Affinage

AARS2

Alanine--tRNA ligase, mitochondrial · UniProt Q5JTZ9

Length
985 aa
Mass
107.3 kDa
Annotated
2026-06-09
35 papers in source corpus 10 papers cited in narrative 9 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/6 claims corpus-supported (83%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

AARS2 is a mitochondrial alanyl-tRNA synthetase whose aminoacylation activity supports mitochondrial protein synthesis, and which additionally functions as an intracellular L-lactate sensor and lactyltransferase (PMID:39322678, PMID:31280959). AARS2 binds L-lactate with micromolar affinity and catalyzes ATP-dependent lysine lactylation of target proteins; acting on cGAS, it lactylates and inactivates the sensor, abolishing its phase separation and DNA-sensing activity to suppress innate immune signaling (PMID:39322678). Through lactylation of metabolic enzymes CPT2 and PDHA1, AARS2 inactivates both, driving free fatty acid accumulation, PPARγ activation, impaired mitochondrial respiration, mTORC1 activation, and premature follicle activation that underlies premature ovarian insufficiency; the de-lactylase SIRT3 opposes these effects (PMID:40301335, PMID:41832996). In cancer, AARS2 lactylates AP-2γ at K444 to enhance TRIM28 binding, K63-linked ubiquitination, and nuclear translocation, promoting tumor progression while restraining cGAS-STING immune gene expression (PMID:42114979). In the heart, AARS2 increases PKM2 translation and shifts cardiomyocyte metabolism toward glycolysis to limit apoptosis and ROS under stress, defining an AARS2-PKM2 axis (PMID:40371904), and its cardiomyocyte splicing is controlled by the RNA-binding protein PCBP1, with aberrant splicing reducing oxidative phosphorylation and the mitochondrial-encoded proteome (PMID:42010330, PMID:37293078). Disease-associated AARS2 mutations compromise aminoacylation activity, reducing ATP production in patient cells and producing loss of function in complementation assays, linking AARS2 to cardiomyopathy, leukodystrophy, and ataxia phenotypes (PMID:25705216, PMID:31280959, PMID:31705293).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 2015 Low

    Established how disease mutations map onto AARS2 functional domains, framing the synthetase's aminoacylation and editing activities as the basis for genotype-phenotype differences in cardiomyopathy versus leukodystrophy.

    Evidence Structural homology modeling mapping disease mutations onto predicted 3D domains

    PMID:25705216

    Open questions at the time
    • Computational modeling only, no experimental biochemical validation of predicted activity
    • Domain contributions to tRNA binding not directly measured
  2. 2019 Medium

    Demonstrated functionally that an aminoacylation-domain mutation impairs mitochondrial energy output, confirming AARS2 loss of function reduces ATP production via defective tRNA-Ala charging.

    Evidence Seahorse metabolic analysis of patient-derived cells versus wild-type

    PMID:31280959

    Open questions at the time
    • Single method, single mutation
    • Direct measurement of aminoacylation activity not shown
  3. 2020 Medium

    Confirmed pathogenicity and severity ranking of specific AARS2 variants, establishing thresholds of lost function sufficient to produce ataxia without leukoencephalopathy.

    Evidence Yeast complementation assay with p.Phe131del and p.Ile328Met variants

    PMID:31705293

    Open questions at the time
    • Single assay in heterologous system
    • Mechanistic link to neuronal phenotype not addressed
  4. 2023 Medium

    Revealed an upstream regulatory layer controlling cardiac AARS2 expression, showing PCBP1-mediated alternative splicing is required for proper Aars2 transcript processing and mitochondrial translation in the heart.

    Evidence Cardiomyocyte-specific Pcbp1 knockout and Aars2 exon-16 skipping mutant mice with splicing, proteomic, OXPHOS, and UPR readouts

    PMID:37293078 PMID:42010330

    Open questions at the time
    • Single lab
    • Mechanism of PCBP1 splice-site selection on Aars2 not detailed
  5. 2024 High

    Redefined AARS2 as a moonlighting L-lactate sensor and lactyltransferase, establishing that it inactivates cGAS by lactylation to suppress DNA sensing — a function distinct from its synthetase activity.

