The DOI matches its Crossref record; 248 of the 248 references it cites were found in a registry or an index.
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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1 retracted
Proapoptotic BAX and BAK Modulate the Unfolded Protein Response by a Direct Interaction with IRE1α
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Self-citationRetractedSignal integration in the endoplasmic reticulum unfolded protein response
Ron, D., & Walter, P. (2007) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2199 · Cited by 6,431
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Walter, P., & Ron, D. (2011) · Science · doi:10.1126/science.1209038 · Cited by 5,897
Control of inositol 1,4,5-trisphosphate-induced Ca2+ release by cytosolic Ca2+
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Proapoptotic BAX and BAK: A Requisite Gateway to Mitochondrial Dysfunction and Death
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Endoplasmic Reticulum Stress Links Obesity, Insulin Action, and Type 2 Diabetes
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An Integrated Stress Response Regulates Amino Acid Metabolism and Resistance to Oxidative Stress
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Sorted by citations
Hallmarks of aging: An expanding universe
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Chen, X., & Cubillos-Ruiz, J. R. (2021) · Nature Reviews Cancer · doi:10.1038/s41568-020-00312-2 · Cited by 1,356
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Loh, J. S., Mak, W. Q., Tan, L. K. S., Ng, C. X., Chan, H. H., Yeow, S. H., Foo, J. B., Ong, Y. S., How, C. W., & Khaw, K. Y. (2024) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-024-01743-1 · Cited by 1,193
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Endoplasmic reticulum stress and unfolded protein response in cardiovascular diseases
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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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