Lactylation Antibodies: Unveiling Metabolic Reprogramming’s Regulation of Innate Immunity

Literature Information

This article dissects groundbreaking research that reveals a novel molecular mechanism by which metabolic reprogramming regulates innate immunity—mediated by lactate-derived protein lactylation modification. The research identifies alanyl-tRNA synthetases AARS1/2 as bifunctional enzymes for lactate sensing and lactylation catalysis, and clarifies how cGAS lactylation impairs innate immune function. Central to this study’s success are specialized lactylation detection tools, including the L-Lactyl Lysine Rabbit Polyclonal Antibody (Cat. No.: S0B0719) and Histone H3 (Lactyl K9) Recombinant Rabbit mAb (Cat. No.: S0B0756)—independently developed and produced by ANT BIO PTE. LTD. These high-specificity antibodies enabled the detection and validation of lactylation modifications, empowering the unraveling of this critical metabolism-immunity crosstalk. This discovery opens new avenues for targeting tumor immune evasion, chronic inflammation, and autoimmune diseases, with ANT BIO’s advanced reagents at the forefront of this emerging research field.

Research Background

Lactate, long regarded as a mere byproduct of glycolysis, has emerged as a key metabolic signal in physiological and pathological processes. It accumulates significantly in tumor microenvironments, inflammatory responses, and stress conditions, and clinical observations link hyperlactatemia to immune suppression—evidenced by reduced interferon levels in affected patients. However, the molecular mechanisms bridging lactate accumulation and immune dysfunction remained elusive until recent studies uncovered protein lactylation: a novel post-translational modification where lactate-derived lactyl groups are covalently attached to lysine residues of target proteins, directly regulating their function.

Innate immunity, particularly the cytosolic DNA sensor cGAS, plays a pivotal role in antiviral defense and autoimmune surveillance. Disruptions in cGAS function are associated with immune suppression and disease progression, making it a critical target for understanding lactate-mediated immune regulation. The need to detect and characterize lactylation modifications drove the development of specialized lactylation antibodies, which have become indispensable tools for deciphering the metabolic-immune regulatory network. ANT BIO PTE. LTD.’s lactylation antibodies address this need, providing high-specificity detection capabilities to advance research in this interdisciplinary field.

Research Rationale

Uncovering the Link Between Lactate Accumulation and Immune Suppression

The research first set out to validate the hypothesis that lactate accumulation induces immune suppression through protein lactylation. It aimed to identify key enzymes mediating lactylation, hypothesizing that lactate-sensing proteins with catalytic activity are central to this process. Genome-wide CRISPR screening was employed to discover genes essential for lactate-mediated immune regulation.

Characterizing the Bifunctional Role of AARS1/2 in Lactylation

A core research objective was to dissect the unexpected function of AARS1 and AARS2—traditionally known as aminoacyl-tRNA synthetases—in lactate sensing and lactylation catalysis. The research designed biochemical and structural biology studies to validate their lactate-binding affinity, catalytic mechanism, and role in global protein lactylation, challenging classical understanding of these enzymes.

Elucidating the Molecular Mechanism of AARS1/2-Catalyzed Lactylation

The research sought to clarify the detailed catalytic mechanism of AARS1/2-mediated lactylation, including substrate recognition, ATP-dependent activation, and lactyl group transfer to target proteins. It aimed to identify conserved amino acid residues involved in lactate binding and catalysis, and to explore regulatory interactions between lactate and natural substrates (e.g., alanine).

Validating the Functional Impact of cGAS Lactylation on Innate Immunity

Finally, the research set out to determine how lactylation modulates the function of key immune proteins, with a focus on cGAS. It hypothesized that cGAS lactylation impairs its DNA-sensing ability, leading to innate immune suppression. The research used lactylation-specific antibodies to detect endogenous cGAS lactylation and validated its functional consequences in cell-based and animal models.

