Lysine Methylpropionylation, a Hybrid Post-Translational Modification Mediated by p300/PCAF Couples Metabolic Dynamics with Protein Function

Lysine alkylation and acylation serve as crucial links between cellular metabolism and a wide range of biological functions. However, hybrid modifications that combine features of both alkylation and acylation remain largely unexplored. Here, we report the discovery and in-depth characterization of lysine methylpropionylation (Kpm), a hybrid post-translational modification (PTM) defined by the propionylation of monomethyllysine residues. Genome-wide chromatin immunoprecipitation coupled with transcriptomic profiling revealed that Kpm exhibits distinct genomic distribution compared to canonical Kac and Kpr, with preferential enrichment at promoters of genes involved in metabolic pathways. Together, our findings establish Kpm as a dual-feature PTM that integrates metabolic cues with both chromatin regulation and non-histone protein function, offering a mechanistic framework for understanding metabolism-proteome crosstalk. ChIP-seq of Kpm, Kac, and Kpr modifications in wild-type and PCCB-knockdown HepG2 cells.

赖氨酸烷基化与酰基化是连接细胞代谢与多种生物学功能的关键纽带。然而，同时兼具烷基化与酰基化特征的混合修饰迄今仍未得到充分研究。本研究报道了赖氨酸甲基丙酰化（Kpm）的发现与深度表征——这是一种以一甲基赖氨酸残基丙酰化为特征的混合翻译后修饰（PTM）。全基因组染色质免疫沉淀联合转录组分析结果显示，相较于经典的乙酰化赖氨酸（Kac）与丙酰化赖氨酸（Kpr），Kpm具有独特的基因组分布模式，且在代谢通路相关基因的启动子区域呈现优先富集。综上，本研究确立Kpm为一种双特征翻译后修饰，可整合代谢信号与染色质调控及非组蛋白功能，为理解代谢-蛋白质组串扰提供了机制框架。本研究对野生型及PCCB基因敲低HepG2细胞中的Kpm、Kac与Kpr修饰开展了染色质免疫沉淀测序（ChIP-seq）实验。