{"gene":"AIMP2","run_date":"2026-06-09T22:02:42","timeline":{"discoveries":[{"year":2005,"finding":"AIMP2/p38 is a substrate of the E3 ubiquitin ligase parkin; parkin directly interacts with AIMP2, ubiquitinates it, and targets it for proteasomal degradation. Loss of parkin leads to accumulation of AIMP2 in the ventral midbrain/hindbrain, and overexpression of AIMP2 induces catecholaminergic cell death that is blocked by wild-type parkin but not by the familial R42P parkin mutant.","method":"Co-immunoprecipitation, ubiquitination assay, parkin knockout mouse analysis, adenovirus-mediated overexpression in substantia nigra, cell death rescue assay","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, in vivo knockout model, multiple orthogonal methods, replicated across cell and animal systems","pmids":["16135753"],"is_preprint":false},{"year":2008,"finding":"Upon DNA damage (genotoxic stress), AIMP2 is phosphorylated, dissociates from the multi-tRNA synthetase complex (MSC), and translocates to the nucleus where it directly interacts with p53, thereby preventing MDM2-mediated ubiquitination and degradation of p53, and promoting apoptosis. Mutations in AIMP2 that disrupt its interaction with p53 abolish this pro-apoptotic activity.","method":"Co-immunoprecipitation, cell fractionation/nuclear translocation assay, AIMP2-deficient cell complementation, MDM2 ubiquitination assay, site-directed mutagenesis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (Co-IP, fractionation, mutagenesis, KO rescue), single lab but rigorous mechanistic dissection","pmids":["18695251"],"is_preprint":false},{"year":2009,"finding":"AIMP2 promotes TNFα-dependent apoptosis by binding to TRAF2 and augmenting the association of the E3 ubiquitin ligase c-IAP1 with TRAF2, leading to ubiquitin-dependent degradation of TRAF2 and consequent suppression of NF-κB signaling. AIMP2-deficient cells show compromised TNFα-induced cell death.","method":"Co-immunoprecipitation (AIMP2–TRAF2 and TRAF2–c-IAP1), AIMP2 knockdown/knockout cell analysis, NF-κB/IκB reporter assay, ubiquitination assay","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, functional KD/KO with defined pathway readout, multiple orthogonal methods in one study","pmids":["19584093"],"is_preprint":false},{"year":2009,"finding":"AIMP2 exhibits haploinsufficiency as a tumor suppressor: heterozygous AIMP2 cells show dose-dependent reduction in apoptotic responses to DNA damage and TNFα, and reduced sensitivity to TGF-β-mediated growth arrest, with heterozygous mice showing increased susceptibility to carcinogen-induced tumorigenesis.","method":"Wild-type vs. hetero- vs. homozygous AIMP2 cell comparison, in vivo carcinogenesis models","journal":"Carcinogenesis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic dosage experiment with defined cellular phenotypes and in vivo validation, single lab","pmids":["19622630"],"is_preprint":false},{"year":2011,"finding":"In response to oxidative stress, AIMP2/JTV1 dissociates from the multi-tRNA synthetase complex, translocates to the nucleus, and associates with the transcription factor FBP (FUBP1) to co-activate transcription of USP29, a deubiquitinating enzyme that cleaves poly-ubiquitin chains from p53, stabilizing p53 and inducing apoptosis.","method":"Co-immunoprecipitation, subcellular fractionation/nuclear translocation, luciferase reporter assay for USP29 transcription, deubiquitination assay for USP29 activity on p53","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (Co-IP, fractionation, transcription assay, deubiquitination assay) establishing a complete pathway","pmids":["21285945"],"is_preprint":false},{"year":2011,"finding":"An alternatively spliced variant of AIMP2 lacking exon 2 (AIMP2-DX2) is highly expressed in human lung cancer cells. AIMP2-DX2 competes with full-length AIMP2 for binding to p53, thereby compromising AIMP2's pro-apoptotic activity and promoting anchorage-independent growth and resistance to cell death.","method":"Competitive binding/Co-immunoprecipitation with p53, colony formation assay, carcinogen-induced tumorigenesis in transgenic mice, cell death assay","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — competitive binding experiment, multiple orthogonal functional assays, in vivo transgenic model, single lab with rigorous controls","pmids":["21483803"],"is_preprint":false},{"year":2013,"finding":"Transgenic overexpression of AIMP2 causes selective, age-dependent, progressive loss of dopaminergic neurons via direct physical association of AIMP2 with PARP1 in the nucleus, leading to PARP1 overactivation (parthanatos) independent of DNA damage. Genetic deletion or pharmacological inhibition of PARP1 rescues behavioral deficits and dopaminergic neuron loss in AIMP2 transgenic mice.","method":"AIMP2 transgenic mouse model, co-immunoprecipitation (AIMP2–PARP1 nuclear association), PARP1 knockout/inhibitor rescue experiments, behavioral testing, dopaminergic neuron counting","journal":"Nature neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo transgenic model, Co-IP establishing direct nuclear interaction, genetic and pharmacological rescue, multiple orthogonal methods","pmids":["23974709"],"is_preprint":false},{"year":2014,"finding":"During influenza A virus infection, AIMP2 interacts with viral NS2 protein (identified by yeast two-hybrid, GST pulldown, and Co-IP). AIMP2 enhances stability of the viral matrix protein M1 by facilitating a switch from ubiquitination to SUMOylation at K242 of M1, thereby promoting viral ribonucleoprotein complex nuclear export and increasing viral replication.","method":"Yeast two-hybrid, GST pulldown, co-immunoprecipitation, site-directed mutagenesis (K242), ubiquitination/SUMOylation assay, viral replication assay","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — multiple binding assays, mutagenesis identifying specific residue, functional viral replication readout, single lab","pmids":["25320310"],"is_preprint":false},{"year":2016,"finding":"TGFβ signaling causes phosphorylation of AIMP2 at S156, promoting its dissociation from the MSC and nuclear translocation. In the nucleus, phospho-AIMP2 binds Smurf2 and enhances Smurf2-mediated ubiquitination of FBP (FUBP1), a transcriptional activator of c-Myc, thereby suppressing c-Myc expression. AIMP2 also inhibits nuclear export of Smurf2 to sustain TGFβ signaling.","method":"Phosphorylation assay, nuclear fractionation, co-immunoprecipitation (AIMP2–Smurf2, Smurf2–FBP), ubiquitination assay for FBP, site-directed mutagenesis (S156), in vivo tumorigenesis