ArticleThe Journal of biological chemistry2018
The protein kinase PERK/EIF2AK3 regulates proinsulin processing not via protein synthesis but by controlling endoplasmic reticulum chaperones.
Article in The Journal of biological chemistry, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 31 papers.
What it found
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
31 citing papers in PubMed, 43 citations in OpenAlex.
- Mitochondria-Endoplasmic Reticulum Crosstalk in Pancreatic β-Cell Stress: A Driver of Diabetes.Cells · 2026Review
- The comparative cell physiology of stem cell-derived and primary human β cells.Nature reviews. Endocrinology · 2026Review
- The PERK inhibitor GSK2606414 evokes developmental defects in zebrafish consistent with Wolcott-Rallison syndrome phenotypes.Pharmacological reports : PR · 2026Article
- The integrated stress response in pancreatic β-cell failure in diabetes: from molecular mechanisms to precision therapeutics.Frontiers in endocrinology · 2026Review
- Endoplasmic reticulum stress-related genes play a role in the prognosis of lung adenocarcinoma.Discover oncology · 2025Article
- PERK-Olating Through Cancer: A Brew of Cellular Decisions.Biomolecules · 2025Review
- Exploring proinsulin proteostasis: insights into beta cell health and diabetes.Frontiers in molecular biosciences · 2025Review
- Protein aggregates and biomolecular condensates: implications for human health and disease.Frontiers in molecular biosciences · 2025Review
- Endoplasmic reticulum stress in diseases.MedComm · 2024Review
- Proinsulin folding and trafficking defects trigger a common pathological disturbance of endoplasmic reticulum homeostasis.Protein science : a publication of the Protein Society · 2024Article
- Review
- The pathology of oxidative stress-induced autophagy in a chronic rotator cuff enthesis tear.Frontiers in physiology · 2023Review
- Reshaping endoplasmic reticulum quality control through the unfolded protein response.Molecular cell · 2022Review
- The Regulation of Endoplasmic Reticulum Stress in Cancer: Special Focuses on Luteolin Patents.Molecules (Basel, Switzerland) · 2022Review
- Stress-responsive regulation of extracellular proteostasis.The Journal of cell biology · 2022Review
- Vertical sleeve gastrectomy triggers fast β-cell recovery upon overt diabetes.Molecular metabolism · 2021Article
- Co-opting regulation bypass repair as a gene-correction strategy for monogenic diseases.Molecular therapy : the journal of the American Society of Gene Therapy · 2021Article
- Living Dangerously: Protective and Harmful ER Stress Responses in Pancreatic β-Cells.Diabetes · 2021Review
- Normal and defective pathways in biogenesis and maintenance of the insulin storage pool.The Journal of clinical investigation · 2021Review
- CTRP1 Attenuates Cerebral Ischemia/Reperfusion Injury via the PERK Signaling Pathway.Frontiers in cell and developmental biology · 2021Article
Corrections and comments
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Authors and funding
11 authors at 4 institutions in 3 countries.
Funding
Abstract
Loss-of-function mutations of the protein kinase PERK (EIF2AK3) in humans and mice cause permanent neonatal diabetes and severe proinsulin aggregation in the endoplasmic reticulum (ER), highlighting the essential role of PERK in insulin production in pancreatic β cells. As PERK is generally known as a translational regulator of the unfolded protein response (UPR), the underlying cause of these β cell defects has often been attributed to derepression of proinsulin synthesis, resulting in proinsulin overload in the ER. Using high-resolution imaging and standard protein fractionation and immunological methods we have examined the PERK-dependent phenotype more closely. We found that whereas proinsulin aggregation requires new protein synthesis, global protein and proinsulin synthesis are down-regulated in PERK-inhibited cells, strongly arguing against proinsulin overproduction being the root cause of their aberrant ER phenotype. Furthermore, we show that PERK regulates proinsulin proteostasis by modulating ER chaperones, including BiP and ERp72. Transgenic overexpression of BiP and BiP knockdown (KD) both promoted proinsulin aggregation, whereas ERp72 overexpression and knockdown rescued it. These findings underscore the importance of ER chaperones working in concert to achieve control of insulin production and identify a role for PERK in maintaining a functional balance among these chaperones.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.