TY - JOUR
T1 - Viral insulin-like peptides activate human insulin and IGF-1 receptor signaling
T2 - A paradigm shift for host–microbe interactions
AU - Altindis, Emrah
AU - Cai, Weikang
AU - Sakaguchi, Masaji
AU - Zhang, Fa
AU - GuoXiao, Wang
AU - Liu, Fa
AU - De Meyts, Pierre
AU - Gelfanov, Vasily
AU - Pan, Hui
AU - DiMarchi, Richard
AU - Ronald Kahn, C.
N1 - Publisher Copyright:
© 2018 National Academy of Sciences. All Rights Reserved.
PY - 2018/3/6
Y1 - 2018/3/6
N2 - 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 Iridoviridae. 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 Iridoviridae 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.
AB - 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 Iridoviridae. 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 Iridoviridae 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.
KW - Diabetes
KW - Insulin
KW - Insulin-like growth factor
KW - Viral hormones
KW - Viral pathogenesis
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U2 - 10.1073/pnas.1721117115
DO - 10.1073/pnas.1721117115
M3 - Article
C2 - 29467286
AN - SCOPUS:85042921086
SN - 0027-8424
VL - 115
SP - 2461
EP - 2466
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 10
ER -