Lopez-Rivas, A. A role for caspase-8 and TRAIL-R2/DR5 in ER-stress-induced apoptosis. Cell Death Differ. 25, 226 (2018).

    CAS  PubMed  Google Scholar 

  51. Lu, M. et al. Opposing unfolded-protein-response signals converge on death receptor 5 to control apoptosis. Science 345, 98–101 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Chang, T. K. et al. Coordination between two branches of the unfolded protein response determines apoptotic cell fate. Mol. Cell 71, 629–636 (2018).

    CAS  PubMed  Google Scholar 

  53. Rojas-Rivera, D. & Hetz, C. TMBIM protein family: ancestral regulators of cell death. Oncogene 34, 269–280 (2015).

    CAS  PubMed  Google Scholar 

  54. Rojas-Rivera, D. et al. TMBIM3/GRINA is a novel unfolded protein response (UPR) target gene that controls apoptosis through the modulation of ER calcium homeostasis. Cell Death Differ. 19, 1013–1026 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Chae, H. J. et al. BI-1 regulates an apoptosis pathway linked to endoplasmic reticulum stress. Mol. Cell 15, 355–366 (2004).

    CAS  PubMed  Google Scholar 

  56. Bertolotti, A., Zhang, Y., Hendershot, L. M., Harding, H. P. & Ron, D. Dynamic interaction of BiP and ER stress transducers in the unfolded-protein response. Nat. Cell Biol. 2, 326–332 (2000). This study indicates that BiP is involved in the regulation of the UPR.

    CAS  PubMed  Google Scholar 

  57. Karagoz, G. E., Acosta-Alvear, D. & Walter, P. The unfolded protein response: detecting and responding to fluctuations in the protein-folding capacity of the endoplasmic reticulum. Cold Spring Harb. Perspect. Biol. 11, a033886 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Liu, C. Y., Wong, H. N., Schauerte, J. A. & Kaufman, R. J. The protein kinase/endoribonuclease IRE1alpha that signals the unfolded protein response has a luminal N-terminal ligand-independent dimerization domain. J. Biol. Chem. 277, 18346–18356 (2002).

    CAS  PubMed  Google Scholar 

  59. Oikawa, D., Kimata, Y., Kohno, K. & Iwawaki, T. Activation of mammalian IRE1alpha upon ER stress depends on dissociation of BiP rather than on direct interaction with unfolded proteins. Exp. Cell Res. 315, 2496–2504 (2009).

    CAS  PubMed  Google Scholar 

  60. Walter, P. & Ron, D. The unfolded protein response: from stress pathway to homeostatic regulation. Science 334, 1081–1086 (2011).

    CAS  PubMed  Google Scholar 

  61. Pincus, D. et al. BiP binding to the ER-stress sensor Ire1 tunes the homeostatic behavior of the unfolded protein response. PLoS Biol. 8, e1000415 (2010).

    PubMed  PubMed Central  Google Scholar 

  62. Kimata, Y., Oikawa, D., Shimizu, Y., Ishiwata-Kimata, Y. & Kohno, K. A role for BiP as an adjustor for the endoplasmic reticulum stress-sensing protein Ire1. J. Cell Biol. 167, 445–456 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Ishiwata-Kimata, Y., Promlek, T., Kohno, K. & Kimata, Y. BiP-bound and nonclustered mode of Ire1 evokes a weak but sustained unfolded protein response. Genes Cell 18, 288–301 (2013).

    CAS  Google Scholar 

  64. Amin-Wetzel, N. et al. A J-protein Co-chaperone recruits BiP to monomerize IRE1 and repress the unfolded protein response. Cell 171, 1625–1637 e1613 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Amin-Wetzel, N., Neidhardt, L., Yan, Y., Mayer, M. P. & Ron, D. Unstructured regions in IRE1alpha specify BiP-mediated destabilisation of the luminal domain dimer and repression of the UPR. eLife 8, e50793 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Carrara, M., Prischi, F., Nowak, P. R., Kopp, M. C. & Ali, M. M. Noncanonical binding of BiP ATPase domain to Ire1 and Perk is dissociated by unfolded protein CH1 to initiate ER stress signaling. eLife 4, e03522 (2015).

    PubMed Central  Google Scholar 

  67. Kopp, M. C., Nowak, P. R., Larburu, N., Adams, C. J. & Ali, M. M. In vitro FRET analysis of IRE1 and BiP association and dissociation upon endoplasmic reticulum stress. eLife 7, e30257 (2018).

    PubMed  PubMed Central  Google Scholar 

  68. Kopp, M. C., Larburu, N., Durairaj, V., Adams, C. J. & Ali, M. M. U. UPR proteins IRE1 and PERK switch BiP from chaperone to ER stress sensor. Nat. Struct. Mol. Biol. 26, 1053–1062 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Gardner, B. M. & Walter, P. Unfolded proteins are Ire1-activating ligands that directly induce the unfolded protein response. Science 333, 1891–1894 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Kimata, Y. et al. Two regulatory steps of ER-stress sensor Ire1 involving its cluster formation and interaction with unfolded proteins. J. Cell Biol. 179, 75–86 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Karagoz, G. E. et al. An unfolded protein-induced conformational switch activates mammalian IRE1. eLife 6, e30700 (2017).

    PubMed  PubMed Central  Google Scholar 

  72. Wang, P., Li, J., Tao, J. & Sha, B. The luminal domain of the ER stress sensor protein PERK binds misfolded proteins and thereby triggers PERK oligomerization. J. Biol. Chem. 293, 4110–4121 (2018).

