ArticleThe Journal of biological chemistry2014
Inefficient translocation of preproinsulin contributes to pancreatic β cell failure and late-onset diabetes.
Article in The Journal of biological chemistry, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 43 papers, 1 of them a synthesis that pooled it.
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Who cites it
43 citing papers in PubMed, 1 synthesis or guideline pooled it, 70 citations in OpenAlex.
- Insulin gene mutations and posttranslational and translocation defects: associations with diabetes.Endocrine · 2020Pooled it
- Lipid Metabolic Disorders: a Pivotal Driver in Type 2 Diabetes Mellitus Pathogenesis.Current obesity reports · 2026Review
- Protocol for detecting cytosol-retained proopiomelanocortin by fractionation and co-immunoprecipitation assay.STAR protocols · 2026Article
- A new form of diabetes caused by INS mutations defined by zygosity, stem cell and population data.EMBO molecular medicine · 2026Article
- Diabetes mellitus and the key role of endoplasmic reticulum stress in pancreatic β cells.Nature reviews. Endocrinology · 2025Review
- Maturity-Onset Diabetes of the Young 10 (MODY10): A Comprehensive Review of Genetics, Clinical Features, and Therapeutic Advances.International journal of molecular sciences · 2025Review
- Trapα deficiency impairs the early events of insulin biosynthesis and glucose homeostasis.The Journal of clinical investigation · 2025Article
- TanGIBLE: A selective probe for evaluating hydrophobicity-exposed defective proteins in live cells.The Journal of cell biology · 2025Article
- The role of mitochondrial function in the pathogenesis of diabetes.Frontiers in endocrinology · 2025Review
- Role of Sec61α2 Translocon in Insulin Biosynthesis.Diabetes · 2024Article
- Characterization of the interaction between the Sec61 translocon complex and ppαF using optical tweezers.Protein science : a publication of the Protein Society · 2024Article
- Loss of Preproinsulin Interaction with Signal Recognition Particle Activates Protein Quality Control, Decreasing mRNA Stability.Journal of molecular biology · 2024Article
- Marchf6: A guardian against cytosol-spilled POMC-induced ferroptosis.Molecules and cells · 2024Article
- Pathogenic signal peptide variants in the human genome.NAR genomics and bioinformatics · 2023Article
- Heat shock protein Hspa13 regulates endoplasmic reticulum and cytosolic proteostasis through modulation of protein translocation.The Journal of biological chemistry · 2022Article
- UDP-glucose, cereblon-dependent proinsulin degrader.Scientific reports · 2022Article
- Association of HLA-DQ Heterodimer Residues -18β and β57 With Progression From Islet Autoimmunity to Diabetes in the Diabetes Prevention Trial-Type 1.Diabetes care · 2022Article
- The Role of TRAPγ/SSR3 in Preproinsulin Translocation Into the Endoplasmic Reticulum.Diabetes · 2022Article
- Peptide Model of the Mutant Proinsulin Syndrome. II. Nascent Structure and Biological Implications.Frontiers in endocrinology · 2022Article
- Signal Peptide Features Determining the Substrate Specificities of Targeting and Translocation Components in Human ER Protein Import.Frontiers in physiology · 2022Review
Corrections and comments
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Authors and funding
12 authors at 4 institutions in 2 countries.
Funding
Abstract
Among the defects in the early events of insulin biosynthesis, proinsulin misfolding and endoplasmic reticulum (ER) stress have drawn increasing attention as causes of β cell failure. However, no studies have yet addressed potential defects at the cytosolic entry point of preproinsulin into the secretory pathway. Here, we provide the first evidence that inefficient translocation of preproinsulin (caused by loss of a positive charge in the n region of its signal sequence) contributes to β cell failure and diabetes. Specifically, we find that, after targeting to the ER membrane, preproinsulin signal peptide (SP) mutants associated with autosomal dominant late-onset diabetes fail to be fully translocated across the ER membrane. The newly synthesized, untranslocated preproinsulin remains strongly associated with the ER membrane, exposing its proinsulin moiety to the cytosol. Rather than accumulating in the ER and inducing ER stress, untranslocated preproinsulin accumulates in a juxtanuclear compartment distinct from the Golgi complex, induces the expression of heat shock protein 70 (HSP70), and promotes β cell death. Restoring an N-terminal positive charge to the mutant preproinsulin SP significantly improves the translocation defect. These findings not only reveal a novel molecular pathogenesis of β cell failure and diabetes but also provide the first evidence of the physiological and pathological significance of the SP n region positive charge of secretory proteins.
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