How Does Protein Lactylation Affect Gene Expression? Unveiling the Mechanism

Research on post-translational modifications (PTMs) of proteins continues to unveil the complexity of cellular regulation, with protein lactylation emerging as a new hotspot in epigenetic studies. As a novel lysine modification following acetylation and methylation, lactylation not only participates in the metabolism-transcription regulatory network but may also play a crucial role in biological processes such as tumor development, immunity, and stem cell fate determination. How does protein lactylation regulate gene expression? What are the molecular mechanisms behind it? This article will take you on an exploration.

 

1. What is Protein Lactylation?

Protein lactylation refers tothe process of covalent modification of lysine residues with a lactyl group, derived from lactic acid.It was first reported in 2019 by Zhang et al. in 'Nature', where they discovered lactylation modification at the K18 site of histone H3 (H3K18la) in murine bone marrow-derived macrophages, and proposed thatlactate can serve as a transcriptional activation signal, linking cellular metabolic state with gene expression regulation. Similar to acetylation, lactylation neutralizes the positive charge on lysine residues, altering chromatin conformation and thus affecting transcription factor binding and promoter activity.

 

2. How Does Protein Lactylation Regulate Gene Expression?

1. A New Layer of Epigenetic Regulation

Lactylation is an important supplementary mechanism in epigenetic regulation. Current research shows that lactylation modificationsprimarily occur at lysine sites on histones H3 and H4,and are significantly upregulated under conditions of high glycolysis. For example, under hypoxic or immune activation states, lactate accumulation induces an increase in H3K18la levels, subsequently activating the transcription of pro-inflammatory factors.

Mechanism Overview:

• High lactate concentration → Increased synthesis of lactyl-CoA

• Lactyl groups are transferred to histone lysines by specific enzymes (not fully identified, possibly similar to acetyltransferases)

• Histone structural changes → Chromatin relaxation → Enhanced transcriptional activity

 

This process emphasizesthe coupling mechanism between metabolic state, epigenetics, and transcriptional programs.。

 

2. Close Association with Immune Gene Expression

In macrophages, lactylation has been proven to promotethe expression of genes related to the M2 anti-inflammatory phenotype,such as Arg1 and Mrc1. This finding suggests that lactylation may participate in the temporal regulation of immune responses: first initiating acute responses with inflammatory factors, then mediating a shift towards inflammation resolution via lactylation. Additionally, lactylation markers are also found to be highly expressed in tumor-associated macrophages (TAMs), indicating potential involvement inimmune evasion in the tumor microenvironment.。

 

3、Potential Mechanisms for the Recruitment of Transcriptional Co-factors

Lactylation may alter the surface characteristics of histones, thusaffecting the binding of 'reader' proteins (such as BRD family proteins).Although specific 'lactylation recognition proteins' have not yet been identified, the chemical properties similar to acetylation suggest the existence of such recognition modules, which play a critical role in the precision of gene transcription regulation.

 

Beyond histones, non-histone lactylation also warrants attention. Although current lactylation research focuses on histones, non-histone lactylation phenomena have also been observed. Lactylation modifications on proteins such as metabolic enzymes and transcription factors may further expand their functions in cell fate regulation, signal transduction, and stress response.

 

Betapack Biotechnology Facilitates In-depth Lactylation Research

The discovery of protein lactylation has driven a new paradigm in epigenetic regulation, yet its research still faceschallenges such as difficulty in identifying modification sites, unclear mechanisms of modifying enzymes, and difficulty in functional validation.High-resolution mass spectrometry technologies, methods for enriching modification sites, and the development of lactylation antibodies are key tools in advancing this field. Betapack Biotechnology, based on thehigh-sensitivity Orbitrap Fusion Lumos platform,has established a comprehensivequantitative analysis process for post-translational modifications (PTMs),particularly suitable for:

• identifying low-abundance lactylation modification sites,

• analyzing co-modification networks with other modifications (such as acetylation and phosphorylation),

• and quantitatively tracking dynamic changes in modifications.

 

We also offer functional validation services for target proteins with lactylation modifications, helping researchers systematically analyze lactylation regulatory networks and accelerate the output of scientific research results. From metabolic byproducts to transcriptional regulatory signaling molecules, lactate, through lactylation, demonstrates a novel mechanism ofmetabolism-epigenetics-transcription coupling.With further research, protein lactylation is expected to become a key node in the epigenetic regulation network and provide new entry points for research directions such as tumor immunity, chronic inflammation, and stem cell reprogramming. Betapack Biotechnology is committed to providing you with high-quality PTM omics solutions to help decipher the regulatory code behind lactylation.

 

Betapack Biotechnology—Your Quality Service Provider for Bioproduct Characterization and Multi-omics Biological Mass Spectrometry Testing

 

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