    CAS  PubMed  Google Scholar 

  73. Sundaram, A., Appathurai, S., Plumb, R. & Mariappan, M. Dynamic changes in complexes of IRE1alpha, PERK, and ATF6alpha during endoplasmic reticulum stress. Mol. Biol. Cell 29, 1376–1388 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Oikawa, D., Kitamura, A., Kinjo, M. & Iwawaki, T. Direct association of unfolded proteins with mammalian ER stress sensor, IRE1beta. PLoS One 7, e51290 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Lam, M., Marsters, S. A., Ashkenazi, A. & Walter, P. Misfolded proteins bind and activate death receptor 5 to induce apoptosis during unresolved endoplasmic reticulum stress. eLife 9, e52291 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Sepulveda, D. et al. Interactome screening identifies the ER luminal chaperone Hsp47 as a regulator of the unfolded protein response transducer IRE1alpha. Mol. Cell 69, 238–252 (2018).

    CAS  PubMed  Google Scholar 

  77. Maiers, J. L. et al. The unfolded protein response mediates fibrogenesis and collagen I secretion through regulating TANGO1 in mice. Hepatology 65, 983–998 (2017).

    CAS  PubMed  Google Scholar 

  78. Eletto, D., Eletto, D., Dersh, D., Gidalevitz, T. & Argon, Y. Protein disulfide isomerase A6 controls the decay of IRE1alpha signaling via disulfide-dependent association. Mol. Cell 53, 562–576 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Groenendyk, J. et al. Interplay between the oxidoreductase PDIA6 and microRNA-322 controls the response to disrupted endoplasmic reticulum calcium homeostasis. Sci. Signal. 7, ra54 (2014).

    PubMed  PubMed Central  Google Scholar 

  80. Oka, O. B. et al. ERp18 regulates activation of ATF6alpha during unfolded protein response. EMBO J 38, e100990 (2019).

    PubMed  PubMed Central  Google Scholar 

  81. Higa, A. et al. Endoplasmic reticulum stress-activated transcription factor ATF6alpha requires the disulfide isomerase PDIA5 to modulate chemoresistance. Mol. Cell Biol. 34, 1839–1849 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Promlek, T. et al. Membrane aberrancy and unfolded proteins activate the endoplasmic reticulum stress sensor Ire1 in different ways. Mol. Biol. Cell 22, 3520–3532 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Volmer, R., van der Ploeg, K. & Ron, D. Membrane lipid saturation activates endoplasmic reticulum unfolded protein response transducers through their transmembrane domains. Proc. Natl Acad. Sci. USA 110, 4628–4633 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Halbleib, K. et al. Activation of the unfolded protein response by lipid bilayer stress. Mol. Cell 67, 673–684 (2017).

    CAS  PubMed  Google Scholar 

  85. Kono, N., Amin-Wetzel, N. & Ron, D. Generic membrane-spanning features endow IRE1alpha with responsiveness to membrane aberrancy. Mol. Biol. Cell 28, 2318–2332 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Tam, A. B. et al. The UPR activator ATF6 responds to proteotoxic and lipotoxic stress by distinct mechanisms. Dev. Cell 46, 327–343 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Fun, X. H. & Thibault, G. Lipid bilayer stress and proteotoxic stress-induced unfolded protein response deploy divergent transcriptional and non-transcriptional programmes. Biochim. Biophys. Acta 1865, 158449 (2019).

    Google Scholar 

  88. Bailly-Maitre, B. et al. Cytoprotective gene bi-1 is required for intrinsic protection from endoplasmic reticulum stress and ischemia-reperfusion injury. Proc. Natl Acad. Sci. USA 103, 2809–2814 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Shi, L. et al. Bax inhibitor-1 is required for resisting the early brain injury induced by subarachnoid hemorrhage through regulating IRE1-JNK pathway. Neurol. Res. 40, 189–196 (2018).

    CAS  PubMed  Google Scholar 

  90. Lisbona, F. et al. BAX inhibitor-1 is a negative regulator of the ER stress sensor IRE1alpha. Mol. Cell 33, 679–691 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Castillo, K. et al. BAX inhibitor-1 regulates autophagy by controlling the IRE1alpha branch of the unfolded protein response. EMBO J. 30, 4465–4478 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Pinkaew, D. et al. Fortilin binds IRE1alpha and prevents ER stress from signaling apoptotic cell death. Nat. Commun. 8, 18 (2017).

    PubMed  PubMed Central  Google Scholar 

  93. Rodriguez, D. A. et al. BH3-only proteins are part of a regulatory network that control the sustained signalling of the unfolded protein response sensor IRE1alpha. EMBO J. 31, 2322–2335 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Hetz, C. & Glimcher, L. H. Fine-tuning of the unfolded protein response: assembling the IRE1alpha interactome. Mol. Cell 35, 551–561 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. He, Y. et al. Nonmuscle myosin IIB links cytoskeleton to IRE1alpha signaling during ER stress. Dev. Cell 23, 1141–1152 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Morita, S. et al. Targeting ABL-IRE1alpha signaling spares ER-stressed pancreatic beta cells to reverse autoimmune diabetes. Cell Metab. 25, 883–897 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Yanagitani, K., Kimata, Y., Kadokura, H. & Kohno, K. Translational pausing ensures membrane targeting and cytoplasmic splicing of XBP1u mRNA. Science 331, 586–589 (2011).

    CAS  PubMed  Google Scholar 

  98. Shanmuganathan, V. et al. Structural and mutational analysis of the ribosome-arresting human XBP1u. eLife 8, e46267 (2019).

    PubMed  PubMed Central  Google Scholar 

  99. Yanagitani, K. et al. Cotranslational targeting of XBP1 protein to the membrane promotes cytoplasmic splicing of its own mRNA. Mol. Cell 34, 191–200 (2009).

    CAS  PubMed  Google Scholar 

  100. Kanda, S., Yanagitani, K., Yokota, Y., Esaki, Y. & Kohno, K. Autonomous translational pausing is required for XBP1u mRNA recruitment to the ER via the SRP pathway. Proc. Natl Acad. Sci. USA 113, E5886–E5895 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Plumb, R., Zhang, Z. R., Appathurai, S. & Mariappan, M. A functional link between the co-translational protein translocation pathway and the UPR. eLife 4, e07426 (2015).

