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Mechanisms, regulation and functions of the unfolded protein response
Open accessAbstract
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. The unfolded protein response (UPR) comprises a network of signalling pathways that reprogramme transcription, translation and protein modifications to relieve the load of unfolded or misfolded proteins in the endoplasmic reticulum lumen and restore proteostasis. Understanding the regulation of the UPR and the role it has in the pathophysiology of various cell types and organs might open new therapeutic avenues.
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“This triggers the activation of both intrinsic (caspase-9-mediated) and extrinsic (caspase-8-mediated) apoptotic pathways, ultimately resulting in DNA fragmentation and cell cycle arrest [45,46].”
From Role of Regulated Cell Death Pathways in Snakebite Envenomation: Mechanisms, Crosstalk, and Therapeutic Opportunities (2026) · cites this paper as [46]
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“This activated UPR tries to rescue cells from ER stress by two pathways—the PERK/EIF2AK3 pathway, which reduces protein synthesis, and the IRE1/ERN1 pathway, which increases protein folding [46].”
From Role of Regulated Cell Death Pathways in Snakebite Envenomation: Mechanisms, Crosstalk, and Therapeutic Opportunities (2026) · cites this paper as [46]
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“Contrary to canonical stress responses that induce a reduction in protein synthesis5,6”
From Proteotoxic stress response drives T cell exhaustion and immune evasion (2025) · cites this paper as [5]
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“The proteostasis network also collapses when mechanisms assuring quality control fail, for instance due to reduced function of the unfolded protein response (UPR) in the endoplasmic reticulum (ER) 84 , when stabilization of correctly folded proteins is compromised, or when mechanisms for the degradation of proteins by the proteasome or the lysosome become insufficient (Fig.”
From Hallmarks of aging: An expanding universe (2023) · cites this paper as [84]
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Items 201–248 of 248
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Imanikia, S., Özbey, N. P., Krueger, C., Casanueva, O., & Taylor, R. C. (2019) · Current Biology · doi:10.1016/j.cub.2019.06.031 · Cited by 110
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Tavernier, S. J., Osorio, F., Vandersarren, L., Vetters, J., Vanlangenakker, N., Isterdael, G. V., Vergote, K., Rycke, R. M. D., Parthoens, E., van de Laar, L., et al. (2017) · Nature Cell Biology · doi:10.1038/ncb3518 · Cited by 109
Acosta‐Alvear, D., Karagöz, G. E., Fröhlich, F., Han, L., Walther, T. C., & Walter, P. (2018) · eLife · doi:10.7554/elife.43036 · Cited by 108
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Plumb, R., Zhang, Z.-R., Appathurai, S., & Mariappan, M. (2015) · eLife · doi:10.7554/elife.07426 · Cited by 104
Oñate, M., Catenaccio, A., Martínez, G., Armentano, D., Parsons, G., Kerr, B., Hetz, C. A., & Court, F. A. (2016) · Scientific Reports · doi:10.1038/srep21709 · Cited by 100
Self-citationMao, T., Shao, M., Qiu, Y., Huang, J., Zhang, Y., Song, B., Wang, Q. A., Jiang, L., Liu, Y., Han, J. J., et al. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1107394108 · Cited by 98
Cell-Nonautonomous Regulation of Proteostasis in Aging and DiseasePreprint
Morimoto, R. I. (2019) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a034074 · Cited by 98
B- and T-cell Development Both Involve Activity of the Unfolded Protein Response Pathway
Brunsing, R. L., Omori, S. A., Weber, F., Bicknell, A. A., Friend, L., Rickert, R. C., & Niwa, M. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m801395200 · Cited by 95
Dufey, E., Pedro, J. M. B., Eggers, C., González-Quiroz, M., Urra, H., Sagredo, A. I., Sepúlveda, D., Pihán, P., Carreras‐Sureda, A., Hazari, Y., et al. (2020) · Nature Communications · doi:10.1038/s41467-020-15694-y · Cited by 92
Self-citationNakato, R., Ohkubo, Y., Konishi, A., Shibata, M., Kaneko, Y., Iwawaki, T., Nakamura, T., Lipton, S. A., & Uehara, T. (2015) · Scientific Reports · doi:10.1038/srep14812 · Cited by 90
Rojas‐Rivera, D., Armisén, R., Colombo, A., Martínez, G., Eguiguren, A. L., Díaz, A., Kiviluoto, S., Rodríguez, D. A., Patrón, M., Rizzuto, R., et al. (2012) · Cell Death and Differentiation · doi:10.1038/cdd.2011.189 · Cited by 86
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Oka, O., van Lith, M., Rudolf, J., Tungkum, W., Pringle, M. A., & Bulleid, N. J. (2019) · The EMBO Journal · doi:10.15252/embj.2018100990 · Cited by 86
Zhu, X., Zhang, J., Sun, H., Jiang, C., Dong, Y., Shan, Q., Su, S., Xie, Y., Xu, N., Lou, X., et al. (2014) · Journal of Biological Chemistry · doi:10.1074/jbc.m114.562868 · Cited by 83
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Shanmuganathan, V., Schiller, N., Magoulopoulou, A., Cheng, J., Braunger, K., Cymer, F., Berninghausen, O., Beatrix, B., Kohno, K., von HEIJNE, G., et al. (2019) · eLife · doi:10.7554/elife.46267 · Cited by 81