assay","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Strong — phosphorylation mapping, Co-IP, mutagenesis, ubiquitination assay, in vivo validation, multiple orthogonal methods","pmids":["27197155"],"is_preprint":false},{"year":2016,"finding":"AIMP2 disrupts the interaction between AXIN and Dishevelled-1 (DVL1) by competing with AXIN, thereby inhibiting Wnt/β-catenin signaling. Hemizygous deletion of Aimp2 results in enhanced Wnt/β-catenin signaling, increased crypt epithelial cell proliferation, expansion of intestinal stem cell compartments, and increased adenoma formation in ApcMin/+ mice.","method":"Co-immunoprecipitation (AXIN–DVL1 competition assay), Aimp2 hemizygous mouse model, ApcMin/+ crossed with Aimp2+/- mice, intestinal organoid assay","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Strong — competitive Co-IP establishing mechanism, genetic mouse model with defined pathway readout, organoid assay, multiple orthogonal methods","pmids":["27262173"],"is_preprint":false},{"year":2017,"finding":"VPS35 co-immunoprecipitates with AIMP2 and with lysosome-associated membrane protein-2a (Lamp2a), facilitating lysosomal degradation of AIMP2. The PD-associated VPS35 D620N mutant disrupts this association. VPS35 overexpression prevents AIMP2-potentiated PARP1 activation and cell death; VPS35 knockdown causes AIMP2-dependent PARP1 activation and cell death.","method":"Co-immunoprecipitation (VPS35–AIMP2, VPS35–Lamp2a), VPS35 overexpression/knockdown, PARP1 activation assay, cell death assay, VPS35 D620N mutant analysis","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, functional KD/OE with defined pathway readout, single lab","pmids":["28383562"],"is_preprint":false},{"year":2019,"finding":"Crystal structure (1.88 Å) of human LysRS in complex with AIMP2 reveals that two AIMP2 N-terminal peptides form an antiparallel scaffold holding two LysRS dimers through four binding motifs. This assembly allows all four LysRS catalytic subunits to remain accessible for tRNA recognition. Two human disease-associated mutations conflict with this assembly and cause LysRS release from the MSC.","method":"X-ray crystallography (1.88 Å), gel-filtration chromatography, co-immunoprecipitation, molecular modeling, disease mutation analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure with functional Co-IP validation and disease mutation mapping, single lab but multiple orthogonal methods","pmids":["30733335"],"is_preprint":false},{"year":2019,"finding":"Crystal structure of the DRS–AIMP2GST–EPRSGST ternary subcomplex shows that AIMP2GST and EPRSGST interact via conventional GST heterodimerization, while DRS strongly interacts with AIMP2GST via hydrogen bonds between the α7-β9 loop of DRS and the β2-α2 loop of AIMP2GST, with AIMP2 Ser156 being essential for this assembly.","method":"X-ray crystallography, structural analysis, site-directed mutagenesis (S156)","journal":"IUCrJ","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure with mutagenesis validation of key residue, single lab","pmids":["31576228"],"is_preprint":false},{"year":2019,"finding":"HSP70 is a critical determinant of AIMP2-DX2 cellular levels. HSP70 recognizes the N-terminal flexible region and GST domain of AIMP2-DX2 via its substrate-binding domain, blocking Siah1-dependent ubiquitination of AIMP2-DX2 and thereby stabilizing it. HSP70 augments AIMP2-DX2-induced cell transformation and cancer progression in vivo.","method":"Interactome analysis, X-ray crystallography, NMR, Co-immunoprecipitation, Siah1 ubiquitination assay, in vivo cancer progression assay, small molecule inhibitor of AIMP2-DX2–HSP70 interaction","journal":"Nature chemical biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — X-ray crystallography + NMR structural characterization, Co-IP, ubiquitination assay, in vivo validation, multiple orthogonal methods","pmids":["31792442"],"is_preprint":false},{"year":2020,"finding":"AIMP2 exhibits self-aggregating (amyloid-like oligomerization) properties and directly binds α-synuclein monomer, seeding α-synuclein fibril formation. Co-expression of AIMP2 and α-synuclein in vitro and in vivo accelerates α-synuclein aggregation and increases toxicity. AIMP2 knockdown ameliorates α-synuclein aggregation and dopaminergic cell death in response to preformed fibril seeding or 6-OHDA.","method":"In vitro aggregation assay, direct binding assay (AIMP2–α-synuclein), co-expression cell model, in vivo mouse model, AIMP2 knockdown with cell death readout, fractionation into soluble/insoluble fractions","journal":"Science translational medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vitro aggregation reconstitution, direct binding, in vivo mouse model, KD rescue, multiple orthogonal methods","pmids":["33177178"],"is_preprint":false},{"year":2020,"finding":"NMR spectroscopy reveals that the transactivation domain 1 (TAD1) of p53 (residues E17–E28) binds to the GST domain of AIMP2 (shared with AIMP2-DX2). The p53 TAD1 adopts a turn structure with hydrophobic interactions by F19, L22, W23, and L26 upon binding, distinct from its MDM2-binding conformation.","method":"NMR chemical shift perturbation (CSP), transferred-NOE (trNOE) structure determination, computational docking","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — NMR structural analysis with residue-level mapping, but single lab and docking component is computational","pmids":["32448505"],"is_preprint":false},{"year":2021,"finding":"O-GlcNAcylation of AIMP2 (mediated by O-GlcNAc transferase, OGT) increases AIMP2 protein stability and promotes its aggregation, leading to PARP1 activation in aging-related hepatic steatosis. O-GlcNAcase knockout increases AIMP2 and PARP1 levels in mouse liver.","method":"Comparative proteomics (LC-MS), O-GlcNAcase knockout mouse model, OGT overexpression and O-GlcNAcase inhibition in vitro, PARP1 activation assay","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — proteomics plus genetic and pharmacological manipulation, multiple orthogonal methods, single lab","pmids":["34817071"],"is_preprint":false},{"year":2021,"finding":"HLD17-associated nonsense mutation Y35X of AIMP2 causes mislocalization of AIMP2 protein to Golgi bodies as aggregates (wild-type AIMP2 distributes throughout the cell body), activates Golgi stress signaling via caspase-2, and inhibits oligodendroglial cell morphological differentiation. Knockdown of CASP2 reverses the differentiation defect caused by Y35X mutant AIMP2.","method":"Immunofluorescence localization, caspase-2 activity assay, differentiation phenotype assay, CASP2 