    PubMed Central  Google Scholar 

  102. Tsukumo, Y. et al. TBL2 is a novel PERK-binding protein that modulates stress-signaling and cell survival during endoplasmic reticulum stress. PLoS One 9, e112761 (2014).

    PubMed  PubMed Central  Google Scholar 

  103. Huber, A. L. et al. p58(IPK)-mediated attenuation of the proapoptotic PERK-CHOP pathway allows malignant progression upon low glucose. Mol. Cell 49, 1049–1059 (2013).

    CAS  PubMed  Google Scholar 

  104. Tyagi, R. et al. Rheb inhibits protein synthesis by activating the PERK-eIF2alpha signaling cascade. Cell Rep. 10, 684–693 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Lee, K. P. et al. Structure of the dual enzyme Ire1 reveals the basis for catalysis and regulation in nonconventional RNA splicing. Cell 132, 89–100 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  106. Korennykh, A. V. et al. The unfolded protein response signals through high-order assembly of Ire1. Nature 457, 687–693 (2009).

    CAS  PubMed  Google Scholar 

  107. Prischi, F., Nowak, P. R., Carrara, M. & Ali, M. M. Phosphoregulation of Ire1 RNase splicing activity. Nat. Commun. 5, 3554 (2014).

    PubMed  Google Scholar 

  108. Mao, T. et al. PKA phosphorylation couples hepatic inositol-requiring enzyme 1alpha to glucagon signaling in glucose metabolism. Proc. Natl Acad. Sci. USA 108, 15852–15857 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Saito, A. et al. Neuronal activity-dependent local activation of dendritic unfolded protein response promotes expression of brain-derived neurotrophic factor in cell soma. J. Neurochem. 144, 35–49 (2018).

    CAS  PubMed  Google Scholar 

  110. Hayashi, A. et al. The role of brain-derived neurotrophic factor (BDNF)-induced XBP1 splicing during brain development. J. Biol. Chem. 282, 34525–34534 (2007).

    CAS  PubMed  Google Scholar 

  111. Qiu, Y. et al. A crucial role for RACK1 in the regulation of glucose-stimulated IRE1alpha activation in pancreatic beta cells. Sci. Signal. 3, ra7 (2010).

    PubMed  PubMed Central  Google Scholar 

  112. Qiu, Q. et al. Toll-like receptor-mediated IRE1alpha activation as a therapeutic target for inflammatory arthritis. EMBO J. 32, 2477–2490 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. Lu, G. et al. PPM1l encodes an inositol requiring-protein 1 (IRE1) specific phosphatase that regulates the functional outcome of the ER stress response. Mol. Metab. 2, 405–416 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  114. Cui, W., Li, J., Ron, D. & Sha, B. The structure of the PERK kinase domain suggests the mechanism for its activation. Acta Crystallogr. D. Biol. Crystallogr. 67, 423–428 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  115. Yang, L. et al. S-Nitrosylation links obesity-associated inflammation to endoplasmic reticulum dysfunction. Science 349, 500–506 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  116. Wang, J. M. et al. IRE1alpha prevents hepatic steatosis by processing and promoting the degradation of select microRNAs. Sci Signal 11, eaao4617 (2018).

    PubMed  PubMed Central  Google Scholar 

  117. Nakato, R. et al. Regulation of the unfolded protein response via S-nitrosylation of sensors of endoplasmic reticulum stress. Sci. Rep. 5, 14812 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  118. Hourihan, J. M., Moronetti Mazzeo, L. E., Fernandez-Cardenas, L. P. & Blackwell, T. K. Cysteine sulfenylation directs IRE-1 to activate the SKN-1/Nrf2 antioxidant response. Mol. Cell 63, 553–566 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  119. Zhu, X. et al. Ubiquitination of inositol-requiring enzyme 1 (IRE1) by the E3 ligase CHIP mediates the IRE1/TRAF2/JNK pathway. J. Biol. Chem. 289, 30567–30577 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  120. Zhu, H. et al. Ufbp1 promotes plasma cell development and ER expansion by modulating distinct branches of UPR. Nat. Commun. 10, 1084 (2019).

    PubMed  PubMed Central  Google Scholar 

  121. Tschurtschenthaler, M. et al. Defective ATG16L1-mediated removal of IRE1alpha drives Crohn’s disease-like ileitis. J. Exp. Med. 214, 401–422 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  122. Gao, B. et al. Synoviolin promotes IRE1 ubiquitination and degradation in synovial fibroblasts from mice with collagen-induced arthritis. EMBO Rep. 9, 480–485 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  123. Nadanaka, S., Okada, T., Yoshida, H. & Mori, K. Role of disulfide bridges formed in the luminal domain of ATF6 in sensing endoplasmic reticulum stress. Mol. Cell Biol. 27, 1027–1043 (2007).

    CAS  PubMed  Google Scholar 

  124. Shemorry, A. et al. Caspase-mediated cleavage of IRE1 controls apoptotic cell commitment during endoplasmic reticulum stress. eLife 8, e47084 (2019).

    PubMed  PubMed Central  Google Scholar 

  125. Fonseca, S. G. et al. Wolfram syndrome 1 gene negatively regulates ER stress signaling in rodent and human cells. J. Clin. Invest. 120, 744–755 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  126. Phillips, M. J. & Voeltz, G. K. Structure and function of ER membrane contact sites with other organelles. Nat. Rev. Mol. Cell Biol. 17, 69–82 (2016).

    CAS  PubMed  Google Scholar 

  127. Verfaillie, T. et al. PERK is required at the ER-mitochondrial contact sites to convey apoptosis after ROS-based ER stress. Cell Death Differ. 19, 1880–1891 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  128. Carreras-Sureda, A. et al. Non-canonical function of IRE1alpha determines mitochondria-associated endoplasmic reticulum composition to control calcium transfer and bioenergetics. Nat. Cell Biol. 21, 755–767 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  129. Munoz, J. P. et al. Mfn2 modulates the UPR and mitochondrial function via repression of PERK. EMBO J. 32, 2348–2361 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  130. Takeda, K. et al. MITOL prevents ER stress-induced apoptosis by IRE1alpha ubiquitylation at ER-mitochondria contact sites. EMBO J 38, e100999 (2019).