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Pinkaew, D., Chattopadhyay, A., King, M. D., Chunhacha, P., Liu, Z., Stevenson, H. L., Chen, Y., Sinthujaroen, P., McDougal, O. M., & Fujise, K. (2017) · Nature Communications · doi:10.1038/s41467-017-00029-1 · Cited by 80
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Daniele, J. R., Higuchi‐Sanabria, R., Durieux, J., Monshietehadi, S., Ramachandran, V., Tronnes, S. U., Kelet, N., Sanchez, M., Metcalf, M. G., Garcia, G., et al. (2020) · Science Advances · doi:10.1126/sciadv.aaz1441 · Cited by 79
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Zheng, Z., Kim, H., Qiu, Y., Chen, X., Méndez, R., Dandekar, A. P., Zhang, X., Zhang, C., Liu, A. C., Yin, L., et al. (2016) · Diabetes · doi:10.2337/db16-0298 · Cited by 76
Self-citationWu, Y., Shan, B., Dai, J., Xia, Z., Cai, J., Chen, T., Lv, S., Feng, Y., Zheng, L., Wang, Y., et al. (2018) · Hepatology · doi:10.1002/hep.29871 · Cited by 75
Kopp, M. C., Nowak, P. R., Larburu, N., Adams, C. J., & Ali, M. M. U. (2018) · eLife · doi:10.7554/elife.30257 · Cited by 73
Fun, X. H., & Thibault, G. (2019) · Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids · doi:10.1016/j.bbalip.2019.04.009 · Cited by 71
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Wang, J., Qiu, Y., Yang, Z.-Q., Li, L., & Zhang, K. (2016) · Diabetes · doi:10.2337/db16-0052 · Cited by 69
Self-citationIdentification of XBP1-u as a novel regulator of the MDM2/p53 axis using an shRNA library
Huang, C., Wu, S., Ji, H., Yan, X., Xie, Y., Murai, S., Zhao, H., Miyagishi, M., & Kasim, V. (2017) · Science Advances · doi:10.1126/sciadv.1701383 · Cited by 67
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Freeman, O. J., & Mallucci, G. R. (2016) · Brain Research · doi:10.1016/j.brainres.2016.03.029 · Cited by 66
Luis, N. M., Wang, L., Ortega, M., Deng, H., Katewa, S. D., Li, P. W.-L., Karpac, J., Jasper, H., & Kapahi, P. (2016) · Cell Reports · doi:10.1016/j.celrep.2016.10.003 · Cited by 65
Amin-Wetzel, N., Neidhardt, L., Yan, Y., Mayer, M. P., & Ron, D. (2019) · eLife · doi:10.7554/elife.50793 · Cited by 63
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He, Y., Beatty, A., Han, X., Ji, Y., Ma, X., Adelstein, R. S., Yates, J. R., Kemphues, K. J., & Qi, L. (2012) · Developmental Cell · doi:10.1016/j.devcel.2012.11.006 · Cited by 61
Kanda, S., Yanagitani, K., Yokota, Y., Esaki, Y., & Kohno, K. (2016) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1604435113 · Cited by 61
Kim, H., Zheng, Z., Walker, P. D., Kapatos, G., & Zhang, K. (2017) · Molecular and Cellular Biology · doi:10.1128/mcb.00048-17 · Cited by 59
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Lü, G., Ota, A., Ren, S. V., Franklin, S., Rau, C. D., Ping, P., Lane, T. F., Zhou, Z. H., Reue, K., Lusis, A. J., et al. (2013) · Molecular Metabolism · doi:10.1016/j.molmet.2013.07.005 · Cited by 47
Lam, M., Lawrence, D. A., Ashkenazi, A., & Walter, P. (2018) · Cell Death and Differentiation · doi:10.1038/s41418-018-0155-y · Cited by 44
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Shi, L., Wang, Z., Liu, X., et al. (2018) · Neurological Research · doi:10.1080/01616412.2018.1424699 · Cited by 18
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Self-citation
Metadata
- Authors
- Hetz, C., Zhang, K., & Kaufman, R. J.
- Affiliations
- Buck Institute for Research on Aging (US)
- Wayne State University (US)
- Sanford Burnham Prebys Medical Discovery Institute (US)
- Corresponding author
- Hetz, Claudio
- Zhang, Kezhong
- Kaufman, Randal J.
- Venue
- Nature Reviews Molecular Cell Biology
- Published
- 2020-05-26
- Volume
- 21
- Issue
- 8
- Pages
- 421-438
- ISSN
- 1471-0072 (ISSN-L)
- 1471-0080
- PMC
- PMC8867924
- OpenAlex
- W3030834164
- Semantic Scholar
- e69807ca7949b3a6a61babc7fbc8afe4f0341b1e
- Cited by
- 2,666
- References
- 248
- Citations by year
- 2026: 480 · 2025: 586 · 2024: 555 · 2023: 412 · 2022: 356 · 2021: 229 · 2020: 44
- FWCI
- 30.36
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature Reviews Molecular Cell Biology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Universidad de Chile (submittedVersion)
- Funders
- National Institutes of Health (2r01dk090313-11a1)
- National Cancer Institute (R01CA198103, P30CA030199)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK113171, R24DK110973, R01-DK-090313, R01DK103185, P30DK063491)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01AR066634)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Endoplasmic Reticulum Stress and Disease
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
- Life Sciences › Neuroscience › Sensory Systems › Ion Channels and Receptors
- Keywords
- unfolded protein response, endoplasmic reticulum stress, ER proteostasis, protein folding, apoptosis, transcriptional reprogramming, translational regulation, protein modification, disease pathophysiology, therapeutic target
- MeSH terms
- Animals, Endoplasmic Reticulum, Humans, Neoplasms, Proteins, Signal Transduction, Apoptosis, Protein Folding, Unfolded Protein Response, Endoplasmic Reticulum Stress
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