    Evidence Biochemical binding assays, in vitro lactylation reconstitution, Co-IP, genetic code expansion, lactyl-mimetic/resistant knock-in mice, phase separation assays

    PMID:39322678

    Open questions at the time
    • Full substrate spectrum of the lactyltransferase activity not defined
    • Relationship between aminoacylation and lactyltransferase active sites not resolved
  6. 2025 Medium

    Connected AARS2 lactyltransferase activity to metabolic enzyme regulation in reproduction, showing lactylation of CPT2 and PDHA1 reprograms granulosa cell metabolism to drive folliculogenesis and ovarian insufficiency.

    Evidence In vitro lactylation assays on CPT2/PDHA1, GC-specific overexpression and knockout mice, metabolic measurements

    PMID:40301335

    Open questions at the time
    • Single lab
    • Site-specific lactylation mapping on CPT2/PDHA1 not fully resolved
  7. 2025 Medium

    Identified a translation-regulatory role for AARS2 in the heart, showing it promotes PKM2 translation to shift cardiomyocytes toward glycolysis and protect against apoptosis and fibrosis.

    Evidence Cardiomyocyte-specific Aars2 deletion/overexpression mice, Ribo-Seq, PKM2 dimer/tetramer assays, TEPP-46 rescue

    PMID:40371904

    Open questions at the time
    • Mechanism by which AARS2 engages ribosomes to favor PKM2 translation not defined
    • Single lab
  8. 2026 Medium

    Linked the AARS2 R194C/R199C pathogenic variant to gain of lactyltransferase function in vivo, showing increased PDHA1/CPT2 lactylation impairs respiration and activates mTORC1 to cause premature ovarian insufficiency, reversible by SIRT3.

    Evidence Homozygous Aars2 R194C knock-in mice, lactylation and respiration assays, mTORC1 analysis, pharmacological PDHA1/CPT2 inhibition rescue

    PMID:41832996

    Open questions at the time
    • Single lab, no independent replication
    • SIRT3-AARS2 regulatory balance not fully characterized
  9. 2026 Medium

    Extended AARS2 lactyltransferase function to oncogenic signaling, showing site-specific lactylation of AP-2γ at K444 promotes its stabilization and tumor progression while suppressing cGAS-STING immune output.

    Evidence MS identification of K444 lactylation, AP-2γ-TRIM28 Co-IP, ubiquitination assays, AARS2 knockdown with lactate and immune gene readouts

    PMID:42114979

    Open questions at the time
    • Single lab
    • Direct contribution of AARS2 catalysis versus lactate supply to AP-2γ lactylation in vivo not separated

Open questions

Synthesis pass · forward-looking unresolved questions
  • How AARS2 partitions between its canonical mitochondrial aminoacylation function and its lactyltransferase activity, and what determines its substrate selectivity across tissues, remains unresolved.
  • No structural model reconciling aminoacylation and lactyltransferase active sites
  • Tissue-specific substrate selection rules unknown
  • Subcellular distribution governing access to nuclear/cytosolic substrates not mapped

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016740 transferase activity 3 GO:0140096 catalytic activity, acting on a protein 3 GO:0140098 catalytic activity, acting on RNA 2 GO:0140299 molecular sensor activity 1 GO:0140657 ATP-dependent activity 1
Localization
GO:0005739 mitochondrion 2
Pathway
R-HSA-1430728 Metabolism 3 R-HSA-392499 Metabolism of proteins 3 R-HSA-168256 Immune System 2
Partners
AP-2ΓCGASCPT2PCBP1PDHA1PKM2SIRT3TRIM28