    PubMed  PubMed Central  Google Scholar 

  131. van Vliet, A. R. et al. The ER stress sensor PERK coordinates ER-plasma membrane contact site formation through interaction with filamin-A and F-actin remodeling. Mol. Cell 65, 885–899 (2017).

    PubMed  Google Scholar 

  132. Ishiwata-Kimata, Y., Yamamoto, Y. H., Takizawa, K., Kohno, K. & Kimata, Y. F-actin and a type-II myosin are required for efficient clustering of the ER stress sensor Ire1. Cell Struct. Funct. 38, 135–143 (2013).

    CAS  PubMed  Google Scholar 

  133. Urra, H. et al. IRE1alpha governs cytoskeleton remodelling and cell migration through a direct interaction with filamin A. Nat. Cell Biol. 20, 942–953 (2018).

    CAS  PubMed  Google Scholar 

  134. Tavernier, Q. et al. Regulation of IRE1 RNase activity by the ribonuclease inhibitor 1 (RNH1). Cell Cycle 17, 1901–1916 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  135. Martinon, F., Chen, X., Lee, A. H. & Glimcher, L. H. TLR activation of the transcription factor XBP1 regulates innate immune responses in macrophages. Nat. Immunol. 11, 411–418 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  136. Woo, C. W., Kutzler, L., Kimball, S. R. & Tabas, I. Toll-like receptor activation suppresses ER stress factor CHOP and translation inhibition through activation of eIF2B. Nat. Cell Biol. 14, 192–200 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  137. Woo, C. W. et al. Adaptive suppression of the ATF4-CHOP branch of the unfolded protein response by toll-like receptor signalling. Nat. Cell Biol. 11, 1473–1480 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  138. Chopra, S. et al. IRE1alpha-XBP1 signaling in leukocytes controls prostaglandin biosynthesis and pain. Science 365, eaau6499 (2019).

    CAS  PubMed  Google Scholar 

  139. Lipson, K. L. et al. Regulation of insulin biosynthesis in pancreatic beta cells by an endoplasmic reticulum-resident protein kinase IRE1. Cell Metab. 4, 245–254 (2006).

    CAS  PubMed  Google Scholar 

  140. Karali, E. et al. VEGF Signals through ATF6 and PERK to promote endothelial cell survival and angiogenesis in the absence of ER stress. Mol. Cell 54, 559–572 (2014).

    CAS  PubMed  Google Scholar 

  141. Iwakoshi, N. N. et al. Plasma cell differentiation and the unfolded protein response intersect at the transcription factor XBP-1. Nat. Immunol. 4, 321–329 (2003).

    CAS  PubMed  Google Scholar 

  142. van Anken, E. et al. Sequential waves of functionally related proteins are expressed when B cells prepare for antibody secretion. Immunity 18, 243–253 (2003).

    PubMed  Google Scholar 

  143. Morimoto, R. I. Cell-nonautonomous regulation of proteostasis in aging and disease. Cold Spring Harb. Perspect. Biol. https://doi.org/10.1101/cshperspect.a034074 (2019).

    Article  Google Scholar 

  144. Williams, K. W. et al. Xbp1s in Pomc neurons connects ER stress with energy balance and glucose homeostasis. Cell Metab. 20, 471–482 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  145. Martinez, G., Duran-Aniotz, C., Cabral-Miranda, F., Vivar, J. P. & Hetz, C. Endoplasmic reticulum proteostasis impairment in aging. Aging Cell 16, 615–623 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  146. Taylor, R. C. & Dillin, A. XBP-1 is a cell-nonautonomous regulator of stress resistance and longevity. Cell 153, 1435–1447 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  147. Imanikia, S., Ozbey, N. P., Krueger, C., Casanueva, M. O. & Taylor, R. C. Neuronal XBP-1 activates intestinal lysosomes to improve proteostasis in C. elegans. Curr. Biol. 29, 2322–2338 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  148. Daniele, J. R. et al. UPR(ER) promotes lipophagy independent of chaperones to extend life span. Sci. Adv. 6, eaaz1441 (2020).

    PubMed  PubMed Central  Google Scholar 

  149. Matai, L. et al. Dietary restriction improves proteostasis and increases life span through endoplasmic reticulum hormesis. Proc. Natl Acad. Sci. USA 116, 17383–17392 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  150. Frakes, A. E. & Dillin, A. The UPR(ER): sensor and coordinator of organismal homeostasis. Mol. Cell 66, 761–771 (2017).

    CAS  PubMed  Google Scholar 

  151. Luis, N. M. et al. Intestinal IRE1 is required for increased triglyceride metabolism and longer lifespan under dietary restriction. Cell Rep. 17, 1207–1216 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  152. Dufey E. et al. Genotoxic stress triggers the selective activation of IRE1α-dependent RNA decay to modulate the DNA damage response. Nat. Commun. In press (2020).

  153. Huang, C. et al. Identification of XBP1-u as a novel regulator of the MDM2/p53 axis using an shRNA library. Sci. Adv. 3, e1701383 (2017).

    PubMed  PubMed Central  Google Scholar 

  154. Zhang, K. et al. The unfolded protein response transducer IRE1alpha prevents ER stress-induced hepatic steatosis. EMBO J. 30, 1357–1375 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  155. Yamamoto, K. et al. Induction of liver steatosis and lipid droplet formation in ATF6alpha-knockout mice burdened with pharmacological endoplasmic reticulum stress. Mol. Biol. Cell 21, 2975–2986 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  156. Rutkowski, D. T. et al. UPR pathways combine to prevent hepatic steatosis caused by ER stress-mediated suppression of transcriptional master regulators. Dev. Cell 15, 829–840 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  157. Zhang, K. et al. Endoplasmic reticulum stress activates cleavage of CREBH to induce a systemic inflammatory response. Cell 124, 587–599 (2006).

