ArticleMolecular metabolism2024
A viral insulin-like peptide inhibits IGF-1 receptor phosphorylation and regulates IGF1R gene expression.
Article in Molecular metabolism, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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Who cites it
10 citing papers in PubMed, 16 citations in OpenAlex.
- Decreased serum IGFBP-7 level is associated with cognitive impairment in first-episode drug-naïve adolescent-onset schizophrenia.Annals of general psychiatry · 2026Article
- Reduced Dietary Protein Induces Changes in the Dental Proteome.Journal of experimental zoology. Part B, Molecular and developmental evolution · 2026Article
- Evolution of Insulin, Insulin-like Growth Factors, and Their Cognate Receptors in Vertebrates, Invertebrates, and Viruses.Molecular biology and evolution · 2026Article
- Targeting IGF1R Overcomes Armored and Cold Tumor Microenvironment and Boosts Immune Checkpoint Blockade in Triple-Negative Breast Cancer.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- Developmentally cascading structures do not lose evolutionary potential, but compound developmental instability in rat molars.bioRxiv : the preprint server for biology · 2025Article
- Viral insulin/IGF-like peptides inhibit IGF-1 receptor signaling to enhance viral replication.Cell reports · 2025Article
- Emerging Mechanisms and Biomarkers Associated with T-Cells and B-Cells in Autoimmune Disorders.Clinical reviews in allergy & immunology · 2025Review
- IGF1R promotes radiation-induced HSCs activation by regulating DNA-PKcs-mediated DNA damage repair.Frontiers in cell and developmental biology · 2025Article
- Exploration of the shared gene signatures and molecular mechanisms between Alzheimer's disease and intracranial aneurysm.Scientific reports · 2024Article
- Identification of functional rare coding variants in IGF-1 gene in humans with exceptional longevity.bioRxiv : the preprint server for biology · 2024Article
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Authors and funding
14 authors at 6 institutions in 3 countries.
Funding
Abstract
objectiveThe insulin/IGF superfamily is conserved across vertebrates and invertebrates. Our team has identified five viruses containing genes encoding viral insulin/IGF-1 like peptides (VILPs) closely resembling human insulin and IGF-1. This study aims to characterize the impact of Mandarin fish ranavirus (MFRV) and Lymphocystis disease virus-Sa (LCDV-Sa) VILPs on the insulin/IGF system for the first time.
methodsWe chemically synthesized single chain (sc, IGF-1 like) and double chain (dc, insulin like) forms of MFRV and LCDV-Sa VILPs. Using cell lines overexpressing either human insulin receptor isoform A (IR-A), isoform B (IR-B) or IGF-1 receptor (IGF1R), and AML12 murine hepatocytes, we characterized receptor binding, insulin/IGF signaling. We further characterized the VILPs' effects of proliferation and IGF1R and IR gene expression, and compared them to native ligands. Additionally, we performed insulin tolerance test in CB57BL/6 J mice to examine in vivo effects of VILPs on blood glucose levels. Finally, we employed cryo-electron microscopy (cryoEM) to analyze the structure of scMFRV-VILP in complex with the IGF1R ectodomain.
resultsVILPs can bind to human IR and IGF1R, stimulate receptor autophosphorylation and downstream signaling pathways. Notably, scMFRV-VILP exhibited a particularly strong affinity for IGF1R, with a mere 10-fold decrease compared to human IGF-1. At high concentrations, scMFRV-VILP selectively reduced IGF-1 stimulated IGF1R autophosphorylation and Erk phosphorylation (Ras/MAPK pathway), while leaving Akt phosphorylation (PI3K/Akt pathway) unaffected, indicating a potential biased inhibitory function. Prolonged exposure to MFRV-VILP led to a significant decrease in IGF1R gene expression in IGF1R overexpressing cells and AML12 hepatocytes. Furthermore, insulin tolerance test revealed scMFRV-VILP's sustained glucose-lowering effect compared to insulin and IGF-1. Finally, cryo-EM analysis revealed that scMFRV-VILP engages with IGF1R in a manner closely resembling IGF-1 binding, resulting in a highly analogous structure.
conclusionsThis study introduces MFRV and LCDV-Sa VILPs as novel members of the insulin/IGF superfamily. Particularly, scMFRV-VILP exhibits a biased inhibitory effect on IGF1R signaling at high concentrations, selectively inhibiting IGF-1 stimulated IGF1R autophosphorylation and Erk phosphorylation, without affecting Akt phosphorylation. In addition, MFRV-VILP specifically regulates IGF-1R gene expression and IGF1R protein levels without affecting IR. CryoEM analysis confirms that scMFRV-VILP' binding to IGF1R is mirroring the interaction pattern observed with IGF-1. These findings offer valuable insights into IGF1R action and inhibition, suggesting potential applications in development of IGF1R specific inhibitors and advancing long-lasting insulins.
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