STAT1的β-羟基丁酰化和O-连接的N-乙酰葡糖胺修饰调节衰老过程中的抗病毒防御。
β-hydroxybutyrylation and O-GlcNAc modifications of STAT1 modulate antiviral defense in aging.
作者信息
Zuo Yibo, Wang Qin, Tian Wanying, Zheng Zhijin, He Wei, Zhang Renxia, Zhao Qian, Miao Ying, Yuan Yukang, Wang Jun, Zheng Hui
机构信息
Department of Laboratory Medicine, Institute of Laboratory Medicine, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, 611731, Sichuan, China.
Institutes of Biology and Medical Sciences, Soochow University, Suzhou, 215123, Jiangsu, China.
出版信息
Cell Mol Immunol. 2025 Apr;22(4):403-417. doi: 10.1038/s41423-025-01266-x. Epub 2025 Feb 20.
Aging changes the protein activity status to affect the body's functions. However, how aging regulates protein posttranslational modifications (PTMs) to modulate the antiviral defense ability of the body remains unclear. Here, we found that aging promotes STAT1 β-hydroxybutyrylation (Kbhb) at Lys592, which inhibits the interaction between STAT1 and type-I interferon (IFN-I) receptor 2 (IFNAR2), thereby attenuating IFN-I-mediated antiviral defense activity. Additionally, we discovered that a small molecule from a plant source, hydroxy camptothecine, can effectively reduce the level of STAT1 Kbhb, thus increasing antiviral defense ability in vivo. Further studies revealed that STAT1 O-GlcNAc modifications at Thr699 block CBP-induced STAT1 Kbhb. Importantly, fructose can improve IFN-I antiviral defense activity by orchestrating STAT1 O-GlcNAc and Kbhb modifications. This study reveals the significance of the switch between STAT1 Kbhb and O-GlcNAc modifications in regulating IFN-I antiviral immunity during aging and provides potential strategies to improve the body's antiviral defense ability in elderly individuals.
衰老会改变蛋白质活性状态，从而影响身体功能。然而，衰老如何调节蛋白质翻译后修饰（PTM）以调节机体的抗病毒防御能力仍不清楚。在此，我们发现衰老会促进STAT1在赖氨酸592位点的β-羟基丁酰化（Kbhb），这会抑制STAT1与I型干扰素（IFN-I）受体2（IFNAR2）之间的相互作用，从而减弱IFN-I介导的抗病毒防御活性。此外，我们发现一种来自植物源的小分子羟基喜树碱能够有效降低STAT1 Kbhb水平，从而增强体内抗病毒防御能力。进一步研究表明，STAT1在苏氨酸699位点的O-连接N-乙酰葡糖胺修饰会阻断CBP诱导的STAT1 Kbhb。重要的是，果糖可以通过协调STAT1的O-连接N-乙酰葡糖胺和Kbhb修饰来提高IFN-I抗病毒防御活性。本研究揭示了STAT1 Kbhb和O-连接N-乙酰葡糖胺修饰之间的转换在衰老过程中调节IFN-I抗病毒免疫的重要性，并提供了提高老年人机体抗病毒防御能力的潜在策略。
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