    CAS  PubMed  Google Scholar 

  158. Bailey, D. & O’Hare, P. Transmembrane bZIP transcription factors in ER stress signaling and the unfolded protein response. Antioxid. Redox Signal. 9, 2305–2321 (2007).

    CAS  PubMed  Google Scholar 

  159. Zhang, C. et al. Endoplasmic reticulum-tethered transcription factor cAMP responsive element-binding protein, hepatocyte specific, regulates hepatic lipogenesis, fatty acid oxidation, and lipolysis upon metabolic stress in mice. Hepatology 55, 1070–1082 (2012).

    CAS  PubMed  Google Scholar 

  160. Zheng, Z. et al. CREBH couples circadian clock with hepatic lipid metabolism. Diabetes 65, 3369–3383 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  161. Kim, H. et al. Regulation of hepatic autophagy by stress-sensing transcription factor CREBH. FASEB J 33, 7896–7914 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  162. Kim, H. et al. Liver-enriched transcription factor CREBH interacts with peroxisome proliferator-activated receptor alpha to regulate metabolic hormone FGF21. Endocrinology 155, 769–782 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  163. Kim, H., Zheng, Z., Walker, P. D., Kapatos, G. & Zhang, K. CREBH maintains circadian glucose homeostasis by regulating hepatic glycogenolysis and gluconeogenesis. Mol. Cell Biol. 37, e00048-17 (2017).

    PubMed  PubMed Central  Google Scholar 

  164. Lee, M. W. et al. Regulation of hepatic gluconeogenesis by an ER-bound transcription factor, CREBH. Cell Metab. 11, 331–339 (2010).

    CAS  PubMed  Google Scholar 

  165. Lee, J. H. et al. The transcription factor cyclic AMP-responsive element-binding protein H regulates triglyceride metabolism. Nat. Med. 17, 812–815 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  166. Cefalu, A. B. et al. Novel CREB3L3 nonsense mutation in a family with dominant hypertriglyceridemia. Arterioscler. Thromb. Vasc. Biol. 35, 2694–2699 (2015).

    CAS  PubMed  Google Scholar 

  167. Harding, H. P. et al. Diabetes mellitus and exocrine pancreatic dysfunction in perk-/- mice reveals a role for translational control in secretory cell survival. Mol. Cell 7, 1153–1163 (2001).

    CAS  PubMed  Google Scholar 

  168. Back, S. H. et al. Translation attenuation through eIF2alpha phosphorylation prevents oxidative stress and maintains the differentiated state in beta cells. Cell Metab. 10, 13–26 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  169. Lee, A. H., Chu, G. C., Iwakoshi, N. N. & Glimcher, L. H. XBP-1 is required for biogenesis of cellular secretory machinery of exocrine glands. EMBO J. 24, 4368–4380 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  170. Delepine, M. et al. EIF2AK3, encoding translation initiation factor 2-alpha kinase 3, is mutated in patients with Wolcott-Rallison syndrome. Nat. Genet. 25, 406–409 (2000).

    CAS  PubMed  Google Scholar 

  171. Scheuner, D. et al. Control of mRNA translation preserves endoplasmic reticulum function in beta cells and maintains glucose homeostasis. Nat. Med. 11, 757–764 (2005).

    CAS  PubMed  Google Scholar 

  172. Song, B., Scheuner, D., Ron, D., Pennathur, S. & Kaufman, R. J. Chop deletion reduces oxidative stress, improves beta cell function, and promotes cell survival in multiple mouse models of diabetes. J. Clin. Invest. 118, 3378–3389 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  173. Ozcan, U. et al. Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes. Science 306, 457–461 (2004).

    PubMed  Google Scholar 

  174. Fu, S. et al. Aberrant lipid metabolism disrupts calcium homeostasis causing liver endoplasmic reticulum stress in obesity. Nature 473, 528–531 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  175. Urra, H., Dufey, E., Avril, T., Chevet, E. & Hetz, C. Endoplasmic reticulum stress and the Hallmarks of cancer. Trends Cancer 2, 252–262 (2016).

    PubMed  Google Scholar 

  176. Lee, A. S. GRP78 induction in cancer: therapeutic and prognostic implications. Cancer Res. 67, 3496–3499 (2007).

    CAS  PubMed  Google Scholar 

  177. Chen, X. et al. XBP1 promotes triple-negative breast cancer by controlling the HIF1alpha pathway. Nature 508, 103–107 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  178. Lhomond, S. et al. Dual IRE1 RNase functions dictate glioblastoma development. EMBO Mol. Med. 10, e7929 (2018).

    PubMed  PubMed Central  Google Scholar 

  179. Lee, A. H., Iwakoshi, N. N., Anderson, K. C. & Glimcher, L. H. Proteasome inhibitors disrupt the unfolded protein response in myeloma cells. Proc. Natl Acad. Sci. USA 100, 9946–9951 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  180. Tang, C. H. et al. Inhibition of ER stress-associated IRE-1/XBP-1 pathway reduces leukemic cell survival. J. Clin. Invest. 124, 2585–2598 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  181. Hetz, C., Axten, J. M. & Patterson, J. B. Pharmacological targeting of the unfolded protein response for disease intervention. Nat. Chem. Biol. 15, 764–775 (2019).

    CAS  PubMed  Google Scholar 

  182. Sheng, X. et al. IRE1alpha-XBP1s pathway promotes prostate cancer by activating c-MYC signaling. Nat. Commun. 10, 323 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  183. Wu, Y. et al. Dual role for inositol-requiring enzyme 1alpha in promoting the development of hepatocellular carcinoma during diet-induced obesity in mice. Hepatology 68, 533–546 (2018).

    CAS  PubMed  Google Scholar 

  184. Rubio-Patino, C. et al. Low-protein diet induces IRE1alpha-dependent anticancer immunosurveillance. Cell Metab. 27, 828–842 (2018).

