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p66Shc介质SUMO2诱导的内皮功能障碍

Jitendra Kumar, Shravan K Uppulapu, Sujata Kumari

bioRxiv : the preprint server for biology

|February 8, 2024

概括

增加的sumoylation,特别是小的泛素类修饰剂2/3 (SUMO2/3),会损害血管健康. 这项研究揭示了SUMO2向p66Shc,调解内皮功能障碍和氧化应激,特别是在高脂血症中.

科学领域:

生物化学生物化学
分子生物学分子生物学
心血管研究研究心血管研究

背景情况:

苏莫化是一种调节生理功能的翻译后修饰.
增加的sumoylation,特别是SUMO2/3,会对血管健康产生负面影响.
在SUMO2的有害血管作用背后,精确的分子机制尚不清楚.

研究的目的:

调查p66Shc作为SUMO2.2的目标的作用.
阐明SUMO2对p66Shc的结合影响血管内皮功能的机制.
为了确定SUMO2-p66Shc相互作用在高脂血症诱导的血管功能障碍的背景下体内相关性.

主要方法:

利用基于细胞的测定和质谱学来确定p66Shc作为SUMO2.2.的直接目标.
产生了p66ShcK81R敲定小鼠,并将它们与LDLr-/-小鼠交叉,以模拟超脂血症.
进行了质谱和英才途径分析,以检查内皮细胞信号变化.

主要成果:

SUMO2在lysine-81 (K81) 中直接修改p66Shc,这种修改对其功能至关重要.
p66Shc的SUMO2ylation增强了它在-36 (S36) 的酸化,促进了线粒体转位和氧化功能.
p66ShcK81R敲击小鼠对SUMO2诱导的内皮功能障碍和与高脂血症相关的血管损伤表现出耐药性.
发明性路径分析确定了Rho-GTPase信号传递是受SUMO2-p66ShcK81.1.影响的关键路径.

结论:

SUMO2-p66Shc信号传递是血管内皮功能的一个关键调节器.
p66ShcK81的化是调节p66Shcc信号的上游事件.
这一途径调解了高脂血症中的内皮功能障碍和氧化应激.

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