Lactic acid is a well-known metabolite, found in almost all cell types and is very abundant in proliferating tumor cells due to the Warburg effect. Although many studies demonstrate that tumor-secreted lactate can enter multiple types of immune cells to form a microenvironment conducive to tumor growth, how intracellular lactate manifests or translates into beneficial signals for tumor growth remains unclear. incomplete. Recently, lactylation of lysine residues has been identified as a new type of post-translational modifications for histones, providing a new perspective for the nonmetabolic functions of lactate. Histone lactylation has been found to play an essential role in stem cell pluripotency, neural excitation, macrophage polarization, and tumor development.
It has also been found in non-histone proteins and although it is attracting interest among biochemists, it is not known for certain which enzyme takes care of the process. Histone acetyltransferase p300 can carry out this reaction but compared to the concentrations of acetyl-CoA, those of lactic acid inside the cell are 1000 times lower, raising doubts about its efficiency and the possibility that this is feasible. This is why, by searching for other potential candidate enzymes, scientists from the Shanghai University School of Medicine saw that the operation is carried out by a protein which is an enzyme involved in a completely different cellular process: protein synthesis. Each amino acid, before becoming a protein chain, must be activated on its transport RNA (tRNA), and then transferred to the growing chain.
All twenty amino acids have their own tRNA and the corresponding synthetase that unites them. Well, tRNA synthetase for the amino acid alanine (AARS1) appears to be the lactyl transferase that scientists were looking for. Furthermore, they found that in response to intracellular lactate accumulation, AARS1 translocated to the nucleus where it directly catalyzed the lactylation of YAP on lysine 90 and TEAD1 on lysine 108, thereby activating downstream target gene expression to promote proliferation of tumor cells. YAP and TEAD1 are two effectors of the Hippo cell pathway, which serves for cell polarity and differentiation, and whose dysregulation can have oncogenic effects. Furthermore, AARS1 was shown to be a direct target gene of YAP-TEAD1, forming a positive feedback loop to manifest high levels of intracellular lactate as a growth signal.
Consistently, researchers found that AARS1 is upregulated and associated with lactylation of YAP-TEAD1 in gastric cancer. Furthermore, 3D structural analysis of the enzyme model indicated that mutating the amino acid residues lining the catalytic pocket of AARS1 would disrupt its interaction with lactate. This proves that lactic acid actually has its own molecular pocket to fit into. Biochemical tests showed that AARS1 effectively catalyzed the lactylation of histone H3 in the presence of physiological concentrations of ATP and lactate, but failed to do so in the presence of even 100-fold higher concentrations of lactyl-CoA. This “two-faced Janus” protein function has been known for more than twenty years as moon-lightning, to indicate a protein that in a specific context has a biological function, while moving to another cellular compartment or in the presence of other substrates behaves differently.
In the case of histone lactylation, the biological and clinical implications are notable: lactic acid has very recently been demonstrated to be the responsible effector of tumor cachexia, or the death of cancer patients due to extreme weight loss. In this specific case, the effects have been shown to depend on a membrane receptor. In parallel, the immune system is also a target of the tumor through the production of lactic acid: tumor cells secrete this “waste” to “immobilize and numb” the immune cells and prevent them from attacking them. In this case, the mechanism depends on the transport of lactate into the lymphocyte through the SLC5A12 transporter channel; it would be the internal increase of the metabolite that “reprograms” the metabolism and induces the immune cells to “fall asleep”. It cannot be excluded that this mechanism occurs through a “lactylation” of some lymphocytic proteins.
Finally, lactic acid at the brain level seems to act as a molecule that relieves depression. According to very recent views, this effect is specific to lactate, as its reduced version (pyruvic acid) does not exert this phenomenon. According to other data, the antidepressant effect of this molecule seems to involve neurogenesis at the level of the hippocampus. In any case, the effect appears if lactic acid enters the cells, as functional data indicate that the conversion of lactate to pyruvate with the concomitant production of NADH2 is necessary for the neurogenic and antidepressant effects of lactate. Given that the NAD+/NADH2 ratio can affect the function not only of enzymes related to energy metabolism, but also related to gene expression (PARP1, CtBP-1, SIRT, etc.), together with histone lactylation or other proteins, lactic acid could regulate brain neurochemistry in favor of mood stability.
- Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
Scientific references
Yu X, Yang J et al. Int J Biol Sci. 2024; 20(5):1833-54.
Campos AM et al. Front Mol Biosci. 2024; 11:1349509.
Gupta S et al. FASEB J. 2023 Nov; 37(11):e23219.
Shegay PV et al. Front Mol Biosci. 2023; 10:1076138.
Kumagai S et al. Cancer Cell. 2022; 40(2):201-218.
Carrard A et al. Mol Psychiatry 2021; 26(11):6723.