    CAS  PubMed  Google Scholar 

  185. Niederreiter, L. et al. ER stress transcription factor Xbp1 suppresses intestinal tumorigenesis and directs intestinal stem cells. J. Exp. Med. 210, 2041–2056 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  186. Bi, M. et al. ER stress-regulated translation increases tolerance to extreme hypoxia and promotes tumor growth. EMBO J. 24, 3470–3481 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  187. Nguyen, H. G. et al. Development of a stress response therapy targeting aggressive prostate cancer. Sci. Transl Med. 10, eaar2036 (2018).

    PubMed  PubMed Central  Google Scholar 

  188. Bettigole, S. E. & Glimcher, L. H. Endoplasmic reticulum stress in immunity. Annu. Rev. Immunol. 33, 107–138 (2015).

    CAS  PubMed  Google Scholar 

  189. Zhang, K. et al. The unfolded protein response sensor IRE1alpha is required at 2 distinct steps in B cell lymphopoiesis. J. Clin. Invest. 115, 268–281 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  190. Todd, D. J. et al. XBP1 governs late events in plasma cell differentiation and is not required for antigen-specific memory B cell development. J. Exp. Med. 206, 2151–2159 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  191. Brunsing, R. et al. B- and T-cell development both involve activity of the unfolded protein response pathway. J. Biol. Chem. 283, 17954–17961 (2008).

    CAS  PubMed  Google Scholar 

  192. Iwakoshi, N. N., Pypaert, M. & Glimcher, L. H. The transcription factor XBP-1 is essential for the development and survival of dendritic cells. J. Exp. Med. 204, 2267–2275 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  193. Tavernier, S. J. et al. Regulated IRE1-dependent mRNA decay sets the threshold for dendritic cell survival. Nat. Cell Biol. 19, 698–710 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  194. Dong, H. et al. The IRE1 endoplasmic reticulum stress sensor activates natural killer cell immunity in part by regulating c-Myc. Nat Immunol 20, 865–878 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  195. Wu, S. et al. Ultraviolet light activates NFkappaB through translational inhibition of IkappaBalpha synthesis. J. Biol. Chem. 279, 34898–34902 (2004).

    CAS  PubMed  Google Scholar 

  196. Deng, J. et al. Translational repression mediates activation of nuclear factor kappa B by phosphorylated translation initiation factor 2. Mol. Cell Biol. 24, 10161–10168 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  197. Iwasaki, Y. et al. Activating transcription factor 4 links metabolic stress to interleukin-6 expression in macrophages. Diabetes 63, 152–161 (2014).

    CAS  PubMed  Google Scholar 

  198. Gargalovic, P. S. et al. The unfolded protein response is an important regulator of inflammatory genes in endothelial cells. Arterioscler. Thromb. Vasc. Biol. 26, 2490–2496 (2006).

    CAS  PubMed  Google Scholar 

  199. Wheeler, M. A. et al. Environmental control of astrocyte pathogenic activities in CNS inflammation. Cell 176, 581–596 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  200. Shan, B. et al. The metabolic ER stress sensor IRE1alpha suppresses alternative activation of macrophages and impairs energy expenditure in obesity. Nat. Immunol. 18, 519–529 (2017).

    CAS  PubMed  Google Scholar 

  201. Martinez, G., Khatiwada, S., Costa-Mattioli, M. & Hetz, C. ER proteostasis control of neuronal physiology and synaptic function. Trends Neurosci. 41, 610–624 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  202. Sidrauski, C. et al. Pharmacological brake-release of mRNA translation enhances cognitive memory. eLife 2, e00498 (2013).

    PubMed  PubMed Central  Google Scholar 

  203. Martinez, G. et al. Regulation of memory formation by the transcription factor XBP1. Cell Rep. 14, 1382–1394 (2016).

    CAS  PubMed  Google Scholar 

  204. Laguesse, S. et al. A dynamic unfolded protein response contributes to the control of cortical neurogenesis. Dev. Cell 35, 553–567 (2015).

    CAS  PubMed  Google Scholar 

  205. Fox, J. W. et al. Mutations in filamin 1 prevent migration of cerebral cortical neurons in human periventricular heterotopia. Neuron 21, 1315–1325 (1998).

    CAS  PubMed  Google Scholar 

  206. Hayashi, A., Kasahara, T., Kametani, M. & Kato, T. Attenuated BDNF-induced upregulation of GABAergic markers in neurons lacking Xbp1. Biochem. Biophys. Res. Commun. 376, 758–763 (2008).

    CAS  PubMed  Google Scholar 

  207. Hetz, C. & Saxena, S. ER stress and the unfolded protein response in neurodegeneration. Nat. Rev. Neurol. 13, 477–491 (2017).

    CAS  PubMed  Google Scholar 

  208. Freeman, O. J. & Mallucci, G. R. The UPR and synaptic dysfunction in neurodegeneration. Brain Res. 1648, 530–537 (2016).

    CAS  PubMed  Google Scholar 

  209. Halliday, M. et al. Repurposed drugs targeting eIF2α-P-mediated translational repression prevent neurodegeneration in mice. Brain 140, 1768–1783 (2017).

    PubMed  PubMed Central  Google Scholar 

  210. Moreno, J. A. et al. Sustained translational repression by eIF2alpha-P mediates prion neurodegeneration. Nature 485, 507–511 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  211. Valdes, P. et al. Control of dopaminergic neuron survival by the unfolded protein response transcription factor XBP1. Proc. Natl Acad. Sci. USA 111, 6804–6809 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  212. Hetz, C. et al. XBP-1 deficiency in the nervous system protects against amyotrophic lateral sclerosis by increasing autophagy. Genes Dev. 23, 2294–2306 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  213. Vidal, R. L. et al. Targeting the UPR transcription factor XBP1 protects against Huntington’s disease through the regulation of FoxO1 and autophagy. Hum. Mol. Genet. 21, 2245–2262 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  214. Duran-Aniotz, C. et al. IRE1 signaling exacerbates Alzheimer’s disease pathogenesis. Acta Neuropathol. 134, 489–506 (2017).