Evidence

Reading pass · 9 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2024 AARS2 (and AARS1) directly bind L-lactate with micromolar affinity and catalyze ATP-dependent lysine lactylation, functioning as intracellular L-lactate sensors and lactyltransferases. In response to elevated L-lactate, AARS2 associates with cGAS and mediates its lactylation and inactivation in cells and in mice, abolishing cGAS liquid-like phase separation and DNA sensing. Biochemical binding assays, in vitro lactylation reconstitution, Co-IP (AARS2–cGAS association), genetic code expansion orthogonal system for lactyl-lysine incorporation, lactyl-mimetic and lactyl-resistant knock-in mouse models, in vitro and in vivo phase separation assays Nature High 39322678
2025 AARS2 lactylates and inactivates carnitine palmitoyl transferase 2 (CPT2), resulting in free fatty acid accumulation that activates PPARγ and potentiates FSH-driven follicle development. AARS2 also promotes PDHA1 inactivation via lactylation, stimulating granulosa cell proliferation and primordial follicle development. GC-specific AARS2 overexpression accelerates follicle depletion, while AARS2 ablation or β-alanine treatment prevents folliculogenesis and POI traits in mice. AARS2 gain-of-function mutation characterization, in vitro lactylation assays on CPT2 and PDHA1, GC-specific AARS2 overexpression and knockout mouse models, metabolic measurements (FFA, PPARγ activation) Cell death discovery Medium 40301335
2026 In a homozygous Aars2 R194C knock-in mouse model (mimicking human R199C pathogenic variant), the mutation increases lysine lactylation of PDHA1 and CPT2, reduces their activity, impairs mitochondrial respiration in granulosa cells, activates mTORC1 signaling, and causes premature follicle activation and POI. SIRT3 (mitochondrial de-lactylase) loss mitigated these abnormalities; pharmacological inhibition of PDHA1/CPT2 in WT mice phenocopied the knock-in. Homozygous knock-in mouse model, lysine lactylation measurements on endogenous substrates, mitochondrial respiration assays, mTORC1 pathway analysis, pharmacological inhibition rescue experiments Reproduction (Cambridge, England) Medium 41832996
2025 AARS2 overexpression in cardiomyocytes suppresses apoptosis and mitochondrial ROS production and shifts cellular metabolism from oxidative phosphorylation toward glycolysis. Ribosome profiling (Ribo-Seq) revealed that Aars2 overexpression increases PKM2 protein translation and promotes the PKM2 dimer-to-tetramer ratio favoring glycolysis. PKM2 activator TEPP-46 reversed cardiomyocyte apoptosis and cardiac fibrosis caused by AARS2 deficiency, defining an AARS2–PKM2 signaling axis. Cardiomyocyte-specific Aars2 deletion and overexpression mouse models, Ribo-Seq (translational profiling), PKM2 dimer/tetramer ratio assays, pharmacological rescue with TEPP-46, cardiac function measurements eLife Medium 40371904
