Lactylation antibody: How to reveal the novel molecular mechanisms of metabolic reprogramming regulating innate immunity?

1. How does lactate become a key metabolic signal for immune regulation?

Lactate, as a core product of cellular metabolism, accumulates significantly in tumor microenvironments, inflammatory responses, and stress conditions. Traditionally viewed as metabolic waste, recent studies have revealed that lactate can enter cells via monocarboxylate transporters (MCT1) and participate in gene expression and signaling pathway regulation. Notably, lactate-derived protein lactylation modification, as a novel post-translational modification, may directly regulate immune cell function. Clinical observations show that patients with hyperlactatemia exhibit significantly reduced interferon levels, suggesting a potential link between lactate accumulation and immune suppression, though the specific molecular mechanisms remain to be elucidated.

2. How were AARS1/2 identified as bifunctional enzymes for lactate sensing and lactylation catalysis?

Through genome-wide CRISPR screening, researchers discovered that alanyl-tRNA synthetases AARS1 and AARS2 play a crucial role in lactate-mediated immune suppression. Traditionally, these enzymes catalyze the linkage of alanine to tRNA, but studies found they can specifically bind lactate with high affinity (Kd values of 16.7 μM and 7.5 μM, respectively), a capability highly conserved in evolution. Further proteomic analysis showed that knockdown of AARS1/2 nearly abolished global protein lactylation levels in cells, while ectopic expression significantly enhanced lactylation modification. This discovery challenges the classical functional understanding of aminoacyl-tRNA synthetases, establishing their new role as bifunctional enzymes for lactate sensing and lactylation catalysis.

3. What is the molecular mechanism of AARS1/2-catalyzed lactylation?

Structural biology and biochemical studies revealed the detailed mechanism of AARS1/2-catalyzed lactylation: lactate molecules enter the enzyme active center in a binding mode similar to the natural substrate alanine, relying on multiple conserved amino acid residues (e.g., M46, R77, N216) for specific recognition. The catalytic process follows an ATP-dependent two-step reaction model: first, lactate is activated by ATP to form a lactate-AMP intermediate with pyrophosphate release; then, the lactate group is transferred to lysine residues on target proteins, completing lactylation modification and releasing AMP. Notably, lactate and alanine compete for substrate binding sites, with natural substrate alanine inhibiting lactylation, revealing a novel regulatory layer of metabolite interaction.

4. How does cGAS lactylation lead to loss of innate immune function?

cGAS, as a cytosolic DNA sensor, plays a central role in antiviral immunity and autoimmune surveillance. Studies found that AARS2 specifically mediates lactylation of cGAS at conserved N-terminal lysine sites (human K131, mouse K156). Lactylated cGAS undergoes conformational rearrangement, reducing its DNA-binding ability by over 100-fold, preventing functional liquid-liquid phase separation structures, and nearly abolishing cGAMP synthesis activity. Mechanistically, lactylation alters cGAS surface charge distribution, switching it from "DNA-sensing mode" to "self-aggregation mode," forming small, dense inactive condensates that effectively block innate immune signaling pathway activation.

5. What is the significance of this regulatory pathway in physiological and pathological processes?

Using gene knockout and point mutation mouse models, research confirmed that cGAS lactylation plays a key role in various physiological and pathological processes: in viral infection models, AARS2 deficiency or non-lactylatable cGAS mutation (KR) effectively resisted lactate-induced immune suppression, significantly improving host survival rates; in autoimmune models, lactylation-mimicking mutations (KQ) alleviated Trex1 deficiency-induced autoimmune damage. Importantly, elevated lactate levels under stress significantly suppressed immune surveillance via this pathway, while MCT1 inhibitors could effectively restore cGAS activity by blocking lactate uptake. These findings provide new insights into metabolism-immune interactions and potential intervention targets for related diseases.

6. What are the development and application prospects of lactylation antibodies?

Lactylation-specific antibodies played a crucial role in this study. Researchers developed cGAS lactylation site-specific antibodies, providing essential tools for detecting endogenous lactylation levels. These antibodies have multifaceted applications: in basic research, they can map protein lactylation profiles under different physiological states; in translational medicine, they serve as potential biomarkers for assessing immune suppression; in drug development, they provide pharmacodynamic biomarkers for metabolic intervention strategies like MCT1 inhibitors. As lactylation research advances, specific lactylation antibodies will become indispensable tools for deciphering metabolism-immune networks.

7. Conclusion

This study systematically reveals a novel mechanism by which lactate regulates innate immunity via AARS1/2-mediated protein lactylation, establishing a direct molecular link between metabolic reprogramming and immune responses. This discovery not only deepens the theoretical framework of immunometabolism but also provides a foundation for developing innovative therapeutic strategies targeting tumor immune evasion, chronic infections, and autoimmune diseases. With improved lactylation-specific detection tools and mechanistic studies, interventions targeting lactylation modifications are poised to become an emerging field in immunotherapy.

8. Which manufacturers provide lactylation antibodies?

Hangzhou Start Biotech Co., Ltd. has independently developed the "L-Lactyl Lysine Rabbit Polyclonal Antibody" (Product Name: L-Lactyl Lysine Rabbit Polyclonal Antibody), a high-specificity, broad-recognition, and high-affinity tool for epigenetic research. This product is prepared using carefully designed synthetic peptide immunogens and rigorously validated across multiple platforms, including immunoprecipitation (IP), Western blot (WB), and immunofluorescence (IF). It holds significant value in emerging interdisciplinary fields such as metabolism-epigenetics, gene expression regulation, and disease mechanism exploration.

Technical Support: We provide comprehensive product documentation, including specificity validation data, experimental protocols for various platforms, target recommendations, and expert consultation, supporting cutting-edge discoveries in the rapidly evolving field of metabolic epigenetics.

Hangzhou Start Biotech Co., Ltd. is committed to delivering high-quality, high-value biological reagents and solutions to global pharmaceutical innovators and research institutions. For more details about the "L-Lactyl Lysine Rabbit Polyclonal Antibody" (Catalog No. S0B0719) or to request samples, please contact us.

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