    CAS  PubMed  Google Scholar 

  215. Hetz, C. et al. Unfolded protein response transcription factor XBP-1 does not influence prion replication or pathogenesis. Proc. Natl Acad. Sci. USA 105, 757–762 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  216. Valenzuela, V. et al. Activation of the unfolded protein response enhances motor recovery after spinal cord injury. Cell Death Dis. 3, e272 (2012).

    CAS  PubMed  Google Scholar 

  217. Onate, M. et al. Activation of the unfolded protein response promotes axonal regeneration after peripheral nerve injury. Sci. Rep. 6, 21709 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  218. Valenzuela, V., Jackson, K. L., Sardi, S. P. & Hetz, C. Gene therapy strategies to restore ER proteostasis in disease. Mol. Ther. 26, 1404–1413 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  219. Belyy, V., Tran, N. H. & Walter, P. Quantitative microscopy reveals dynamics and fate of clustered IRE1alpha. Proc. Natl Acad. Sci. USA 117, 1533–1542 (2020).

    CAS  PubMed  Google Scholar 

  220. Hughes, D. & Mallucci, G. R. The unfolded protein response in neurodegenerative disorders - therapeutic modulation of the PERK pathway. FEBS J. 286, 342–355 (2019).

    CAS  PubMed  Google Scholar 

  221. Axten, J. M. et al. Discovery of GSK2656157: an optimized PERK inhibitor selected for preclinical development. ACS Med. Chem. Lett. 4, 964–968 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  222. Spaan, C. N. et al. Expression of UPR effector proteins ATF6 and XBP1 reduce colorectal cancer cell proliferation and stemness by activating PERK signaling. Cell Death Dis. 10, 490 (2019).

    PubMed  PubMed Central  Google Scholar 

  223. Kohl, S. et al. Mutations in the unfolded protein response regulator ATF6 cause the cone dysfunction disorder achromatopsia. Nat. Genet. 47, 757–765 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  224. Richardson, P. G., Mitsiades, C., Hideshima, T. & Anderson, K. C. Bortezomib: proteasome inhibition as an effective anticancer therapy. Annu. Rev. Med. 57, 33–47 (2006).

    CAS  PubMed  Google Scholar 

  225. Shiu, R. P., Pouyssegur, J. & Pastan, I. Glucose depletion accounts for the induction of two transformation-sensitive membrane proteinsin Rous sarcoma virus-transformed chick embryo fibroblasts. Proc. Natl Acad. Sci. USA 74, 3840–3844 (1977).

    CAS  PubMed  PubMed Central  Google Scholar 

  226. Haas, I. G. & Wabl, M. Immunoglobulin heavy chain binding protein. Nature 306, 387–389 (1983).

    CAS  PubMed  Google Scholar 

  227. Munro, S. & Pelham, H. R. An Hsp70-like protein in the ER: identity with the 78 kd glucose-regulated protein and immunoglobulin heavy chain binding protein. Cell 46, 291–300 (1986).

    CAS  PubMed  Google Scholar 

  228. Fornace, A. J. Jr. et al. Mammalian genes coordinately regulated by growth arrest signals and DNA-damaging agents. Mol. Cell Biol. 9, 4196–4203 (1989).

    CAS  PubMed  PubMed Central  Google Scholar 

  229. Kozutsumi, Y., Segal, M., Normington, K., Gething, M. J. & Sambrook, J. The presence of malfolded proteins in the endoplasmic reticulum signals the induction of glucose-regulated proteins. Nature 332, 462–464 (1988).

    CAS  PubMed  Google Scholar 

  230. Dorner, A. J., Wasley, L. C. & Kaufman, R. J. Increased synthesis of secreted proteins induces expression of glucose-regulated proteins in butyrate-treated Chinese hamster ovary cells. J. Biol. Chem. 264, 20602–20607 (1989).

    CAS  PubMed  Google Scholar 

  231. Cox, J. S., Shamu, C. E. & Walter, P. Transcriptional induction of genes encoding endoplasmic reticulum resident proteins requires a transmembrane protein kinase. Cell 73, 1197–1206 (1993).

    CAS  PubMed  Google Scholar 

  232. Mori, K., Ma, W., Gething, M. J. & Sambrook, J. A transmembrane protein with a cdc2 + /CDC28-related kinase activity is required for signaling from the ER to the nucleus. Cell 74, 743–756 (1993).

    CAS  PubMed  Google Scholar 

  233. Cox, J. S. & Walter, P. A novel mechanism for regulating activity of a transcription factor that controls the unfolded protein response. Cell 87, 391–404 (1996).

    CAS  PubMed  Google Scholar 

  234. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  235. Wang, X. Z. et al. Cloning of mammalian Ire1 reveals diversity in the ER stress responses. EMBO J. 17, 5708–5717 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  236. Liou, H. C. et al. A new member of the leucine zipper class of proteins that binds to the HLA DR alpha promoter. Science 247, 1581–1584 (1990).

    CAS  PubMed  Google Scholar 

  237. Shi, Y. et al. Identification and characterization of pancreatic eukaryotic initiation factor 2 alpha-subunit kinase, PEK, involved in translational control. Mol. Cell Biol. 18, 7499–7509 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  238. Yoshida, H., Haze, K., Yanagi, H., Yura, T. & Mori, K. Identification of the cis-acting endoplasmic reticulum stress response element responsible for transcriptional induction of mammalian glucose-regulated proteins. Involvement of basic leucine zipper transcription factors. J. Biol. Chem. 273, 33741–33749 (1998).

    CAS  PubMed  Google Scholar 

  239. Wu, H., Carvalho, P. & Voeltz, G. K. Here, there, and everywhere: the importance of ER membrane contact sites. Science 361 (2018).

