Post-translational protein lactylation modification in health and diseases: a double-edged sword

Abstract

As more is learned about lactate, it acts as both a product and a substrate and functions as a shuttle system between different cell populations to provide the energy for sustaining tumor growth and proliferation. Recent discoveries of protein lactylation modification mediated by lactate play an increasingly significant role in human health (e.g., neural and osteogenic differentiation and maturation) and diseases (e.g., tumors, fibrosis and inflammation, etc.). These views are critically significant and first described in detail in this review. Hence, here, we focused on a new target, protein lactylation, which may be a "double-edged sword" of human health and diseases. The main purpose of this review was to describe how protein lactylation acts in multiple physiological and pathological processes and their potential mechanisms through an in-depth summary of preclinical in vitro and in vivo studies. Our work aims to provide new ideas for treating different diseases and accelerate translation from bench to bedside.

Keywords: Lactate; Lactylation; Post-translational modification.

Fig. 1

Regulation of lactate metabolism progress in normal, glycolytic and oxidative cells. Glucose metabolism mainly contains glycolysis and the TCA cycle in the mitochondrion. With sufficient oxygen, normal cells produce energy mainly through the TCA cycle. Under stimulation with hypoxia, tumors, and inflammation, glycolytic cells trigger a large uptake of glucose and participate in glycolysis in the cytoplasm, where pyruvate is turned into lactate by LDHA, which then is excreted to the extracellular matrix by MCT4. Of note, lactate uptake by oxidative cells via MCT1 leads to the conversion of it back to pyruvate in the cytoplasm via LDHB, which is then transported to the mitochondria via MCT1 to complete the TAC and contributes to energy metabolism

Fig. 2

Lactate from extracellular matrix or glycolysis resulted in lactylation. A Lactate may synthesize lactyl-CoA, and then, the lactyl group is transferred by “writer” to lysine, leading to lactylation of histones or non-histones to affect gene expression or downstream signaling pathways. B Three types of interactions (in different color blocks) between lactylation (pink residues with La) and other PTMs (green residues with R) are shown