β-hydroxybutyrylation and O-GlcNAc modifications of STAT1 modulate antiviral defense in aging

IF 21.8 1区医学 Q1 IMMUNOLOGY

Cellular &Molecular Immunology Pub Date : 2025-02-20 DOI:10.1038/s41423-025-01266-x

Yibo Zuo, Qin Wang, Wanying Tian, Zhijin Zheng, Wei He, Renxia Zhang, Qian Zhao, Ying Miao, Yukang Yuan, Jun wang, Hui Zheng

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Abstract

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.

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STAT1的β-羟基丁基化和O-GlcNAc修饰可调节衰老过程中的抗病毒防御。

衰老会改变蛋白质的活性状态，从而影响机体的功能。然而，衰老如何调节蛋白质翻译后修饰（PTMs）来调节机体的抗病毒防御能力尚不清楚。在这里，我们发现衰老促进STAT1 β-羟基丁基化（Kbhb）在Lys592位点，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的小分子羟基喜树碱可以有效降低STAT1 Kbhb的水平，从而提高体内的抗病毒防御能力。进一步的研究表明，STAT1 O-GlcNAc修饰在Thr699阻断cbp诱导STAT1 Kbhb。重要的是，果糖可以通过协调STAT1 O-GlcNAc和Kbhb修饰来改善IFN-I的抗病毒防御活性。本研究揭示了STAT1 Kbhb和O-GlcNAc修饰之间的转换在衰老过程中调节IFN-I抗病毒免疫的意义，并为提高老年人机体抗病毒防御能力提供了潜在的策略。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cellular &Molecular Immunology 医学-免疫学

CiteScore

31.20

自引率

1.20%

发文量

903

审稿时长

1 months

期刊介绍： Cellular & Molecular Immunology, a monthly journal from the Chinese Society of Immunology and the University of Science and Technology of China, serves as a comprehensive platform covering both basic immunology research and clinical applications. The journal publishes a variety of article types, including Articles, Review Articles, Mini Reviews, and Short Communications, focusing on diverse aspects of cellular and molecular immunology.