  240. Theurey, P. & Rieusset, J. Mitochondria-associated membranes response to nutrient availability and role in metabolic diseases. Trends Endocrinol. Metab. 28, 32–45 (2017).

    CAS  PubMed  Google Scholar 

  241. Novikoff, A. B., Novikoff, P. M., Rosen, O. M. & Rubin, C. S. Organelle relationships in cultured 3T3-L1 preadipocytes. J. Cell Biol. 87, 180–196 (1980).

    CAS  PubMed  Google Scholar 

  242. Rambold, A. S., Cohen, S. & Lippincott-Schwartz, J. Fatty acid trafficking in starved cells: regulation by lipid droplet lipolysis, autophagy, and mitochondrial fusion dynamics. Dev. Cell 32, 678–692 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  243. Settembre, C., Fraldi, A., Medina, D. L. & Ballabio, A. Signals from the lysosome: a control centre for cellular clearance and energy metabolism. Nat. Rev. Mol. Cell Biol. 14, 283–296 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors thank H. Urra for initial figure and table design. This work was directly funded by ANID/FONDAP/15150012, the Chilean Millennium Institute of Biomedical Neuroscience Institute BNI (grant P09-015-F), CONICYT–Brazil 441921/2016-7, FONDEF ID16I10223, FONDEF D11E1007 and FONDECYT 1180186 (C.H.). In addition, the authors thank the US Air Force Office of Scientific Research (grant FA9550-16-1-0384) (C.H.), the Michael J Fox Research Foundation, Target Validation Grant 12473.01 and ECOS CONICYT Cooperation grant Chile-France ECOS170032 (C.H.), the US National Institutes of Health (grants DK090313 and AR066634) (K.Z.) and the American Heart Association (grants 0635423Z and 09GRNT2280479) (K.Z.) for support. The authors acknowledge support from National Institutes of Health/National Cancer Institute grants R01DK113171, R01DK103185, R24DK110973, R01AG06219 and R01CA198103 and the Sanford Burnham Prebys Cancer Center grant P30 CA030199 (R.J.K.). R.J.K. is a member of the University of California, San Diego Diabetes Research Center (P30 DK063491) and an adjunct professor in the Department of Pharmacology, University of California, San Diego. The authors thank J. Yong and C. Lebeaupin for critical comments on the manuscript.

Author information

Authors and Affiliations

Authors

Contributions

The authors contributed equally to the writing and revisions of the article.

Corresponding authors

Correspondence to Claudio Hetz, Kezhong Zhang or Randal J. Kaufman.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Glossary

Signal recognition particle

A conserved, cytosolic ribonucleoprotein that recognizes and targets specific proteins to the endoplasmic reticulum membrane or plasma membrane.

Apoptosome

A quaternary protein complex, composed of mitochondrial cytochrome c, apoptotic protease activating factor 1 and deoxyadenosine triphosphate, formed in the process of apoptosis in response to cell death stimulus.

BCL-2 family

A protein family consisting of approximately 25 members that either promote or inhibit apoptosis by protein interactions that regulate mitochondrial outer membrane permeabilization.

Proteotoxicity

Adverse effects of aberrant or misfolded proteins that cause impairment of cell function.

Pre-B lymphocytes

A developmental stage of B lymphocytes defined by the expression of membrane µ-chains with surrogate light chains in the pre-B receptor, which is composed of two surrogate light chains and two immunoglobulin heavy chains expressed on the cell surface.

HSP70

A family of conserved ubiquitously expressed heat shock proteins that function as molecular chaperones or folding catalysts to assist protein folding or protect cells from stress.

COPII

A type of vesicle coat protein that transports newly synthesized proteins from the endoplasmic reticulum to the Golgi apparatus.

Collagens

The most abundant structural proteins in the extracellular matrix in connective tissues in mammals.

Foldases

Molecular chaperones that support the folding of nascent protein peptides in the endoplasmic reticulum.

Translocon

A complex of proteins associated with the translocation of nascent protein peptides into the luminal space of the endoplasmic reticulum from the cytosol within a cell.

Inositsol 1,4,5-trisphosphate receptors

Endoplasmic reticulum membrane glycoprotein complexes that act as the Ca2+ release channels within cells.

Lamellipodia

Thin plates of cytoplasm produced by cytoskeletal protein actin on the leading edge of a cell.

Filopodia

Thin, actin-rich cytoplasmic projections that extend beyond the edge of lamellipodia in cells.

Phospholipase Cγ1

(PLCγ). Catalyses the formation of inositol 1,4,5-trisphosphate and diacylglycerol from phosphatidylinositol 4,5-bisphosphate and plays an important role in signal transduction of receptor-mediated tyrosine kinase activators.

CCAAT/enhancer-binding protein

A member of a family of leucine zipper domain-containing transcription factors that are functionally involved in different cellular responses, such as in the control of cell growth and differentiation, metabolism and immunity.

Peroxisome proliferator-activated receptor

A member of a group of ligand-regulated transcription factors that control gene expression by binding to specific peroxisome proliferator hormone response elements within promoters.

Hepatic steatosis

A reversible condition in which excessive triglyceride fat accumulate in the liver cells, causing liver inflammation and fibrosis when the condition persists.

Innate immune response

The first line of non-specific immune response consisting of physical, chemical and cellular defences against the spread and movement of foreign pathogens.

Adaptive immune response

The acquired immune response that is primarily mediated by T and B lymphocytes to attack specific pathogens.

Isotype switching

A biological process that changes immunoglobulin production of B lymphocytes from one type to another; also known as immunoglobulin class switching.

UPRosome

A protein complex assembled at the level of IRE1α that regulates its activity and mediates the crosstalk with other signalling pathways and biological processes.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Hetz, C., Zhang, K. & Kaufman, R.J. Mechanisms, regulation and functions of the unfolded protein response. Nat Rev Mol Cell Biol 21, 421–438 (2020). https://doi.org/10.1038/s41580-020-0250-z

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41580-020-0250-z

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing