Perk is essential for translational regulation and cell survival during the unfolded protein response
Open accessAbstract
Malfolded proteins in the endoplasmic reticulum (ER) inhibit translation initiation. This response is believed to be mediated by increased phosphorylation of eukaryotic initiation factor 2alpha (eIF2alpha) and is hypothesized to reduce the work load imposed on the folding machinery during stress. Here we report that mutating the gene encoding the ER stress-activated eIF2alpha kinase PERK abolishes the phosphorylation of eIF2alpha in response to accumulation of malfolded proteins in the ER resulting in abnormally elevated protein synthesis and higher levels of ER stress. Mutant cells are markedly impaired in their ability to survive ER stress and inhibition of protein synthesis by cycloheximide treatment during ER stress ameliorates this impairment. PERK thus plays a major role in the ability of cells to adapt to ER stress.
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In mice, homozygous deletion of the gene encoding PERK causes massive and rapid β-cell apoptosis, leading to infantile diabetes.
“Coherently, in mice homozygous deletion of the gene encoding PERK causes massive and rapid β-cell apoptosis, leading to infantile diabetes.”
From GANAB and N-Glycans Substrates Are Relevant in Human Physiology, Polycystic Pathology and Multiple Sclerosis: A Review (2022) · cites this paper as [394]
β-cells in Perk-null mice are distended with electron-dense proteinaceous material and exhibit a high rate of apoptosis.
“Interestingly, β-cells in Perk-null mice are distended with electron-dense proteinaceous material, also exhibiting a high rate of apoptosis [393,394].”
From GANAB and N-Glycans Substrates Are Relevant in Human Physiology, Polycystic Pathology and Multiple Sclerosis: A Review (2022) · cites this paper as [394]
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“Interestingly, β-cells in Perk-null mice are distended with electron-dense proteinaceous material, also exhibiting a high rate of apoptosis [393,394].”
BackgroundCuinat, S., Bézieau, S., Deb, W., Mercier, S., Vignard, V., Isidor, B., Küry, S., & Ebstein, F. (2024) · Genes & Diseases · doi:10.1016/j.gendis.2023.101130 · Cited by 10 · see citing works
- Authors
- Harding, H. P., Zhang, Y., Bertolotti, A., Zeng, H., & Ron, D.
- Affiliations
- NYU Langone Health (US)
- Corresponding author
- Ron, David
- Venue
- Molecular Cell
- Publisher
- Elsevier BV
- Published
- 2000-05
- Volume
- 5
- Issue
- 5
- Pages
- 897-904
- ISSN
- 1097-2765 (ISSN-L)
- OpenAlex
- W1991999080
- Cited by
- 2,021
- References
- 25
- Citations by year
- 2026: 54 · 2025: 62 · 2024: 69 · 2023: 71 · 2022: 91 · 2021: 115 · 2020: 110 · 2019: 98 · 2018: 104 · 2017: 108 · 2016: 86 · 2015: 93 · 2014: 116 · 2013: 103 · 2012: 92
- FWCI
- 16.60
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Molecular Cell (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Funders
- National Institute of Diabetes and Digestive and Kidney Diseases (DK-47119)
- National Institute of Environmental Health Sciences (ES 08681, R01ES008681)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Endoplasmic Reticulum Stress and Disease
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
- Keywords
- PERK, unfolded protein response, endoplasmic reticulum stress, eIF2α phosphorylation, translational regulation, endoplasmic reticulum, cell survival, protein synthesis, cycloheximide, stress adaptation
- MeSH terms
- Adaptation, Physiological, Animals, Cell Survival, Cycloheximide, Endoplasmic Reticulum, Gene Expression Regulation, Mutation, Phosphorylation, Protein Synthesis Inhibitors, Protein Biosynthesis, Tunicamycin, Eukaryotic Initiation Factor-2, Protein Folding, eIF-2 Kinase, Mice
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