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Spermidine-mediated hypusination of RBBP7 suppresses histone H4 acetylation and regulates inflammatory responses

ABSTRACT: Spermidine, a ubiquitous polyamine, activates autophagy and extends lifespan in diverse model organisms. Its levels decline with age in humans and mice, making its supplementation a promising health and longevity promoting intervention. While spermidine is known to regulate acetylation of both histone and non histone proteins through multiple pathways, its precise mechanisms remain incompletely defined. In this study, using a spermidine based chemical probe (Alk Spd), we uncovered a novel pathway through which spermidine specifically suppresses cytoplasmic histone H4 K5/K12 acetylation. We found that spermidine covalently modifies RBBP7 via hypusination, thereby disrupting its interaction with key binding partners, including HAT1 and histone H4. Specifically, hypusination at K263 of RBBP7 is critical for impairing the RBBP7–H4 association. This reduction in histone H4K5ac and H4K12ac levels leads to significant downregulation of NFKB1 expression, ultimately attenuating inflammatory responses in cells and in vivo.

ORGANISM(S): Homo Sapiens

SUBMITTER: Yaoyang Zhang

PROVIDER: PXD076333 | iProX | Sun Mar 29 00:00:00 GMT 2026

REPOSITORIES: iProX

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