ArticleInternational journal of obesity (2005)2016
Endoplasmic reticulum-associated degradation of the mouse PC1/3-N222D hypomorph and human PCSK1 mutations contributes to obesity.
Article in International journal of obesity (2005), 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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14 citing papers in PubMed, 17 citations in OpenAlex.
- A domain-swapped proPC1/3 structure reveals a conformational checkpoint for ER export.bioRxiv : the preprint server for biology · 2026Article
- The promise of new anti-obesity therapies arising from knowledge of genetic obesity traits.Nature reviews. Endocrinology · 2022Review
- The G209R mutant mouse as a model for human PCSK1 polyendocrinopathy.Endocrinology · 2022Article
- Obesity, POMC, and POMC-processing Enzymes: Surprising Results From Animal Models.Endocrinology · 2021Review
- Mouse Models of Human Proprotein Convertase Insufficiency.Endocrine reviews · 2021Review
- Novel Homozygous Inactivating Mutation in theGenes · 2021Article
- Mice lacking PC1/3 expression in POMC-expressing cells do not develop obesity.Endocrinology · 2021Article
- High-Throughput Screening of Mouse Gene Knockouts Identifies Established and Novel High Body Fat Phenotypes.Diabetes, metabolic syndrome and obesity : targets and therapy · 2021Article
- A multicomponent screen for feeding behaviour and nutritional status in Drosophila to interrogate mammalian appetite-related genes.Molecular metabolism · 2021Article
- Obesity ofDiabetes, metabolic syndrome and obesity : targets and therapy · 2020Article
- Reduced Stability and pH-Dependent Activity of a Common Obesity-Linked PCSK1 Polymorphism, N221D.Endocrinology · 2019Article
- POMC: The Physiological Power of Hormone Processing.Physiological reviews · 2018Review
- Article
- Functional analysis of PCSK2 coding variants: A founder effect in the Old Order Amish population.Diabetes research and clinical practice · 2017Article
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9 authors at 1 institution in 1 country.
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No grant is acknowledged in the PubMed record.
Abstract
backgroundThe proprotein convertase 1/3 (PC1/3), encoded by proprotein convertase subtilisin/kexin type 1 (PCSK1), cleaves and hence activates several orexigenic and anorexigenic proproteins. Congenital inactivation of PCSK1 leads to obesity in human but not in mice. However, a mouse model harboring the hypomorphic mutation N222D is obese. It is not clear why the mouse models differ in phenotype.
methodsGene expression analysis was performed with pancreatic islets from Pcsk1(N222D/N222D) mice. Subsequently, biosynthesis, maturation, degradation and activity were studied in islets, pituitary, hypothalamus and cell lines. Coimmunoprecipitation of PC1/3-N222D and human PC1/3 variants associated with obesity with the endoplasmic reticulum (ER) chaperone BiP was studied in cell lines.
resultsGene expression analysis of islets of Pcsk1(N222D/N222D) mice showed enrichment of gene sets related to the proteasome and the unfolded protein response. Steady-state levels of PC1/3-N222D and in particular the carboxy-terminally processed form were strongly reduced in islets, pituitary and hypothalamus. However, impairment of substrate cleavage was tissue dependent. Proinsulin processing was drastically reduced, while processing of proopiomelanocortin (POMC) to adrenocorticotropic hormone (ACTH) in pituitary was only mildly impaired. Growth hormone expression and IGF-1 levels were normal, indicating near-normal processing of hypothalamic proGHRH. PC1/3-N222D binds to BiP and is rapidly degraded by the proteasome. Analysis of human PC1/3 obesity-associated mutations showed increased binding to BiP and prolonged intracellular retention for all investigated mutations, in particular for PC1/3-T175M, PC1/3-G226R and PC1/3-G593R.
conclusionsThis study demonstrates that the hypomorphic mutation in Pcsk1(N222D) mice has an effect on catalytic activity in pancreatic islets, pituitary and hypothalamus. Reduced substrate processing activity in Pcsk1(N222D/N222D) mice is due to enhanced degradation in addition to reduced catalytic activity of the mutant. PC1/3-N222D binds to BiP, suggesting impaired folding and reduced stability. Enhanced BiP binding is also observed in several human obesity-associated PC1/3 variants, suggesting a common mechanism.
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