共 50 条
A viral insulin-like peptide inhibits IGF-1 receptor phosphorylation and regulates IGF1R gene expression
被引:4
作者:
Chrudinova, Martina
[1
]
Kirk, Nicholas S.
[2
,3
]
Chuard, Aurelien
[1
]
Venugopal, Hari
[4
]
Zhang, Fa
[5
]
Lubos, Marta
[6
]
Gelfanov, Vasily
[7
]
Panikova, Terezie
[6
]
Zakova, Lenka
[6
]
Cutone, Julianne
[1
]
Mojares, Matthew
[1
]
DiMarchi, Richard
[5
]
Jiracek, Jiri
[6
]
Altindis, Emrah
[1
,8
]
机构:
[1] Boston Coll, Biol Dept, Chestnut Hill, MA USA
[2] WEHI, Parkville, Vic, Australia
[3] Univ Melbourne, Fac Med Dent & Hlth Sci, Dept Med Biol, Parkville, Vic, Australia
[4] Monash Univ, Ramaciotti Ctr Cryo Electron Microscopy, Clayton, Vic, Australia
[5] Indiana Univ, Dept Chem, Bloomington, IN USA
[6] Inst Organ Chem & Biochem, Czech Acad Sci, Prague, Czech Republic
[7] Novo Nordisk, Indianapolis, IN USA
[8] Boston Coll, Biol Dept, Higgins Hall,140 Commonwealth Ave, Chestnut Hill, MA 02467 USA
基金:
澳大利亚研究理事会;
澳大利亚国家健康与医学研究理事会;
关键词:
Viral insulin/IGF-1 like peptides (VILPs);
IGF-1;
Insulin;
IGF1;
receptor;
IGF1 receptor inhibition;
Biased signaling;
Iridoviridae;
GROWTH-FACTOR-I;
CRYO-EM;
METABOLISM;
EVOLUTION;
BINDING;
CLONING;
ACID;
D O I:
10.1016/j.molmet.2023.101863
中图分类号:
R5 [内科学];
学科分类号:
1002 ;
100201 ;
摘要:
Objective: The 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. Methods: We 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. Results: VILPs can bind to human IR and IGF1R, stimulate receptor autophosphorylation and downstream signaling pathways. Notably, scMFRVVILP exhibited a particularly strong affinity for IGF1R, with a mere 10 -fold decrease compared to human IGF-1. At high concentrations, scMFRVVILP 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 scMFRVVILP'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. Conclusions: This 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. (c) 2024 The Authors. Published by Elsevier GmbH. This is an open access article under the CC BY -NC -ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
引用
收藏
页数:19
相关论文
共 50 条