Lactylation Antibodies: Deciphering Novel Molecular Mechanisms of Metabolic Reprogramming in Innate Immunity Regulation

1. Literature Information
Research Focus: Uncovering the molecular pathway by which lactate-mediated protein lactylation regulates innate immunity, with a focus on the bifunctional role of AARS1/2 and the functional impairment of cGAS via lactylation.
Core Innovation: Identifying AARS1/2 as lactate sensors and lactylation catalysts, and elucidating how cGAS lactylation disrupts innate immune signaling—establishing a direct link between metabolic reprogramming and immune regulation.

2. Research Background
Lactate, a central metabolite of cellular metabolism, accumulates to substantial levels in tumor microenvironments, inflammatory responses, and various stress conditions. Historically dismissed as metabolic waste, lactate has recently emerged as a key signaling molecule. It enters cells through monocarboxylate transporters (MCT1) and mediates protein lactylation, a novel post-translational modification that modulates immune cell function. Clinical evidence shows that patients with hyperlactatemia exhibit significantly reduced interferon production, implying a potential association between lactate accumulation and immune suppression. However, the precise molecular mechanisms underlying this metabolic-immune crosstalk have long remained unclear, creating a critical gap in the field of immunometabolism.

3. Research Approaches
To unravel the role of lactylation in immune regulation, the research team employed a multi-disciplinary strategy:
* Genome-wide CRISPR screening to identify key mediators of lactate-induced immune suppression.
* Biochemical and structural biology analyses to characterize the binding affinity and catalytic mechanism of candidate enzymes (AARS1/2) with lactate.
* Proteomic and site-specific modification studies to validate lactylation targets (e.g., cGAS) and their functional consequences.
* In vitro functional assays and in vivo mouse models (gene knockout, point mutation) to assess the physiological and pathological significance of the lactylation pathway.
* Development and application of lactylation-specific antibodies to detect endogenous modification levels and validate key findings.

4. Research Outcomes
4.1 Identification of AARS1/2 as Bifunctional Lactate Sensors and Catalysts
Genome-wide CRISPR screening revealed that alanyl-tRNA synthetases AARS1 and AARS2 are critical for lactate-mediated immune suppression. Beyond their classical role in linking alanine to tRNA during protein synthesis, AARS1/2 bind lactate with high affinity (Kd = 16.7 μM for AARS1; Kd = 7.5 μM for AARS2)—a function conserved across evolution. Depletion of AARS1/2 nearly abolished global protein lactylation in cells, while their overexpression significantly enhanced lactylation, establishing them as bifunctional enzymes for lactate sensing and lactylation catalysis.

4.2 Molecular Mechanism of AARS1/2-Mediated Lactylation
Structural and biochemical studies uncovered a two-step ATP-dependent catalytic mechanism:
* Lactate binds to the active site of AARS1/2 in a conformation mimicking alanine, stabilized by conserved residues (e.g., M46, R77, N216).
* ATP activates lactate to form a lactate-AMP intermediate (releasing pyrophosphate), followed by transfer of the lactate moiety to lysine residues of target proteins—completing lactylation and releasing AMP.

Notably, alanine competes with lactate for the active site, inhibiting lactylation and revealing a novel regulatory interplay between metabolites.

4.3 cGAS Lactylation Induces Innate Immune Dysfunction
cGAS, a cytosolic DNA sensor critical for antiviral immunity and autoimmune surveillance, was identified as a key lactylation target. AARS2 specifically mediates lactylation of cGAS at conserved N-terminal lysine residues (K131 in humans; K156 in mice). This modification triggers conformational changes in cGAS, reducing its DNA-binding affinity by over 100-fold, disrupting functional liquid-liquid phase separation, and nearly eliminating cGAMP synthesis (the core second messenger in innate immune signaling). Mechanistically, lactylation alters cGAS’s surface charge, shifting it from a "DNA-sensing mode" to a "self-aggregation mode"—forming dense, inactive condensates that block downstream signaling activation.

4.4 Physiological and Pathological Significance
In vivo studies using mouse models confirmed the critical role of the lactylation pathway:
Viral infection: AARS2 deficiency or non-lactylatable cGAS (KR mutation) reversed lactate-induced immune suppression, significantly improving host survival.
Autoimmunity: Lactylation-mimicking cGAS (KQ mutation) alleviated autoimmune pathology in Trex1-deficient mice.
Stress conditions: Elevated lactate suppressed immune surveillance via this pathway, while MCT1 inhibitors restored cGAS activity by blocking lactate uptake—highlighting potential therapeutic targets for immune-related diseases.

5. Product Empowerment by ANT BIO PTE. LTD.
ANT BIO PTE. LTD.’s STARTER brand, a specialist in high-quality antibodies, provided indispensable tools for this groundbreaking research. The "L-Lactyl Lysine Rabbit Polyclonal Antibody" (Catalog No.: S0B0719) stands out as a core product enabling the detection and characterization of lactylation modifications.

Key Roles of the Product in the Study:
Validation of Lactylation Events: The antibody’s high specificity for L-lactyl lysine residues (minimal cross-reactivity with acetylation, crotonylation, etc.) allowed precise detection of endogenous lactylation levels in cells and tissues—critical for confirming AARS1/2-mediated modification of cGAS and other targets.
Functional Assay Support: Compatible with immunoprecipitation (IP), Western blot (WB), and immunofluorescence (IF), the antibody facilitated studies on cGAS conformational changes, protein-protein interactions, and subcellular localization post-lactylation.
Batch-to-Batch Consistency: Rigorous quality control ensured reliable performance across experiments, supporting long-term proteomic and in vivo studies on lactylation dynamics.
Additionally, ANT BIO PTE. LTD.’s Histone H3 (Lactyl K9) Recombinant Rabbit mAb (Catalog No.: S0B0756) provides researchers with specialized tools to investigate histone lactylation—expanding the scope of metabolic epigenetics research.

6. Brand Mission
ANT BIO PTE. LTD. is dedicated to empowering the global life science community through innovative, high-quality biological reagents and solutions. With three specialized sub-brands—ABSIN (general reagents, ELISA kits), STARTER (antibodies), and UA (recombinant proteins)—we leverage advanced development platforms (recombinant monoclonal antibodies, rapid antibody generation, recombinant protein expression systems including E.coli, CHO, HEK293, and Insect Cells; One-Step ELISA Platform; PTM Pan-Modification Antibody Platform) to deliver products that meet the highest standards of quality and performance. Our certifications (EU 98/79/EC, ISO9001, ISO13485) underscore our commitment to reliability. We strive to be a trusted partner for pharmaceutical innovators, research institutions, and scientists worldwide, accelerating discoveries in immunometabolism, cancer biology, and precision medicine.

7. Related Product List

S0B0756	Histone H3 (Lactyl K9) Recombinant Rabbit mAb (S-R397)	Host : Rabbit Conjugation: Unconjugated
S0B0719	L-Lactyl Lysine Rabbit Polyclonal Antibody	Host : Rabbit Conjugation: Unconjugated

8. AI Disclaimer
This article is AI-compiled and interpreted based on the original work. All intellectual property (e.g., images, data) of the original publication shall belong to the journal and the research team. For any infringement, please contact us promptly and we will take immediate action.
 
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