knockdown rescue","journal":"Neurochemical research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization experiment with functional consequence, genetic rescue by CASP2 KD, single lab","pmids":["34523057"],"is_preprint":false},{"year":2022,"finding":"AIMP2-DX2 specifically binds to the hypervariable region and G-domain of KRAS in the cytosol prior to farnesylation, competitively blocking Smurf2 access to KRAS and thereby preventing ubiquitin-mediated KRAS degradation. This stabilizes KRAS and augments KRAS-driven tumorigenesis.","method":"Co-immunoprecipitation (AIMP2-DX2–KRAS, competition with Smurf2), domain mapping, in vitro binding assay, small molecule inhibitor of AIMP2-DX2–KRAS interaction, in vivo xenograft model","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP with domain mapping, competitive binding, functional in vivo xenograft validation, multiple orthogonal methods","pmids":["35546148"],"is_preprint":false},{"year":2022,"finding":"Binding of mutant SOD1 (ALS-associated) to LysRS (KARS1) releases AIMP2 from its KARS1-containing complex; free AIMP2 then induces TRAF2 degradation and TNFα-induced neuronal cell death. AIMP2-DX2 competes with full-length AIMP2 for TRAF2 binding, suppressing TRAF2 degradation and TNFα-induced cell death.","method":"Co-immunoprecipitation (mutant SOD1–KARS1–AIMP2 complex), TRAF2 degradation assay, ALS mouse model (motor neuron function), DX2 overexpression rescue, AAV-DX2 intrathecal injection","journal":"Molecular neurobiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP establishing complex, functional rescue in mouse model, single lab with multiple orthogonal methods","pmids":["36242734"],"is_preprint":false},{"year":2023,"finding":"HK2 forms a complex with AIMP2 and promotes its autophagic lysosomal-dependent degradation, thereby attenuating ionizing radiation-mediated apoptosis and conferring radio-resistance in hepatocellular carcinoma cells.","method":"Co-immunoprecipitation (HK2–AIMP2), autophagy inhibition assay, HK2 knockdown with apoptosis readout, xenograft model","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, functional KD with defined apoptosis readout, in vivo validation, single lab","pmids":["37524692"],"is_preprint":false},{"year":2024,"finding":"AIMP2-DX2 binds to PARP1 with higher affinity than full-length AIMP2, inhibiting PARP1-induced neuronal cell death (parthanatos) rather than activating it. DX2 translocates to the nucleus more rapidly than full-length AIMP2 under ROS stress. In vivo, AAV-mediated DX2 expression ameliorates behavioral deficits in 6-OHDA Parkinson's disease mouse models.","method":"Co-immunoprecipitation (AIMP2 vs. DX2 binding to PARP1), nuclear translocation imaging, PARP1 activation assay, in vivo AAV injection and behavioral assessment","journal":"Acta neuropathologica communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP binding comparison, live imaging, functional in vivo rescue, single lab","pmids":["38172953"],"is_preprint":false},{"year":2024,"finding":"AIMP2 restricts EV71 replication by binding to the viral 3D polymerase (RdRp) and recruiting the E3 ligase SMURF2, which mediates polyubiquitination and degradation of the 3D polymerase.","method":"Co-immunoprecipitation (AIMP2–3D polymerase, AIMP2–SMURF2), ubiquitination assay, viral replication assay, knockdown/overexpression","journal":"Virologica Sinica","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP establishing ternary complex, ubiquitination assay, functional viral replication readout, single lab","pmids":["38945214"],"is_preprint":false},{"year":2009,"finding":"JTV1/AIMP2 physically interacts with NLS-RARα (nuclear localization signal-containing retinoic acid receptor alpha) as shown by yeast two-hybrid and co-immunoprecipitation in HEK293 cells.","method":"Yeast two-hybrid, co-immunoprecipitation","journal":"Sichuan da xue xue bao. Yi xue ban","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP and yeast two-hybrid, no functional follow-up, single lab","pmids":["19626986"],"is_preprint":false}],"current_model":"AIMP2 is a multifunctional scaffold protein of the multi-tRNA synthetase complex (MSC) that, upon cellular stress signals (DNA damage, oxidative stress, TGFβ, TNFα), undergoes phosphorylation, dissociates from the MSC, and translocates to the nucleus to act as a tumor suppressor and pro-apoptotic factor: it stabilizes p53 by blocking MDM2-mediated ubiquitination; co-activates FBP-dependent transcription of the deubiquitinase USP29 to further stabilize p53; promotes Smurf2-mediated ubiquitination of FBP/c-Myc; competes with AXIN to suppress Wnt/β-catenin signaling; augments c-IAP1-mediated ubiquitination and degradation of TRAF2 to sensitize cells to TNFα-induced apoptosis; and in dopaminergic neurons directly activates PARP1 (parthanatos) by nuclear association, leading to neurodegeneration that is relevant to Parkinson's disease; additionally, AIMP2 self-aggregates and seeds α-synuclein aggregation, and its cellular level is regulated by parkin-mediated ubiquitination, VPS35-dependent lysosomal clearance, O-GlcNAcylation, and HK2-mediated autophagic degradation, while an oncogenic splice variant lacking exon 2 (AIMP2-DX2) antagonizes these tumor-suppressive functions by competing for binding to p53, TRAF2, and other partners, and is itself stabilized by HSP70 blocking Siah1-mediated ubiquitination."},"narrative":{"mechanistic_narrative":"AIMP2 (JTV1/p38) is a structural scaffold of the multi-tRNA synthetase complex (MSC) that doubles as a stress-activated tumor suppressor and pro-apoptotic effector. As an MSC component, two AIMP2 N-terminal peptides form an antiparallel scaffold that holds two LysRS dimers, keeping all four catalytic subunits accessible for tRNA recognition, while its GST domain mediates conventional GST-type heterodimerization with EPRS and a strong contact with DRS that depends on AIMP2 Ser156 [PMID:30733335, PMID:31576228]. Diverse stress signals — DNA damage, oxidative stress, and TGFβ (via S156 phosphorylation) — trigger AIMP2 dissociation from the MSC and nuclear translocation, where it executes several pro-death programs: it binds p53 to block MDM2-mediated ubiquitination, the p53 transactivation domain 1 docking onto the AIMP2 GST domain [PMID:18695251, PMID:32448505]; it co-activates FBP/FUBP1-dependent transcription of the deubiquitinase USP29 to further stabilize p53 [PMID:21285945]; it enhances Smurf2-mediated ubiquitination of FBP to suppress c-Myc [PMID:27197155]; it competes with AXIN to inhibit Wnt/β-catenin signaling [PMID:27262173]; and it binds