https://clinicalepigeneticsjournal.biomedcentral.com/articles/10.1186/s13148-024-01682-2
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- Open access
- Published:
Lactylation: the novel histone modification influence on gene expression, protein function, and disease
Clinical Epigenetics 16, Article number: 72 (2024)
Abstract
Lactic acid, traditionally considered as a metabolic waste product arising from glycolysis, has undergone a resurgence in scientific interest since the discovery of the Warburg effect in tumor cells. Numerous studies have proved that lactic acid could promote angiogenesis and impair the function of immune cells within tumor microenvironments. Nevertheless, the precise molecular mechanisms governing these biological functions remain inadequately understood. Recently, lactic acid has been found to induce a posttranslational modification, lactylation, that may offer insight into lactic acid's non-metabolic functions. Notably, the posttranslational modification of proteins by lactylation has emerged as a crucial mechanism by which lactate regulates cellular processes. This article provides an overview of the discovery of lactate acidification, outlines the potential “writers” and “erasers” responsible for protein lactylation, presents an overview of protein lactylation patterns across different organisms, and discusses the diverse physiological roles of lactylation. Besides, the article highlights the latest research progress concerning the regulatory functions of protein lactylation in pathological processes and underscores its scientific significance for future investigations.
The discovery of protein lactylation modification
In 2019 and 2020, two separate research teams led by Zhao et al. and Galligan et al. made significant strides in the field of protein lactylation (Kla), an emerging posttranslational modification [16, 17].
Zhao et al. utilized mass spectrometry techniques to detect a mass shift of 72.021 Da on-lysine residues of histones, thus unveiling the widespread occurrence of histone lysine lactylation through isotope metabolic labeling methods. Following this discovery,
Galligan et al. further demonstrated that proteins are also susceptible to lactic acid modifications. These two research groups delved into various facets of this modification, including its characteristics, the sources of substrates, and the specific target proteins involved.
Zhao et al. postulated that lactylation modification is an actively enzymatic posttranslational process reliant on lactoyl coenzyme A (lactyl-CoA) as a substrate. Recently, the presence of lactoyl-CoA has been confirmed in mammalian cells and tissues using liquid chromatography–tandem mass spectrometry [18] (Fig. 1).
In contrast, Galligan et al. suggested that lactylation modification is a passive, non-enzymatic acyl transfer process that employs lactoyl glutathione (LGSH) as a substrate.
They also emphasized the role of glyoxalase II (GLO2) in regulating LGSH levels within cells
. Additionally, Zhao et al. research primarily focused on lactylation modifications occurring on histones, revealing that histone lactylation represents a novel form of epigenetic regulation with profound implications for gene transcription.
Conversely, Galligan et al. discovered lactylation modifications on several metabolic enzymes, indicating that lactylation of these enzymes can provide negative feedback regulation on the glycolytic pathway.
Their study underscored the widespread presence of lactylation in human tissues and cells, emphasizing its regulatory impact on proteins beyond histones.
In subsequent study,
Zhao et al. identified potential “eraser” for lactylation, such as HDAC1 and HDAC2 [19]. Furthermore, latest studies have demonstrated that lactylation modification of proteins and histones is accomplished by enzymes, such as the p300 which the writer of lactylation, histone lactylation was significantly impaired upon p300 knockdown in mouse bone marrow-derived macrophages [20]. Therefore, as we see, the process is mostly an enzymatic reaction, but the modification exists not only in histone lysine but also in non-histone proteins.
Despite ongoing debates within the scientific community, the discovery of protein lactylation has not only expanded the horizon of research on posttranslational protein modifications but has also yielded valuable insights into the molecular mechanisms underpinning lactate’s role in critical physiological and pathological processes, including cancer, metabolism, and immunity. This groundbreaking revelation holds the potential to open up new avenues of exploration and deepen our comprehension of the multifaceted roles of lactate in diverse biological contexts.
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