L-valine is in cellular signal transduction

L-valine, as one of the essential branched-chain amino acids (BCAAs) in humans, is not only a basic raw material for protein synthesis but also participates in the regulation of multiple intracellular signaling pathways directly or indirectly, playing a key role in physiological processes such as cellular metabolism, proliferation, and stress response. Its role in signal transduction is mainly reflected in the regulation of metabolic sensing pathways, stress signaling pathways, and cell survival pathways, and is often closely related to intracellular environmental homeostasis and energy status.

I. Activation of the mTORC1 Signaling Pathway: Regulation of Cell Growth and Metabolism

mTORC1 (mammalian target of rapamycin complex 1) is a core signaling molecule for cells to sense nutrients, energy, and growth factors, responsible for integrating external signals to regulate protein synthesis, cell proliferation, and autophagy. As one of the key activators of mTORC1, L-valine has specific regulatory mechanisms:

Direct activation mechanism: After entering cells through amino acid transporters (such as the LAT1/4F2hc complex), L-valine binds to Rag GTPases and induces conformational changes, prompting Rag proteins to recruit mTORC1 to the lysosomal membrane surface, where it binds to the activator Rheb, ultimately triggering the kinase activity of mTORC1. In this process, L-valine synergizes with other branched-chain amino acids (such as leucine), but valine’s activation of Rag GTPases has a unique dose dependence—it can initiate the signal cascade at physiological concentrations, while high concentrations may inhibit excessive activation through negative feedback.

Downstream effects: Activated mTORC1 promotes the translation of genes related to ribosomal protein synthesis by phosphorylating its downstream target proteins (such as S6K1 and 4E-BP1), enhancing cell proliferation capacity; at the same time, it inhibits autophagy-related proteins (such as ULK1) to reduce cellular autophagy and maintain energy reserves. This pathway is particularly active in pancreatic β cells, muscle cells, and tumor cells. For example, in muscle cells, L-valine-mediated activation of mTORC1 can promote muscle protein synthesis, which is closely related to exercise-induced muscle growth.

II. Participation in the AMPK Signaling Pathway: Balancing Energy Metabolism and Stress Adaptation

AMPK (AMP-dependent protein kinase) is a "sensor" of cellular energy homeostasis. When cells are in energy deficiency (increased AMP/ATP ratio), it is activated to maintain energy balance by inhibiting anabolic metabolism and enhancing catabolic metabolism. L-valine indirectly regulates AMPK activity through metabolic intermediates, forming an antagonistic balance with mTORC1:

L-valine is catabolized to produce succinyl-CoA and ATP. When valine supply is sufficient, intracellular ATP levels rise, and the AMP/ATP ratio decreases, inhibiting AMPK activation, thereby synergizing with mTORC1 to promote anabolic metabolism; conversely, valine deficiency leads to insufficient energy supply, activating AMPK, which inhibits fat synthesis by phosphorylating downstream target proteins (such as ACC1) and promotes mitochondrial oxidative metabolism to supplement energy.

This "valine-mTORC1-AMPK" antagonistic regulatory network is the core mechanism for cells to adapt to nutritional fluctuations. For example, in a state of starvation, valine levels decrease, AMPK is activated, and mTORC1 is inhibited, and cells preferentially initiate autophagy and fatty acid oxidation to maintain survival; when nutrients are sufficient, valine-mediated signal reversal promotes cell growth.

III. Regulation of Stress Signaling Pathways: Mediating Cellular Antioxidation and Damage Repair

When cells respond to stress such as oxidative stress and endoplasmic reticulum stress, L-valine participates in the regulation of stress signaling pathways through metabolites to maintain intracellular environmental stability:

Antioxidative stress: α-ketoisovalerate produced by L-valine metabolism can serve as a precursor for glutathione (GSH) synthesis. GSH is an important intracellular antioxidant molecule that can scavenge reactive oxygen species (ROS) and inhibit excessive activation of oxidative stress pathways (such as NF-κB). When cells are subjected to oxidative damage, the rapid metabolism of valine can enhance GSH reserves, indirectly inhibiting the continuous activation of stress signaling pathways such as JNK/p38 MAPK and avoiding cell apoptosis.

Endoplasmic reticulum stress regulation: When intracellular protein synthesis demand surges (such as in hormone-secreting cells), the endoplasmic reticulum may activate the UPR (unfolded protein response) due to the accumulation of unfolded proteins. L-valine coordinates the rate of protein synthesis with endoplasmic reticulum processing capacity by maintaining moderate mTORC1 activity—it not only ensures necessary protein synthesis but also reduces the load of unfolded proteins by regulating the PERK/eIF2α pathway, thereby alleviating endoplasmic reticulum stress. This role is particularly important in secretory cells (such as pancreatic β cells).

IV. Influence on Immune Signaling Pathways: Regulation of Inflammation and Immune Response

In immune cells (such as macrophages and T cells), L-valine participates in the fine regulation of immune responses by regulating inflammation-related signaling pathways:

In macrophages, L-valine deficiency can lead to excessive activation of the NF-κB pathway, promoting the release of pro-inflammatory factors (such as TNF-α and IL-6) and exacerbating inflammatory reactions; sufficient valine can prevent excessive inflammation by inhibiting the phosphorylation of IκBα and blocking the nuclear translocation of NF-κB. This mechanism is related to the energy support of valine metabolism for anti-inflammatory protein synthesis and its maintenance of intracellular redox balance to inhibit the initiation of inflammatory signals.

During T cell activation, L-valine promotes the transformation of T cells from a quiescent state to an effector state by activating mTORC1, enhances IL-2 secretion and cell proliferation, and regulates T cell subset differentiation (such as promoting Th1 cell polarization). Its signal deficiency can lead to T cell dysfunction and affect adaptive immune responses.

Conclusion: Multidimensionality and Specificity of Signal Regulation

L-valine’s role in cellular signal transduction has "duality": on the one hand, it acts as a nutritional signal to activate anabolic pathways such as mTORC1, promoting cell growth and function execution; on the other hand, it participates in energy sensing and stress signal regulation through metabolic intermediates to maintain cell homeostasis. Its specific role is reflected in the synergy or antagonism with other amino acids (such as co-activating mTORC1 with leucine, but being more dependent on its own metabolic state in AMPK regulation), and there are functional differences in different cell types (such as focusing on anabolic metabolism in muscle cells and inflammatory regulation in immune cells). A deep understanding of the signal regulatory network of L-valine not only helps to reveal the relationship between amino acid metabolism and cell function but also provides potential ideas for targeted intervention in metabolic diseases, tumors, and other diseases.