TRAF2 to promote its c-IAP1-dependent degradation, sensitizing cells to TNFα-induced apoptosis [PMID:19584093]. Consistent with these activities AIMP2 behaves as a haploinsufficient tumor suppressor [PMID:19622630]. In dopaminergic neurons, accumulated AIMP2 directly associates with PARP1 in the nucleus to drive parthanatos, and also self-aggregates and seeds α-synuclein fibrillization, linking it to Parkinson's-relevant neurodegeneration [PMID:23974709, PMID:33177178]. AIMP2 abundance is tightly controlled by parkin-mediated proteasomal degradation, VPS35/Lamp2a-dependent lysosomal clearance, HK2-driven autophagic degradation, and O-GlcNAcylation that stabilizes and aggregates it [PMID:16135753, PMID:28383562, PMID:34817071, PMID:37524692]. An exon-2-deleted splice variant, AIMP2-DX2, antagonizes these tumor-suppressive functions by competing for p53, TRAF2, and PARP1 and by stabilizing KRAS against Smurf2-mediated degradation; DX2 itself is stabilized by HSP70, which shields it from Siah1-mediated ubiquitination [PMID:21483803, PMID:31792442, PMID:35546148, PMID:38172953]. An AIMP2 nonsense mutation (Y35X) causes hypomyelinating leukodystrophy 17 through Golgi mislocalization and caspase-2-dependent oligodendroglial differentiation failure [PMID:34523057].","teleology":[{"year":2005,"claim":"Established that AIMP2 abundance is degradation-controlled and that its accumulation is neurotoxic, framing AIMP2 as a parkin substrate relevant to dopaminergic survival.","evidence":"Co-IP, ubiquitination assay, parkin-knockout mice, and overexpression-induced catecholaminergic cell death rescued by wild-type but not R42P parkin","pmids":["16135753"],"confidence":"High","gaps":["Did not define how accumulated AIMP2 kills neurons","Mechanism downstream of AIMP2 buildup unresolved at this stage"]},{"year":2008,"claim":"Answered how stress converts AIMP2 from a cytoplasmic scaffold into a nuclear apoptotic effector, defining the p53-stabilization axis.","evidence":"Co-IP, nuclear fractionation, MDM2 ubiquitination assay, and interaction-disrupting mutagenesis in AIMP2-deficient cells after genotoxic stress","pmids":["18695251"],"confidence":"High","gaps":["Phosphorylation site driving dissociation not mapped here","Did not address other stress inputs"]},{"year":2009,"claim":"Showed AIMP2 also enforces apoptosis through a p53-independent route by destabilizing TRAF2 and dampening NF-κB.","evidence":"Reciprocal Co-IP of AIMP2-TRAF2 and TRAF2-c-IAP1, NF-κB reporters, and AIMP2 knockdown/knockout in TNFα-treated cells","pmids":["19584093"],"confidence":"High","gaps":["How AIMP2 promotes c-IAP1-TRAF2 association mechanistically unclear","Stress signal coupling to this pathway not defined"]},{"year":2009,"claim":"Quantified the tumor-suppressive dosage of AIMP2, establishing it as haploinsufficient across multiple death/growth-arrest pathways.","evidence":"WT vs heterozygous vs homozygous AIMP2 cell comparison and carcinogen-induced tumorigenesis in heterozygous mice","pmids":["19622630"],"confidence":"Medium","gaps":["Did not separate contributions of individual downstream pathways","Single lab"]},{"year":2011,"claim":"Connected oxidative stress to p53 stabilization via a transcriptional arm, adding USP29-mediated p53 deubiquitination to AIMP2's repertoire.","evidence":"Co-IP with FBP/FUBP1, fractionation, USP29 luciferase reporter, and USP29 deubiquitination assay on p53","pmids":["21285945"],"confidence":"High","gaps":["How AIMP2 activates FBP transcriptionally not fully defined","Relation to direct p53 binding not integrated"]},{"year":2011,"claim":"Identified the oncogenic exon-2-deleted variant AIMP2-DX2 as a dominant antagonist that competes for p53 binding.","evidence":"Competitive Co-IP with p53, colony formation, cell death assays, and carcinogen-induced tumorigenesis in transgenic mice","pmids":["21483803"],"confidence":"High","gaps":["How DX2 splicing is regulated in cancer not addressed","DX2 effects on non-p53 partners not yet explored here"]},{"year":2013,"claim":"Defined the mechanism of AIMP2-driven dopaminergic neurodegeneration as DNA-damage-independent PARP1 overactivation (parthanatos).","evidence":"AIMP2 transgenic mice, nuclear AIMP2-PARP1 Co-IP, and PARP1 genetic deletion/inhibitor rescue with behavioral and neuron-count readouts","pmids":["23974709"],"confidence":"High","gaps":["How AIMP2 activates PARP1 structurally unresolved","Trigger for AIMP2 nuclear accumulation in neurons not defined"]},{"year":2014,"claim":"Revealed a proviral function in which AIMP2 stabilizes influenza M1 by switching its modification from ubiquitination to SUMOylation.","evidence":"Yeast two-hybrid, GST pulldown, Co-IP with NS2, K242 mutagenesis, modification assays, and viral replication readout","pmids":["25320310"],"confidence":"High","gaps":["How AIMP2 directs the ubiquitin-to-SUMO switch mechanistically unclear","Relevance to MSC dissociation not addressed"]},{"year":2016,"claim":"Mapped the TGFβ-responsive phospho-switch (S156) and showed AIMP2 suppresses c-Myc through Smurf2-mediated FBP ubiquitination.","evidence":"Phosphorylation mapping, fractionation, Co-IP of AIMP2-Smurf2 and Smurf2-FBP, FBP ubiquitination, S156 mutagenesis, and in vivo tumorigenesis","pmids":["27197155"],"confidence":"High","gaps":["Kinase responsible for S156 phosphorylation not identified","Interplay with FBP's role in USP29 transcription not reconciled"]},{"year":2016,"claim":"Added a Wnt-suppressive role, showing AIMP2 competes with AXIN for DVL1 to restrain intestinal stem-cell expansion and adenoma formation.","evidence":"Competitive Co-IP of AXIN-DVL1, Aimp2 hemizygous mice, ApcMin/+ crosses, and intestinal organoids","pmids":["27262173"],"confidence":"High","gaps":["How nuclear vs cytoplasmic AIMP2 pools are partitioned among pathways unclear","Stress dependence of Wnt suppression not defined"]},{"year":2019,"claim":"Provided structural definition of AIMP2's scaffolding role within the MSC and the basis for disease-causing LysRS release.","evidence":"1.88 Å crystal structure of LysRS-AIMP2 plus gel filtration, Co-IP, and disease-mutation mapping; and crystal structure of the DRS-AIMP2GST-EPRSGST subcomplex with S156 mutagenesis","pmids":["30733335","31576228"],"confidence":"High","gaps":["Structural transition accompanying stress-induced MSC dissociation not captured","Conformation of nuclear AIMP2 unknown"]},{"year":2019,"claim":"Explained how the oncogenic DX2 variant accumulates, identifying HSP70 as a chaperone that blocks Siah1-mediated DX2 degradation.","evidence":"Interactome analysis, X-ray