一种类似于胰岛素的病毒性抑制IGF-1受体的酸化,并调节IGF1R基因表达
Martina Chrudinová1, Nicholas S Kirk2, Aurelien Chuard1
1Boston College Biology Department, Chestnut Hill, MA, USA.
Molecular metabolism
|January 5, 2024
概括
来自MFRV和LCDV-Sa的病毒性胰岛素/IGF-1类似 (VILPs) 结合人类受体并影响信号传递. 在小鼠中,scMFRV-VILP显示了IGF1R信号的偏向抑制和持续的葡萄糖降低.
科学领域:
- 内分泌学和病毒学.
- 分子和细胞生物学分子和细胞生物学
- 结构生物学 结构生物学
背景情况:
- 胰岛素/IGF超级家族是进化保守的.
- 病毒性胰岛素/IGF-1类似 (VILP) 已在几种病毒中被确定.
- 鱼 ranavirus (MFRV) 和淋巴结核病病毒-Sa (LCDV-Sa) 的VILPs对胰岛素/IGF系统的功能影响仍然未被描述.
研究的目的:
- 描述MFRV和LCDV-Sa VILP对人体胰岛素/IGF系统的影响.
- 研究VILPs对受体结合,信号传递,增殖和基因表达的影响.
- 评估VILPs对血糖水平的体内影响及其与IGF1R的结构相互作用.
主要方法:
- 单链 (sc) 和双链 (dc) VILP 的化学合成.
- 在体外表征使用过度表达人类胰岛素受体 (IR-A,IR-B) 或IGF-1受体 (IGF1R) 的细胞系和AML12肝细胞.
- 在小鼠体内进行胰岛素耐受性测试和冷电子显微镜 (cryoEM) 用于结构分析.
主要成果:
- 维尔普结合并激活人体IR和IGF1R,刺激下游信号传输.
- scMFRV-VILP表现出强烈的IGF1R亲和力,并表现出偏向抑制IGF1R信号传递 (Erk酸化),同时节省了Akt酸化.
- scMFRV-VILP在体内诱导持续降低葡萄糖,其与IGF1R的结合结构类似于IGF-1.
结论:
- MFRV和LCDV-Sa VILPs是胰岛素/IGF超级家族的新成员.
- scMFRV-VILP对IGF1R信号传递具有独特的偏向抑制功能,并调节IGF1R基因表达.
- 研究结果表明,VILPs在开发IGF1R抑制剂和长效胰岛素方面具有潜在的应用.
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