2023 PCBP1 interacts with the Aars2 transcript to mediate its alternative splicing in cardiomyocytes. Cardiomyocyte-specific deletion of Pcbp1 causes aberrant alternative splicing and premature termination of Aars2, reducing oxidative phosphorylation and triggering mitonuclear communication and the unfolded protein response. Aars2 mutant mice with exon-16 skipping recapitulate heart developmental defects, and loss of Pcbp1 or Aars2 reduces the mitochondrial-encoded proteome. Cardiomyocyte-specific Pcbp1 knockout mice, Aars2 exon-16 skipping mutant mice, RNA splicing analysis, oxidative phosphorylation measurements, proteomics of mitochondrial-encoded proteins, UPR pathway analysis Nature cardiovascular research Medium 37293078 42010330
2015 Structural modeling of AARS2 predicts that the cardiomyopathy-causing R592W mutation resides in the editing domain responsible for deacylating mischarged tRNAs, while leukodystrophy mutations affect other domains; all mutations are predicted to reduce aminoacylation activity because all AARS2 domains contribute to tRNA binding. The cardiomyopathy allele is predicted to severely compromise aminoacylation, whereas leukodystrophy allele combinations retain partial activity. Structural homology modeling of AARS2 domains, mapping of disease mutations onto predicted 3D structure Frontiers in genetics Low 25705216
2019 A homozygous AARS2 mutation (p.G113R) in the aminoacylation domain significantly reduced ATP production in patient-derived cells compared to wild-type (3.58 vs 6.96 fmol/min/cell), consistent with impaired mitochondrial translation due to defective aminoacylation of tRNA-Ala. Seahorse XFe96 metabolic analyzer measuring oxygen consumption, ATP production, and extracellular acidification rate in patient cells carrying the AARS2 mutation vs. wild-type Fertility and sterility Medium 31280959
2020 Yeast complementation assays demonstrated that the AARS2 p.Phe131del variant dramatically impairs AARS2 gene function, while p.Ile328Met is a hypomorphic allele, establishing that these variants cause loss of AARS2 function sufficient to produce ataxia without leukoencephalopathy. Yeast complementation assay using AARS2 variants (p.Phe131del and p.Ile328Met) Cerebellum (London, England) Medium 31705293
2026 AARS2 catalyzes lactylation of AP-2γ at K444, enhancing TRIM28 binding and promoting K63-linked ubiquitination and nuclear translocation of AP-2γ to facilitate HCC tumor progression. AARS2 knockdown in HCT116 colon cancer cells reduced extracellular lactate accumulation and attenuated global protein lactylation, and upregulated cGAS-STING pathway genes (CCL5, CXCL10, IFNB1). Mass spectrometry identification of lactylation site on AP-2γ (K444), Co-IP of AP-2γ–TRIM28, ubiquitination assays, AARS2 knockdown in cancer cell lines, extracellular lactate measurement, qRT-PCR of immune genes Gut Medium 42114979