crystallography, NMR, Co-IP, Siah1 ubiquitination assay, in vivo progression, and a DX2-HSP70 small-molecule inhibitor","pmids":["31792442"],"confidence":"High","gaps":["Whether HSP70 similarly affects full-length AIMP2 not resolved","In vivo therapeutic window of the inhibitor not defined"]},{"year":2020,"claim":"Demonstrated AIMP2 self-aggregation and direct α-synuclein seeding, linking AIMP2 to proteinopathy in Parkinson's-relevant models.","evidence":"In vitro aggregation and binding assays, co-expression cell and mouse models, and AIMP2 knockdown rescue of fibril-/6-OHDA-induced death","pmids":["33177178"],"confidence":"High","gaps":["Structural determinants of AIMP2 amyloid-like oligomerization not defined","Relation between aggregation and PARP1 activation not integrated"]},{"year":2020,"claim":"Resolved the structural basis for p53 recognition, mapping p53 TAD1 binding to the AIMP2 GST domain shared with DX2.","evidence":"NMR chemical-shift perturbation, transferred-NOE structure determination, and computational docking","pmids":["32448505"],"confidence":"Medium","gaps":["Docking component is computational","Affinity comparison with MDM2-bound p53 not quantified in cells"]},{"year":2021,"claim":"Connected post-translational modification to AIMP2 stability and aggregation, showing O-GlcNAcylation drives PARP1 activation in hepatic steatosis.","evidence":"LC-MS proteomics, O-GlcNAcase knockout mice, OGT overexpression/OGA inhibition, and PARP1 activation assay","pmids":["34817071"],"confidence":"Medium","gaps":["O-GlcNAc site(s) on AIMP2 not mapped","Tissue specificity beyond liver not tested"]},{"year":2021,"claim":"Linked AIMP2 to a Mendelian disease, showing the Y35X nonsense mutation causes HLD17 via Golgi mislocalization and caspase-2-dependent myelination failure.","evidence":"Immunofluorescence localization, caspase-2 activity assay, oligodendroglial differentiation phenotype, and CASP2 knockdown rescue","pmids":["34523057"],"confidence":"Medium","gaps":["How a truncated protein reaches the Golgi mechanistically unclear","Relationship to MSC scaffolding loss not addressed"]},{"year":2022,"claim":"Expanded DX2 oncogenicity to RAS signaling, showing DX2 stabilizes pre-farnesylation KRAS by blocking Smurf2 access.","evidence":"Co-IP and domain mapping of DX2-KRAS, Smurf2 competition, in vitro binding, a DX2-KRAS inhibitor, and xenografts","pmids":["35546148"],"confidence":"High","gaps":["Whether full-length AIMP2 also engages KRAS not established","Effect on downstream RAS effector pathways not detailed"]},{"year":2022,"claim":"Placed AIMP2 in an ALS pathway, showing mutant SOD1 binding to KARS1 releases AIMP2 to trigger TRAF2 degradation and neuronal death, antagonized by DX2.","evidence":"Co-IP of mutant SOD1-KARS1-AIMP2, TRAF2 degradation assay, ALS mouse model, and AAV-DX2 intrathecal rescue","pmids":["36242734"],"confidence":"Medium","gaps":["Direct contribution of free AIMP2 vs other factors to motor neuron death not isolated","Single lab"]},{"year":2023,"claim":"Added a cancer-relevant degradation route, showing HK2-driven autophagic clearance of AIMP2 confers radio-resistance in hepatocellular carcinoma.","evidence":"HK2-AIMP2 Co-IP, autophagy inhibition, HK2 knockdown with apoptosis readout, and xenografts","pmids":["37524692"],"confidence":"Medium","gaps":["How HK2 routes AIMP2 to autophagy mechanistically unclear","Interplay with other AIMP2 degradation systems not compared"]},{"year":2024,"claim":"Revised the DX2-PARP1 relationship, showing DX2 outcompetes AIMP2 for PARP1 to inhibit parthanatos, with therapeutic benefit in a Parkinson's model.","evidence":"Comparative Co-IP of AIMP2 vs DX2 with PARP1, nuclear translocation imaging, PARP1 activation assay, and AAV-DX2 rescue in 6-OHDA mice","pmids":["38172953"],"confidence":"Medium","gaps":["How DX2's higher PARP1 affinity arises structurally not defined","Long-term safety of DX2 delivery not addressed"]},{"year":2024,"claim":"Generalized AIMP2's Smurf2-recruiting activity to antiviral defense, showing it degrades the EV71 3D polymerase.","evidence":"Co-IP of AIMP2-3D polymerase and AIMP2-SMURF2, ubiquitination assay, and viral replication with knockdown/overexpression","pmids":["38945214"],"confidence":"Medium","gaps":["How AIMP2 distinguishes viral substrates for Smurf2 recruitment unclear","Single lab"]},{"year":null,"claim":"It remains unresolved how a single scaffold partitions among its many mutually exclusive nuclear functions (p53, FBP/USP29, Smurf2/FBP, AXIN, TRAF2, PARP1) and what structural state AIMP2 adopts upon stress-induced MSC release and aggregation.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structure of stress-released or nuclear AIMP2","Determinants selecting among competing partners undefined","Kinases/signals targeting each modification not fully mapped"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[1,2,4,8,9,11]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[11,12]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[1,2,6,18]},{"term_id":"GO:0140110","term_label":"transcription regulator 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Mediates ubiquitination and degradation of FUBP1, a transcriptional activator of MYC, leading to MYC down-regulation which is required for aveolar type II cell differentiation. Blocks MDM2-mediated ubiquitination and degradation of p53/TP53. Functions as a proapoptotic factor","subcellular_location":"Cytoplasm, cytosol; Nucleus","url":"https://www.uniprot.org/uniprotkb/Q13155/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/AIMP2","classification":"Not Classified","n_dependent_lines":31,"n_total_lines":1208,"dependency_fraction":0.02566225165562914},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/AIMP2","total_profiled":1310},"omim":[{"mim_id":"619196","title":"DEAFNESS, CONGENITAL, AND ADULT-ONSET PROGRESSIVE LEUKOENCEPHALOPATHY; DEAPLE","url":"https://www.omim.org/entry/619196"},{"mim_id":"618006","title":"LEUKODYSTROPHY, HYPOMYELINATING, 17; HLD17","url":"https://www.omim.org/entry/618006"},{"mim_id":"613914","title":"ZINC FINGER PROTEIN 746; ZNF746","url":"https://www.omim.org/entry/613914"},{"mim_id":"608309","title":"PTEN-INDUCED KINASE 1; PINK1","url":"https://www.omim.org/entry/608309"},{"mim_id":"602544","title":"PARKIN RBR E3 UBIQUITIN PROTEIN LIGASE; PRKN","url":"https://www.omim.org/entry/602544"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Cytosol","reliability":"Approved"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"skeletal muscle","ntpm":151.1}],"url":"https://www.proteinatlas.org/search/AIMP2"},"hgnc":{"alias_symbol":["p38","PRO0992","JTV-1","JTV1"],"prev_symbol":[]},"alphafold":{"accession":"Q13155","domains":[{"cath_id":"1.20.1050.130","chopping":"107-219","consensus_level":"high","plddt":87.6953,"start":107,"end":219},{"cath_id":"1.20.1050.130","chopping":"226-317","consensus_level":"high","plddt":94.2787,"start":226,"end":317}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q13155","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q13155-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q13155-F1-predicted_aligned_error_v6.png","plddt_mean":81.12},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=AIMP2","jax_strain_url":"https://www.jax.org/strain/search?query=AIMP2"},"sequence":{"accession":"Q13155","fasta_url":"https://rest.uniprot.org/uniprotkb/Q13155.