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

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.