Source papers

Stage 0 corpus · 35 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2024 AARS1 and AARS2 sense L-lactate to regulate cGAS as global lysine lactyltransferases. Nature 277 39322678
2016 Analysis of Mutations in AARS2 in a Series of CSF1R-Negative Patients With Adult-Onset Leukoencephalopathy With Axonal Spheroids and Pigmented Glia. JAMA neurology 80 27749956
2017 Redefining the phenotype of ALSP and AARS2 mutation-related leukodystrophy. Neurology. Genetics 65 28243630
2015 Structural modeling of tissue-specific mitochondrial alanyl-tRNA synthetase (AARS2) defects predicts differential effects on aminoacylation. Frontiers in genetics 51 25705216
2016 The first Japanese case of leukodystrophy with ovarian failure arising from novel compound heterozygous AARS2 mutations. Journal of human genetics 31 27251004
2016 Novel AARS2 gene mutation producing leukodystrophy: a case report. Journal of human genetics 27 27734837
2019 Expansion of the clinical spectrum associated with AARS2-related disorders. American journal of medical genetics. Part A 26 31099476
2019 AARS2 leukoencephalopathy: A new variant of mitochondrial encephalomyopathy. Molecular genetics & genomic medicine 24 30706699
2018 AARS2-related ovarioleukodystrophy: Clinical and neuroimaging features of three new cases. Acta neurologica Scandinavica 21 29749055
2020 Alanyl-tRNA Synthetase 2 (AARS2)-Related Ataxia Without Leukoencephalopathy. Cerebellum (London, England) 18 31705293
2017 Retinopathy and optic atrophy: Expanding the phenotypic spectrum of pathogenic variants in the AARS2 gene. Ophthalmic genetics 18 28820624
2019 Novel alanyl-tRNA synthetase 2 (AARS2) homozygous mutation in a consanguineous Chinese family with premature ovarian insufficiency. Fertility and sterility 16 31280959
2018 AARS2 Compound Heterozygous Variants in a Case of Adult-Onset Leukoencephalopathy With Axonal Spheroids and Pigmented Glia. Journal of neuropathology and experimental neurology 16 30272204
2025 AARS2-catalyzed lactylation induces follicle development and premature ovarian insufficiency. Cell death discovery 13 40301335
2018 An adolescence-onset male leukoencephalopathy with remarkable cerebellar atrophy and novel compound heterozygous AARS2 gene mutations: a case report. Journal of human genetics 13 29666464
2019 Siblings with lethal primary pulmonary hypoplasia and compound heterozygous variants in the AARS2 gene: further delineation of the phenotypic spectrum. Cold Spring Harbor molecular case studies 12 30819764
2021 The emerging neurological spectrum of AARS2-associated disorders. Parkinsonism & related disorders 10 34784527
2021 Case report: 'AARS2 leukodystrophy'. Molecular genetics and metabolism reports 9 34285876
2025 AARS1 and AARS2: From Protein Synthesis to Lactylation-Driven Oncogenesis. Biomolecules 6 41008630
2022 AARS2-Related Leukodystrophy: a Case Report and Literature Review. Cerebellum (London, England) 6 35084689
2025 AARS2 ameliorates myocardial ischemia via fine-tuning PKM2-mediated metabolism. eLife 5 40371904
2023 Report of A Family with Adult-Onset Leukoencephalopathy with Axonal Spheroids and Pigmented Glia (ALSP) Without Mutations in CSF1R, AARS1 or AARS2. Movement disorders clinical practice 5 36825047
2023 PCBP1 regulates alternative splicing of AARS2 in congenital cardiomyopathy. bioRxiv : the preprint server for biology 3 37293078
2019 A novel compound heterozygous mutation in AARS2 gene (c.965 G > A, p.R322H; c.334 G > C, p.G112R) identified in a Chinese patient with leukodystrophy involved in brain and spinal cord. Journal of human genetics 3 31388113
2026 PCBP1 regulates alternative splicing of AARS2 in congenital cardiomyopathy. Nature cardiovascular research 1 42010330
2024 Pearls & Oy-sters: AARS2 Leukodystrophy-Tremor and Tribulations. Neurology 1 38507676
2023 Uterus infantilis: a novel phenotype associated with AARS2 new genetic variants. A case report. Frontiers in neurology 1 37456626
2022 Novel mitochondrial alanyl-tRNA synthetase 2 (AARS2) heterozygous mutations in a Chinese patient with adult-onset leukoencephalopathy. BMC neurology 1 35676634
2026 AARS2 R199C mutation induces lactylation-driven premature ovarian insufficiency phenotypes partially reversible by SIRT3. Reproduction (Cambridge, England) 0 41832996
2026 Integrative pan-cancer analysis reveals AARS2 as a lactylation-associated biomarker and therapeutic target in colon adenocarcinoma. Frontiers in immunology 0 41836446
2026 Landscape screening identifies the lactate-modifying enzyme AARS2 as a master regulator and therapeutic target in hepatocellular carcinoma. Gut 0 42114979
2025 Clinical Diagnosis and Differential Diagnosis Between CSF1R- and AARS2-Related Leukoencephalopathy. Journal of molecular neuroscience : MN 0 39853526
2025 Expanding the Phenotype: A Case Report of a Novel Alanyl-tRNA Synthetase 2 (AARS2) Homozygous Mutation in a 17-Month-Old Child. Cureus 0 40688999
2024 A novel disease-causing variant associated with a milder phenotype of AARS2-related leukodystrophy - A case report. Molecular genetics and metabolism reports 0 39539319
2022 Gait Apraxia with Exaggerated Upper Limb Movements as Presentation of AARS2 Related Leukoencephalopathy. Tremor and other hyperkinetic movements (New York, N.Y.) 0 35975211

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