Mechanism of Protein Lactylation

Post-translational modifications (PTMs) are pivotal in regulating the function, localization, stability, and interactions of proteins. Among these, lactylation is an emerging type of PTM that has garnered significant interest in recent years. Lactylation involves the covalent attachment of lactate molecules to lysine residues in proteins, impacting critical biological processes such as metabolism, gene expression, and immune responses.

 

Discovery of Lactylation

Lactylation was first identified in 2019 when scientists detected lactylated lysine residues in histones using mass spectrometry. This groundbreaking discovery demonstrated that lactate, traditionally viewed as merely a glycolytic byproduct, also functions as a signaling molecule capable of modifying proteins to regulate various biological processes.

 

Mechanisms Underlying Lactylation

Lactylation is closely associated with lactate concentration within cells. Under conditions where oxygen is limited or glucose levels are elevated, glycolysis intensifies, leading to an accumulation of lactate. This lactate can then be transported into the nucleus and participate in the lactylation of histones. The underlying mechanisms include:

 

1. Lactate Production and Accumulation

Under hypoxic conditions, cellular metabolism shifts from oxidative phosphorylation to anaerobic glycolysis. During this process, pyruvate is reduced to lactate by lactate dehydrogenase (LDH), increasing intracellular lactate levels.

 

2. Transport of Lactate into the Nucleus

Lactate, being a small molecule, is transported into the nucleus via monocarboxylate transporters (MCTs). Once in the nucleus, lactate covalently attaches to lysine residues, forming lactylation modifications.

 

3. Histone Lactylation

Lactylation primarily occurs on lysine residues of histones. The covalent bonding of lactate with the ε-amino group of lysine side chains results in the formation of lactyl-lysine (Kla). This modification alters histone-DNA interactions, affecting chromatin structure and gene expression.

 

4. Regulation by Lactylation

Lactylation significantly influences gene expression. It has been shown to promote the expression of specific genes involved in processes such as inflammation, tumorigenesis, and cell differentiation. For instance, lactylation in macrophages enhances the expression of inflammatory factors, thereby boosting the immune response.

 

Biological Significance of Lactylation

Lactylation plays a role not only in gene expression regulation but also in various cellular processes, including metabolism and signal transduction. Given its involvement in both physiological and pathological processes, lactylation has become a focus of research. For example, lactylation has been implicated in cancer biology, where it may promote tumor cell proliferation and survival. Additionally, lactylation's role in immune cell activation and differentiation presents potential applications in immunotherapy.