Viral insulin-like peptides activate human insulin and IGF-1 receptor signaling: A paradigm shift for host–microbe interactions

Abstract

Viruses are the most abundant biological entities and carry a wide variety of genetic material, including the ability to encode host-like proteins. Here we show that viruses carry sequences with significant homology to several human peptide hormones including insulin, insulin-like growth factors (IGF)-1 and -2, FGF-19 and -21, endothelin-1, inhibin, adiponectin, and resistin. Among the strongest homologies were those for four viral insulin/IGF-1-like peptides (VILPs), each encoded by a different member of the family VILPs show up to 50% homology to human insulin/IGF-1, contain all critical cysteine residues, and are predicted to form similar 3D structures. Chemically synthesized VILPs can bind to human and murine IGF-1/insulin receptors and stimulate receptor autophosphorylation and downstream signaling. VILPs can also increase glucose uptake in adipocytes and stimulate the proliferation of fibroblasts, and injection of VILPs into mice significantly lowers blood glucose. Transfection of mouse hepatocytes with DNA encoding a VILP also stimulates insulin/IGF-1 signaling and DNA synthesis. Human microbiome studies reveal the presence of these in blood and fecal samples. Thus, VILPs are members of the insulin/IGF superfamily with the ability to be active on human and rodent cells, raising the possibility for a potential role of VILPs in human disease. Furthermore, since only 2% of viruses have been sequenced, this study raises the potential for discovery of other viral hormones which, along with known virally encoded growth factors, may modify human health and disease.

Characterization of Viral Insulins Reveals White Adipose Tissue Specific Effects in Mice

“…Based on our in vitro data showing about 0.05 % relative affinity for the IR, we decided to use 0.3 µmol/kg (50x higher concentration than insulin) GIV and SGIV dcVILPs in male mice. Consistent with previous studies 9,40 , insulin caused ~ 60% decrease in blood glucose in 60 minutes, after which glucose started to increase. Surprisingly, injection with 50x GIV or SGIV dcVILPs led to very severe hypoglycemia such that we needed to terminate the experiment in 30 minutes by injecting glucose to save the animals (Fig.…”

“…We recently showed that four viruses that belong to Iridoviridae family possess genes that show significant homology to human insulin/IGF-1 which we termed viral insulin/IGF-1-like peptides or VILPs for short 9,10 . Although viruses encoding these sequences were originally isolated from fish [11][12][13][14] , reanalyzing published human microbiome data, we identified the DNA of some of these viruses in human fecal and blood samples 9 . In our previous study, three VILPs were also chemically synthetized as single chain peptides (sc), i.e.…”

“…In our previous study, three VILPs were also chemically synthetized as single chain peptides (sc), i.e. IGF-1 like peptides, and we showed that scVILPs are weak ligands of the insulin receptor but strong ligands of the IGF-1 receptor in vitro and also possessed some glucose lowering effects in vivo 9 .…”

The Role of Gut Microbiota and Environmental Factors in Type 1 Diabetes Pathogenesis

“…Taken together, perhaps future efforts should look further into specific community interactions and overall function to gain a better understanding of the varying disease etiologies. For instance, we recently hypothesized that the presence of microbes carrying an insulin-like peptide could instigate a molecular mimicry mechanism in T1D and have since discovered viral insulins (273,274). We also showed the presence of the sequences of these viruses in human fecal and plasma samples.…”

Pathways to Understanding Virus-Host Metabolism Interactions

“…Viruses may also encode factors that mimic hormones and growth factors that could regulate metabolism. A bioinformatic search led to the discovery that iridoviruses encode insulin-like peptides capable of stimulating signaling in mammalian cells [57], which could possibly lead to transcriptional control of over 100 genes [58]. In contrast to the balance shifting towards increased synthesis of enzymes, HSV-1 controls metabolism by targeting at least one enzyme for depletion [28].…”