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q13155/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q13155"}},"corpus_meta":[{"pmid":"16135753","id":"PMC_16135753","title":"Accumulation 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Loss of parkin leads to accumulation of AIMP2 in the ventral midbrain/hindbrain, and overexpression of AIMP2 induces catecholaminergic cell death that is blocked by wild-type parkin but not by the familial R42P parkin mutant.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, parkin knockout mouse analysis, adenovirus-mediated overexpression in substantia nigra, cell death rescue assay\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, in vivo knockout model, multiple orthogonal methods, replicated across cell and animal systems\",\n      \"pmids\": [\"16135753\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Upon DNA damage (genotoxic stress), AIMP2 is phosphorylated, dissociates from the multi-tRNA synthetase complex (MSC), and translocates to the nucleus where it directly interacts with p53, thereby preventing MDM2-mediated ubiquitination and degradation of p53, and promoting apoptosis. Mutations in AIMP2 that disrupt its interaction with p53 abolish this pro-apoptotic activity.\",\n      \"method\": \"Co-immunoprecipitation, cell fractionation/nuclear translocation assay, AIMP2-deficient cell complementation, MDM2 ubiquitination assay, site-directed mutagenesis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (Co-IP, fractionation, mutagenesis, KO rescue), single lab but rigorous mechanistic dissection\",\n      \"pmids\": [\"18695251\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"AIMP2 promotes TNFα-dependent apoptosis by binding to TRAF2 and augmenting the association of the E3 ubiquitin ligase c-IAP1 with TRAF2, leading to ubiquitin-dependent degradation of TRAF2 and consequent suppression of NF-κB signaling. AIMP2-deficient cells show compromised TNFα-induced cell death.\",\n      \"method\": \"Co-immunoprecipitation (AIMP2–TRAF2 and TRAF2–c-IAP1), AIMP2 knockdown/knockout cell analysis, NF-κB/IκB reporter assay, ubiquitination assay\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, functional KD/KO with defined pathway readout, multiple orthogonal methods in one study\",\n      \"pmids\": [\"19584093\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"AIMP2 exhibits haploinsufficiency as a tumor suppressor: heterozygous AIMP2 cells show dose-dependent reduction in apoptotic responses to DNA damage and TNFα, and reduced sensitivity to TGF-β-mediated growth arrest, with heterozygous mice showing increased susceptibility to carcinogen-induced tumorigenesis.\",\n      \"method\": \"Wild-type vs. hetero- vs. homozygous AIMP2 cell comparison, in vivo carcinogenesis models\",\n      \"journal\": \"Carcinogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic dosage experiment with defined cellular phenotypes and in vivo validation, single lab\",\n      \"pmids\": [\"19622630\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"In response to oxidative stress, AIMP2/JTV1 dissociates from the multi-tRNA synthetase complex, translocates to the nucleus, and associates with the transcription factor FBP (FUBP1) to co-activate transcription of USP29, a deubiquitinating enzyme that cleaves poly-ubiquitin chains from p53, stabilizing p53 and inducing apoptosis.\",\n      \"method\": \"Co-immunoprecipitation, subcellular fractionation/nuclear translocation, luciferase reporter assay for USP29 transcription, deubiquitination assay for USP29 activity on p53\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (Co-IP, fractionation, transcription assay, deubiquitination assay) establishing a complete pathway\",\n      \"pmids\": [\"21285945\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"An alternatively spliced variant of AIMP2 lacking exon 2 (AIMP2-DX2) is highly expressed in human lung cancer cells. AIMP2-DX2 competes with full-length AIMP2 for binding to p53, thereby compromising AIMP2's pro-apoptotic activity and promoting anchorage-independent growth and resistance to cell death.\",\n      \"method\": \"Competitive binding/Co-immunoprecipitation with p53, colony formation assay, carcinogen-induced tumorigenesis in transgenic mice, cell death assay\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — competitive binding experiment, multiple orthogonal functional assays, in vivo transgenic model, single lab with rigorous controls\",\n      \"pmids\": [\"21483803\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Transgenic overexpression of AIMP2 causes selective, age-dependent, progressive loss of dopaminergic neurons via direct physical association of AIMP2 with PARP1 in the nucleus, leading to PARP1 overactivation (parthanatos) independent of DNA damage. Genetic deletion or pharmacological inhibition of PARP1 rescues behavioral deficits and dopaminergic neuron loss in AIMP2 transgenic mice.\",\n      \"method\": \"AIMP2 transgenic mouse model, co-immunoprecipitation (AIMP2–PARP1 nuclear association), PARP1 knockout/inhibitor rescue experiments, behavioral testing, dopaminergic neuron counting\",\n      \"journal\": \"Nature neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo transgenic model, Co-IP establishing direct nuclear interaction, genetic and pharmacological rescue, multiple orthogonal methods\",\n      \"pmids\": [\"23974709\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"During influenza A virus infection, AIMP2 interacts with viral NS2 protein (identified by yeast two-hybrid, GST pulldown, and Co-IP). AIMP2 enhances stability of the viral matrix protein M1 by facilitating a switch from ubiquitination to SUMOylation at K242 of M1, thereby promoting viral ribonucleoprotein complex nuclear export and increasing viral replication.