Lactylation is a recently discovered biological process where lactate, a molecule from energy metabolism, attaches to proteins. This modification expands our understanding of how metabolic byproducts impact cellular functions and gene regulation. Its importance stems from its widespread presence and involvement in fundamental biological processes.
The Basics of Lactylation
Lactylation is a type of post-translational modification that alters a protein’s function after synthesis. It involves a lactyl group, derived from lactate, covalently attaching to lysine residues on target proteins. Lysine is an amino acid commonly found in proteins, and its modification can change the protein’s shape, stability, or interactions with other molecules.
While lactylation can occur on various proteins, it was initially identified and is most extensively studied on histone proteins. Histones are proteins that act as spools around which DNA wraps, forming structures called nucleosomes that compact DNA within the cell nucleus. The attachment of a lactyl group to histones, such as H3K18la and H3K23la, can influence how tightly DNA is packed. Lactate, the precursor for this modification, is an end product of glycolysis, the pathway that breaks down glucose for energy. Enzymes responsible for adding and removing lactyl groups, often called “writers” and “erasers,” are an active research area; p300 has been implicated as a “writer.”
How Lactylation Influences Cell Activity
Lactylation impacts cell activity by influencing gene expression, a process known as epigenetics. When lactyl groups attach to histone proteins, they can alter the structure of chromatin, the complex of DNA and proteins that makes up chromosomes. This modification can either loosen or tighten the DNA’s grip on histones, thereby affecting which genes are accessible for transcription and ultimately turned on or off. For example, histone lactylation in gene promoter regions can positively correlate with messenger RNA production, indicating increased gene activation.
Lactylation also plays a role in cellular metabolism and energy regulation, linking lactate levels directly to cellular responses. The concentration of intracellular lactate, which increases under conditions like high glucose or hypoxia, directly influences the levels of protein lactylation. This links a cell’s metabolic state with its gene expression patterns. For instance, in macrophages, increased lactate levels due to a shift towards aerobic glycolysis lead to elevated histone lactylation, which in turn influences the expression of specific genes. Lactylation thus allows cells to integrate their metabolic environment with gene transcription, adapting to various physiological and pathological stimuli.
Lactylation’s Role in Our Body and Disease
Lactylation plays a role in various physiological states and disease conditions. In the context of intense exercise, lactylation is involved in maintaining cellular homeostasis in skeletal muscle. For instance, the lactylation of a protein called Vps34, a component of the PI3K complex, increases its activity, which enhances processes like autophagy and endolysosomal degradation, promoting muscle recovery and function. While some research suggests a link, studies have not consistently shown elevated muscle protein lactylation, indicating its role in muscle adaptation might be more complex.
Lactylation is also connected to inflammation and immune responses. Lactate, traditionally seen as a waste product, is now recognized as a signaling molecule that can either promote or reduce inflammatory reactions. Lactylation influences the activity of immune cells and inflammatory signaling pathways. For example, increased histone lactylation has been observed in macrophages during inflammation, contributing to their activation and polarization, and affecting their ability to regulate inflammatory processes.
In cancer, lactylation is recognized for its contribution to tumor growth and progression. Cancer cells often exhibit high levels of glycolysis, leading to increased lactate production and accumulation in the tumor microenvironment. This lactate acts as a precursor for lactylation, which can influence gene transcription and signaling pathways in cancer cells. For instance, elevated histone lactylation has been observed in various cancers, including ocular melanoma and colorectal cancer, where it can promote the expression of genes that support tumor proliferation, invasion, and even resistance to treatment. Lactylation can also influence immune cells within the tumor microenvironment, such as tumor-associated macrophages, promoting an immunosuppressive state that aids tumor evasion of the immune system.