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Transcriptomic Profiling of HepG2 Cells under PCCB Depletion Reveals Kpm-Mediated Metabolic Gene Regulation

ABSTRACT: 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. Mechanistically, we show that Kpm is metabolically regulated by propionyl-CoA homeostasis and is markedly upregulated upon depletion of the propionyl-CoA carboxylase beta subunit (PCCB). 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. To investigate the site-specific function of Kpm on non-histone proteins, we developed a genetic code expansion system to incorporate Kpm at defined sites. Using this system, we demonstrate that methylpropionylation of NSMCE3 at lysine 260 disrupts a critical electrostatic interaction with E284, thereby impairing its association with NSMCE4A and compromising DNA damage repair. 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE294818 | GEO | 2025/04/20

REPOSITORIES: GEO

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Project description:Cholesterol of the host macrophage membrane is vital for mycobacterial infection, replication, and persistence. During chronic infection within host lung tissues, cholesterol facilitates the phagocytosis of mycobacteria into macrophages. Cholesterol degradation leads to increased ﬂux of acetyl-coenzyme A (CoA) and propionyl-CoA, providing energy and building blocks for virulence macromolecules as well as donors for global protein acylation. Potential functions of lysine acylation are gradually revealed in bacterial survival and pathogenesis. However, the mycobacterial proteome and posttranslational modification (PTM) changes involved in the cholesterol catabolism bioprocess remain unclear. Here, we used nonpathogenic Mycobacterium smegmatis as a model and simultaneously monitored mycobacterial proteome and acetylome changes in the presence of glucose and cholesterol. We discovered that cholesterol metabolic enzymes were upregulated with respect to both protein expression levels and lysine acylation levels during the metabolic shift from glucose to cholesterol. After that, adenylating enzymes related to cholesterol metabolism were proven to be precisely regulated at the propionylation level by mycobacterial acyltransferase M. smegmatis Kat (MsKat) in response to cellular propionyl-CoA accumulation. Furthermore, the kinase expression and phosphorylation levels were also changed along with fluctuations in cholesterol levels. Our results expanded current knowledge of acylation regulation in the cholesterol catabolism of mycobacteria and provided references for possible antimycobacterium strategy.IMPORTANCE Cholesterol assimilation is a critical step in mycobacterial chronic infection. However, knowledge from the dynamic characterization of cholesterol metabolism in mycobacteria at the protein expression and PTM levels remains limited. Our study uncovered the landscape of protein expression, lysine acetylation, lysine propionylation, and S/T/Y phosphorylation during the metabolic changes from glucose to cholesterol in mycobacteria. The data showed that cholesterol-induced carbon shift resulted in the elevation of protein expression and lysine acylation in diverse metabolic enzymes involved in cholesterol degradation and that the presence of cholesterol also promoted the perturbations at the phosphorylation level in the kinase system in mycobacteria. This study systematically characterized the regulation of cholesterol catabolism at several different levels, which provided the detailed references in mycobacterial proteome and potential antimycobacterial strategies.

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Transcriptomic Profiling of HepG2 Cells under PCCB Depletion Reveals Kpm-Mediated Metabolic Gene Regulation

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