\",\n      \"method\": \"Yeast two-hybrid, GST pulldown, co-immunoprecipitation, site-directed mutagenesis (K242), ubiquitination/SUMOylation assay, viral replication assay\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — multiple binding assays, mutagenesis identifying specific residue, functional viral replication readout, single lab\",\n      \"pmids\": [\"25320310\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"TGFβ signaling causes phosphorylation of AIMP2 at S156, promoting its dissociation from the MSC and nuclear translocation. In the nucleus, phospho-AIMP2 binds Smurf2 and enhances Smurf2-mediated ubiquitination of FBP (FUBP1), a transcriptional activator of c-Myc, thereby suppressing c-Myc expression. AIMP2 also inhibits nuclear export of Smurf2 to sustain TGFβ signaling.\",\n      \"method\": \"Phosphorylation assay, nuclear fractionation, co-immunoprecipitation (AIMP2–Smurf2, Smurf2–FBP), ubiquitination assay for FBP, site-directed mutagenesis (S156), in vivo tumorigenesis assay\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — phosphorylation mapping, Co-IP, mutagenesis, ubiquitination assay, in vivo validation, multiple orthogonal methods\",\n      \"pmids\": [\"27197155\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"AIMP2 disrupts the interaction between AXIN and Dishevelled-1 (DVL1) by competing with AXIN, thereby inhibiting Wnt/β-catenin signaling. Hemizygous deletion of Aimp2 results in enhanced Wnt/β-catenin signaling, increased crypt epithelial cell proliferation, expansion of intestinal stem cell compartments, and increased adenoma formation in ApcMin/+ mice.\",\n      \"method\": \"Co-immunoprecipitation (AXIN–DVL1 competition assay), Aimp2 hemizygous mouse model, ApcMin/+ crossed with Aimp2+/- mice, intestinal organoid assay\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — competitive Co-IP establishing mechanism, genetic mouse model with defined pathway readout, organoid assay, multiple orthogonal methods\",\n      \"pmids\": [\"27262173\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"VPS35 co-immunoprecipitates with AIMP2 and with lysosome-associated membrane protein-2a (Lamp2a), facilitating lysosomal degradation of AIMP2. The PD-associated VPS35 D620N mutant disrupts this association. VPS35 overexpression prevents AIMP2-potentiated PARP1 activation and cell death; VPS35 knockdown causes AIMP2-dependent PARP1 activation and cell death.\",\n      \"method\": \"Co-immunoprecipitation (VPS35–AIMP2, VPS35–Lamp2a), VPS35 overexpression/knockdown, PARP1 activation assay, cell death assay, VPS35 D620N mutant analysis\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, functional KD/OE with defined pathway readout, single lab\",\n      \"pmids\": [\"28383562\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Crystal structure (1.88 Å) of human LysRS in complex with AIMP2 reveals that two AIMP2 N-terminal peptides form an antiparallel scaffold holding two LysRS dimers through four binding motifs. This assembly allows all four LysRS catalytic subunits to remain accessible for tRNA recognition. Two human disease-associated mutations conflict with this assembly and cause LysRS release from the MSC.\",\n      \"method\": \"X-ray crystallography (1.88 Å), gel-filtration chromatography, co-immunoprecipitation, molecular modeling, disease mutation analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure with functional Co-IP validation and disease mutation mapping, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"30733335\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Crystal structure of the DRS–AIMP2GST–EPRSGST ternary subcomplex shows that AIMP2GST and EPRSGST interact via conventional GST heterodimerization, while DRS strongly interacts with AIMP2GST via hydrogen bonds between the α7-β9 loop of DRS and the β2-α2 loop of AIMP2GST, with AIMP2 Ser156 being essential for this assembly.\",\n      \"method\": \"X-ray crystallography, structural analysis, site-directed mutagenesis (S156)\",\n      \"journal\": \"IUCrJ\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure with mutagenesis validation of key residue, single lab\",\n      \"pmids\": [\"31576228\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"HSP70 is a critical determinant of AIMP2-DX2 cellular levels. HSP70 recognizes the N-terminal flexible region and GST domain of AIMP2-DX2 via its substrate-binding domain, blocking Siah1-dependent ubiquitination of AIMP2-DX2 and thereby stabilizing it. HSP70 augments AIMP2-DX2-induced cell transformation and cancer progression in vivo.\",\n      \"method\": \"Interactome analysis, X-ray crystallography, NMR, Co-immunoprecipitation, Siah1 ubiquitination assay, in vivo cancer progression assay, small molecule inhibitor of AIMP2-DX2–HSP70 interaction\",\n      \"journal\": \"Nature chemical biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — X-ray crystallography + NMR structural characterization, Co-IP, ubiquitination assay, in vivo validation, multiple orthogonal methods\",\n      \"pmids\": [\"31792442\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"AIMP2 exhibits self-aggregating (amyloid-like oligomerization) properties and directly binds α-synuclein monomer, seeding α-synuclein fibril formation. Co-expression of AIMP2 and α-synuclein in vitro and in vivo accelerates α-synuclein aggregation and increases toxicity. AIMP2 knockdown ameliorates α-synuclein aggregation and dopaminergic cell death in response to preformed fibril seeding or 6-OHDA.\",\n      \"method\": \"In vitro aggregation assay, direct binding assay (AIMP2–α-synuclein), co-expression cell model, in vivo mouse model, AIMP2 knockdown with cell death readout, fractionation into soluble/insoluble fractions\",\n      \"journal\": \"Science translational medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vitro aggregation reconstitution, direct binding, in vivo mouse model, KD rescue, multiple orthogonal methods\",\n      \"pmids\": [\"33177178\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"NMR spectroscopy reveals that the transactivation domain 1 (TAD1) of p53 (residues E17–E28) binds to the GST domain of AIMP2 (shared with AIMP2-DX2). The p53 TAD1 adopts a turn structure with hydrophobic interactions by F19, L22, W23, and L26 upon binding, distinct from its MDM2-binding conformation.