Crosstalk between Lactylation and Other PTMs
Lactate was once regarded as a metabolic by-product of glycolysis, but recent studies have fundamentally changed this understanding. In 2019, Zhang et al. first reported histone lactylation in Nature, demonstrating that lactate can participate in epigenetic regulation by covalently modifying lysine residues on histones. This discovery opened a new direction in the study of post-translational modifications (PTMs) and prompted extensive investigation into the synergistic and competitive mechanisms between lactylation and other PTMs. This article systematically reviews the crosstalk mechanisms between lactylation and PTMs such as acetylation, methylation, phosphorylation, and ubiquitination, and discusses their coordinated roles in immune regulation, tumor metabolism, and cell fate determination.
What Is Lactylation?
Lactylation is a newly identified lysine post-translational modification that is primarily derived from lactyl-CoA, which is generated from intracellular lactate and coenzyme A. Under enzymatic or non-enzymatic conditions, lactyl groups can be covalently attached to proteins. Current research mainly focuses on histone lactylation, particularly at sites such as H3K18la and H4K8la.
Similar PTMs include:
(1) Acetylation: Regulates chromatin relaxation and transcriptional activation.
(2) Methylation: Regulates gene silencing or activation in a highly site-specific manner.
(3) Phosphorylation: Rapidly responds to changes in signaling pathways.
(4) Ubiquitination: Participates in protein degradation and signal transduction.
The discovery of lactylation has not only expanded the spectrum of PTMs but also raised new questions regarding how different modifications “communicate” with one another.
Crosstalk Between Lactylation and Other Post-Translational Modifications
1. “Resource Competition” and “Functional Synergy” Between Lactylation and Acetylation
(1) Resource Competition: Competition for Lysine Sites and Acyl Donors
Lactylation and acetylation often occur on the same lysine residues, such as H3K18. Both modifications depend on acyl donors, namely lactyl-CoA and acetyl-CoA, as well as transferases such as p300/CBP. Under highly glycolytic conditions, lactate accumulation increases lactylation levels and may inhibit acetylation at the same sites. This “resource competition” is considered a mechanism through which metabolic status regulates gene expression. For example, in M1-activated macrophages, lactylation promotes the expression of anti-inflammatory genes such as Arg1, thereby reversing the earlier inflammatory phenotype.
(2) Functional Synergy: Coordinated Regulation of Transcriptional Activity
Although lactylation and acetylation may compete at specific sites, they can also act synergistically at different sites. Some promoter regions show coordinated enrichment of H3K18la and H3K27ac, thereby enhancing gene transcription.
2. The “Antagonistic Mechanism” Between Lactylation and Methylation
Methylation, such as H3K27me3, often exhibits an antagonistic relationship with lactylation in epigenetic regulation. Lactylation tends to activate gene expression, whereas methylation is frequently associated with gene silencing. Some studies have found that increased lactylation is accompanied by decreased H3K27me3, suggesting the possible existence of a “counterbalancing mechanism” in epigenetic reprogramming. In addition, a negative correlation between lactylation and H3K9me3 has been observed in cancer cells, which may be associated with heterochromatin decondensation under tumor metabolic reprogramming.
3. Signaling Crosstalk Between Lactylation and Phosphorylation
As a rapidly responsive PTM, phosphorylation is closely associated with intracellular signaling pathways. In contrast, lactylation is more metabolically dependent and represents a slow-changing variable of cellular homeostasis.
The interaction points between these two modifications are mainly concentrated in the regulation of enzyme activity, for example:
(1) AMPK activation reduces glycolysis, indirectly decreases lactate production, and thereby affects lactylation levels;
(2) p300 itself can also be phosphorylated, which regulates its ability to mediate lactylation.
Therefore, lactylation and phosphorylation can jointly regulate transcriptional programs through signaling-metabolic crosstalk.
4. Cross-Regulation Between Lactylation and Ubiquitination
Although research in this area remains limited, preliminary evidence suggests that lactylation may regulate ubiquitination substrate selection or influence ubiquitination efficiency by altering substrate conformation. In addition, at the histone level, lactylation may affect the recognition sites of E3 ubiquitin ligases, thereby indirectly participating in chromatin remodeling.
Challenges and Solutions in PTM Omics Research at MtoZ Biolabs
MtoZ Biolabs leverages advanced Orbitrap Exploris mass spectrometry platforms, together with optimized immunoaffinity enrichment and multi-PTM co-detection strategies, to enable highly sensitive detection of multiple modifications, including lactylation, acetylation, phosphorylation, and ubiquitination. By constructing global PTM interaction maps, our customized PTM omics services have been widely applied in multiple research fields, including inflammation, autophagy, cancer, and metabolism, providing robust support for scientists seeking to elucidate complex cellular regulatory networks.
The discovery of lactylation marks the entry of PTM research into a new era integrating metabolism, epigenetics, and signaling. Its crosstalk with other post-translational modifications not only reveals multidimensional mechanisms underlying cell fate regulation but also provides new targets for disease mechanism studies and targeted intervention. In exploring unknown PTM interactions, MtoZ Biolabs will continue to support life science researchers with high-quality mass spectrometry platforms and professional research services, helping decode deeper layers of biological complexity.
MtoZ Biolabs, an integrated chromatography and mass spectrometry (MS) services provider.
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