Research Outcomes

This research systematically unravels the novel metabolic-immune regulatory pathway mediated by lactylation, yielding transformative findings that advance immunometabolism research:

1. Lactate acts as a key metabolic signal regulating innate immunity: Lactate accumulates in tumor microenvironments, inflammation, and stress, entering cells via MCT1 transporters to induce protein lactylation. This modification directly regulates immune cell function, with hyperlactatemia associated with immune suppression—closing the gap between metabolic reprogramming and immune dysfunction.
2. AARS1/2 are bifunctional enzymes for lactate sensing and lactylation catalysis: Genome-wide CRISPR screening identified AARS1 and AARS2 as critical mediators of lactate-induced immune suppression. These enzymes, traditionally involved in alanine-tRNA ligation, bind lactate with high affinity (Kd = 16.7 μM for AARS1, 7.5 μM for AARS2)—a conserved evolutionary trait. Knockdown of AARS1/2 abolishes global lactylation, while their overexpression enhances it, establishing their novel role as bifunctional lactate sensors and lactylation catalysts.
3. AARS1/2 catalyze lactylation via an ATP-dependent two-step mechanism: Structural and biochemical studies reveal that lactate binds the enzyme active center similarly to alanine, relying on conserved residues (M46, R77, N216) for recognition. The catalytic process involves: (1) ATP-dependent activation of lactate to form a lactate-AMP intermediate; (2) transfer of the lactyl group to lysine residues of target proteins. Lactate and alanine compete for binding, with alanine inhibiting lactylation—revealing a metabolite-driven regulatory layer.
4. cGAS lactylation abrogates innate immune function: AARS2 specifically mediates lactylation of cGAS at conserved N-terminal lysine sites (human K131, mouse K156). This modification induces conformational rearrangement, reducing cGAS DNA-binding affinity by over 100-fold, preventing functional liquid-liquid phase separation, and abolishing cGAMP synthesis. Lactylation alters cGAS surface charge, promoting self-aggregation into inactive condensates and blocking innate immune signaling.
5. Lactylation regulation is critical for physiological and pathological processes: Animal models confirm that AARS2 deficiency or non-lactylatable cGAS mutations (KR) resist lactate-induced immune suppression, improving survival in viral infection models. Lactylation-mimicking mutations (KQ) alleviate autoimmune damage in Trex1-deficient mice. MCT1 inhibitors restore cGAS activity by blocking lactate uptake, highlighting lactylation as a potential therapeutic target for immune-related diseases.

Product Empowerment: The Indispensable Role of ANT BIO’s Lactylation Antibodies in This Research

ANT BIO PTE. LTD.’s specialized lactylation antibodies are core tools that enabled the discovery and validation of the lactylation-mediated immune regulatory pathway, with their key applications including:

1. Detection of global and site-specific lactylation: The L-Lactyl Lysine Rabbit Polyclonal Antibody (S0B0719) exhibits broad recognition of lactylated lysine residues across diverse proteins, enabling global lactylation profiling in proteomic studies. Its high modification specificity—minimal cross-reactivity with acetylation, crotonylation, and other acylations—ensured accurate quantification of lactylation levels following AARS1/2 knockdown or overexpression. The Histone H3 (Lactyl K9) Recombinant Rabbit mAb (S0B0756) provides site-specific detection, supporting studies on histone lactylation’s role in gene expression regulation.
2. Validation of cGAS lactylation and functional consequences: The antibodies enabled the detection of endogenous cGAS lactylation at K131/K156 sites, verifying AARS2 as the specific catalyst. They supported immunoprecipitation and immunofluorescence experiments to characterize cGAS conformational changes and aggregation, directly linking lactylation to loss of DNA-sensing function.
3. High affinity and batch consistency for reliable results: Both antibodies exhibit high affinity for lactylated targets, facilitating the enrichment and detection of low-abundance lactylated proteins. Strict quality control ensures minimal inter-batch variability, critical for reproducible proteomic analysis and long-term research projects.
4. Support for diverse experimental platforms: Rigorously validated for immunoprecipitation (IP), Western Blot (WB), and immunofluorescence (IF), the antibodies provide versatile tools for studying lactylation in protein interaction, expression, and subcellular localization—covering all key experimental needs in this research.
5. Foundational tools for translational research: Beyond basic science, these antibodies serve as potential pharmacodynamic biomarkers for evaluating metabolic interventions (e.g., MCT1 inhibitors) in preclinical studies. They enable the assessment of lactylation levels in clinical samples, supporting the development of diagnostic strategies for immune-related diseases.

ANT BIO PTE. LTD.’s lactylation antibodies are engineered for the rigorous demands of metabolic epigenetics and immunometabolism research. Their high specificity, broad recognition (polyclonal) and site-specificity (monoclonal), and cross-platform performance make them the gold-standard tools for deciphering lactylation-mediated regulatory networks, empowering breakthroughs in cancer immunotherapy, inflammation, and autoimmune disease research.

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