How Protein Lactylation Affects Gene Expression: Mechanistic Insights
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Identification of low-abundance lactylation sites
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Network analysis of co-occurring modifications (e.g., acetylation, phosphorylation)
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Quantitative monitoring of dynamic modification changes
Research on protein post-translational modifications (PTMs) continues to reveal the intricate complexity of cellular regulation. Among these, protein lactylation has emerged as an important new focus in epigenetic studies. As a novel lysine modification, in addition to acetylation and methylation, lactylation not only participates in the metabolism–transcription regulatory network but may also play critical roles in diverse biological processes, including tumorigenesis, immune regulation, and stem cell fate determination. This review summarizes current knowledge on how protein lactylation modulates gene expression and discusses the underlying molecular mechanisms.
What Is Protein Lactylation?
Protein lactylation refers to the covalent modification of lysine residues by a lactyl group derived from lactic acid. First reported in 2019 by Zhang et al. in Nature, this modification was identified at the K18 site of histone H3 (H3K18la) in mouse bone marrow-derived macrophages. The authors proposed that lactic acid may serve as a transcriptional activation signal, linking the cellular metabolic state with the regulation of gene expression. Similar to acetylation, lactylation neutralizes the positive charge on lysine residues, thereby modulating chromatin architecture and influencing both transcription factor binding and promoter activity.
Mechanisms by Which Protein Lactylation Regulates Gene Expression
1. An Additional Layer of Epigenetic Regulation
Lactylation represents an important complementary mechanism in epigenetic control. Current evidence indicates that lactylation primarily occurs at lysine residues of histones H3 and H4, with levels markedly increased under conditions of elevated glycolysis. For example, under hypoxic or immune-activated states, the accumulation of lactic acid induces an upregulation of H3K18la, which in turn activates the transcription of pro-inflammatory genes.
Proposed mechanism:
Elevated lactic acid concentration leads to increased synthesis of lactyl-CoA. The lactyl group is then transferred to histone lysine residues via specific enzymes (yet to be fully identified, but potentially analogous to acetyltransferases). This modification induces conformational changes in histones, resulting in chromatin relaxation and enhanced transcriptional activity.
This pathway underscores the coupling between cellular metabolic status, epigenetic modification, and transcriptional programming.
2. Close Association with Immune Gene Expression
In macrophages, histone lactylation has been shown to promote the expression of genes characteristic of the M2 anti-inflammatory phenotype, such as Arg1 and Mrc1. This observation suggests that lactylation may contribute to the temporal regulation of immune responses: initiating with an acute inflammatory phase driven by pro-inflammatory mediators, followed by a resolution phase mediated in part by lactylation. Moreover, high expression levels of lactylation markers have been detected in tumor-associated macrophages (TAMs), implicating a potential role in facilitating immune evasion within the tumor microenvironment.
3. Potential Recruitment of Transcriptional Co-Factors
Lactylation may modify the surface properties of histones, thereby influencing the binding of “reader” proteins, such as members of the bromodomain (BRD) family. While no lactylation-specific reader proteins have been identified to date, the chemical similarity of lactylation to acetylation suggests that such recognition modules may exist and play a role in the fine-tuning of transcriptional regulation.
Beyond histones, non-histone lactylation is also of interest. Although most current research focuses on histones, lactylation has also been observed on proteins such as metabolic enzymes and transcription factors, potentially expanding its functional repertoire in cellular fate determination, signal transduction, and stress responses.
Advancing Lactylation Research Through High-Resolution Analytical Platforms
The identification of protein lactylation has introduced a novel paradigm in epigenetic regulation. However, significant challenges remain, including difficulties in detecting modification sites, incomplete knowledge of the enzymatic machinery, and the complexity of functional validation. High-resolution mass spectrometry, targeted enrichment of modification sites, and the development of lactylation-specific antibodies are essential tools for further progress in this field.
Leveraging a high-sensitivity Orbitrap Fusion Lumos platform, MtoZ Biolabs has established a comprehensive workflow for quantitative analysis of protein PTMs, particularly suited for:
Additionally, functional assays for lactylated target proteins can facilitate systematic mapping of lactylation-regulated networks, thereby accelerating the generation of research outputs. From a metabolic byproduct to a transcriptional regulatory signal, lactic acid, through lactylation, illustrates a unique mechanism coupling metabolism, epigenetics, and transcription. With continued research, protein lactylation is poised to become a key regulatory node in epigenetic networks, offering novel entry points for investigations into tumor immunity, chronic inflammation, and stem cell reprogramming. MtoZ Biolabs is committed to providing you with high-quality PTM omics solutions to help decode the regulatory secrets behind lactylation.
MtoZ Biolabs, an integrated chromatography and mass spectrometry (MS) services provider.
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