12389 Viral Insulin/IGF-1-like Peptides: A New Dimension In Understanding The Insulin/IGF System

Abstract Disclosure: M. Chrudinova: None. A. Chuard: None. F. Zhang: None. Y.D. Dogru: None. P. De Meyts: None. J.K. Kim: None. N. Kirk: None. J. Jiracek: None. R.D. DiMarchi: None. E. Altindis: None. Viral Insulin/IGF-1-Like Peptides: A New Dimension in Understanding the Insulin/IGF System Martina Chrudinova, Aurelien Chuard, Dogus Dogru, Nicholas Kirk, Pierre De Meyts, Jason Kim, Richard Di Marchi, Jiri Jiracek, Emrah AltindisMammals have separate insulin and IGF-1 receptors, and in most species, one insulin and two IGFs interact with them. The mammalian Insulin receptor (IR) primarily controls metabolism, while the insulin-like growth factor-1 (IGF-1) receptor (IGF1R) regulates cell apoptosis, growth, and prenatal and postnatal differentiation. Despite their distinct functions, due to high structural similarity, insulin and IGF-1 can bind to each other's receptors with different potencies. However, the presence of viral insulin/IGF-1-like peptides (VILPs) and their effects on mammalian cells were unknown until our recent discovery.For the first time, we demonstrated that viruses possess active gene products that mimic human insulin and IGF-1. These VILPs are approximately 30-50% identical to human insulin and IGF-1 and exhibit atypical effects on the insulin/IGF system. Our initial studies provided insights into VILPs and this complex signaling system: •Introducing the novel concept of a system of viral hormones and viral insulins. •Identifying VILPs in six different Iridoviridae viruses and discovering sequences of these viruses in human samples. •Providing evidence that all VILPs bind to human IR and IGF-1 receptors and that agonist VILPs can stimulate downstream signaling. •Demonstrating that agonist VILPs can increase glucose uptake in vitro and in vivo and have tissue-specific and long-lasting effects. •Showing the expression of VILPs during viral infection and their stimulation of insulin/IGF signaling. •Identifying Mandarin fish ranavirus (MFRV) and Lymphocystis disease virus-1 (LCDV-1) VILPs as potent inhibitors of human IGF1R. To the best of our knowledge, these are the first peptide inhibitors of the IGF1R. •CryoEM studies revealed that two LCDV-1 VILPs bind to IGF1R and lock it. •Unlike the evolution of host insulin/IGFs, these unique characteristics of the VILPs are most likely acquired as a result of distinct co-evolution in viral genomes to facilitate viral pathogenesis in the host.In conclusion, VILPs, as active members of the insulin/IGF superfamily, possess unique characteristics. Our findings on the characterization of the VILPs and their distinct functions open new avenues for a deeper understanding of the insulin/IGF-1 signaling system. Furthermore, VILP research will guide us in designing specific and potent agonists and antagonists of the IR/IGF1R system, with the potential to lead to new therapeutic strategies for a wide range of human diseases. Presentation: 6/2/2024