\",\n      \"method\": \"NMR chemical shift perturbation (CSP), transferred-NOE (trNOE) structure determination, computational docking\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — NMR structural analysis with residue-level mapping, but single lab and docking component is computational\",\n      \"pmids\": [\"32448505\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"O-GlcNAcylation of AIMP2 (mediated by O-GlcNAc transferase, OGT) increases AIMP2 protein stability and promotes its aggregation, leading to PARP1 activation in aging-related hepatic steatosis. O-GlcNAcase knockout increases AIMP2 and PARP1 levels in mouse liver.\",\n      \"method\": \"Comparative proteomics (LC-MS), O-GlcNAcase knockout mouse model, OGT overexpression and O-GlcNAcase inhibition in vitro, PARP1 activation assay\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — proteomics plus genetic and pharmacological manipulation, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"34817071\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"HLD17-associated nonsense mutation Y35X of AIMP2 causes mislocalization of AIMP2 protein to Golgi bodies as aggregates (wild-type AIMP2 distributes throughout the cell body), activates Golgi stress signaling via caspase-2, and inhibits oligodendroglial cell morphological differentiation. Knockdown of CASP2 reverses the differentiation defect caused by Y35X mutant AIMP2.\",\n      \"method\": \"Immunofluorescence localization, caspase-2 activity assay, differentiation phenotype assay, CASP2 knockdown rescue\",\n      \"journal\": \"Neurochemical research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization experiment with functional consequence, genetic rescue by CASP2 KD, single lab\",\n      \"pmids\": [\"34523057\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"AIMP2-DX2 specifically binds to the hypervariable region and G-domain of KRAS in the cytosol prior to farnesylation, competitively blocking Smurf2 access to KRAS and thereby preventing ubiquitin-mediated KRAS degradation. This stabilizes KRAS and augments KRAS-driven tumorigenesis.\",\n      \"method\": \"Co-immunoprecipitation (AIMP2-DX2–KRAS, competition with Smurf2), domain mapping, in vitro binding assay, small molecule inhibitor of AIMP2-DX2–KRAS interaction, in vivo xenograft model\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP with domain mapping, competitive binding, functional in vivo xenograft validation, multiple orthogonal methods\",\n      \"pmids\": [\"35546148\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Binding of mutant SOD1 (ALS-associated) to LysRS (KARS1) releases AIMP2 from its KARS1-containing complex; free AIMP2 then induces TRAF2 degradation and TNFα-induced neuronal cell death. AIMP2-DX2 competes with full-length AIMP2 for TRAF2 binding, suppressing TRAF2 degradation and TNFα-induced cell death.\",\n      \"method\": \"Co-immunoprecipitation (mutant SOD1–KARS1–AIMP2 complex), TRAF2 degradation assay, ALS mouse model (motor neuron function), DX2 overexpression rescue, AAV-DX2 intrathecal injection\",\n      \"journal\": \"Molecular neurobiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP establishing complex, functional rescue in mouse model, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"36242734\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"HK2 forms a complex with AIMP2 and promotes its autophagic lysosomal-dependent degradation, thereby attenuating ionizing radiation-mediated apoptosis and conferring radio-resistance in hepatocellular carcinoma cells.\",\n      \"method\": \"Co-immunoprecipitation (HK2–AIMP2), autophagy inhibition assay, HK2 knockdown with apoptosis readout, xenograft model\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, functional KD with defined apoptosis readout, in vivo validation, single lab\",\n      \"pmids\": [\"37524692\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"AIMP2-DX2 binds to PARP1 with higher affinity than full-length AIMP2, inhibiting PARP1-induced neuronal cell death (parthanatos) rather than activating it. DX2 translocates to the nucleus more rapidly than full-length AIMP2 under ROS stress. In vivo, AAV-mediated DX2 expression ameliorates behavioral deficits in 6-OHDA Parkinson's disease mouse models.\",\n      \"method\": \"Co-immunoprecipitation (AIMP2 vs. DX2 binding to PARP1), nuclear translocation imaging, PARP1 activation assay, in vivo AAV injection and behavioral assessment\",\n      \"journal\": \"Acta neuropathologica communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP binding comparison, live imaging, functional in vivo rescue, single lab\",\n      \"pmids\": [\"38172953\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"AIMP2 restricts EV71 replication by binding to the viral 3D polymerase (RdRp) and recruiting the E3 ligase SMURF2, which mediates polyubiquitination and degradation of the 3D polymerase.\",\n      \"method\": \"Co-immunoprecipitation (AIMP2–3D polymerase, AIMP2–SMURF2), ubiquitination assay, viral replication assay, knockdown/overexpression\",\n      \"journal\": \"Virologica Sinica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP establishing ternary complex, ubiquitination assay, functional viral replication readout, single lab\",\n      \"pmids\": [\"38945214\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"JTV1/AIMP2 physically interacts with NLS-RARα (nuclear localization signal-containing retinoic acid receptor alpha) as shown by yeast two-hybrid and co-immunoprecipitation in HEK293 cells.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation\",\n      \"journal\": \"Sichuan da xue xue bao. Yi xue ban\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP and yeast two-hybrid, no functional follow-up, single lab\",\n      \"pmids\": [\"19626986\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"AIMP2 is a multifunctional scaffold protein of the multi-tRNA synthetase complex (MSC) that, upon cellular stress signals (DNA damage, oxidative stress, TGFβ, TNFα), undergoes phosphorylation, dissociates from the MSC, and translocates to the nucleus to act as a tumor suppressor and pro-apoptotic factor: it stabilizes p53 by blocking MDM2-mediated ubiquitination; co-activates FBP-dependent transcription of the deubiquitinase USP29 to further stabilize p53; promotes Smurf2-mediated ubiquitination of FBP/c-Myc; competes with AXIN to suppress Wnt/β-catenin signaling; augments c-IAP1-mediated ubiquitination and degradation of TRAF2 to sensitize cells to TNFα-induced apoptosis; and in dopaminergic neurons directly activates PARP1 (parthanatos) by nuclear association, leading to neurodegeneration that is relevant to Parkinson's disease; additionally, AIMP2 self-aggregates and seeds α-synuclein aggregation, and its cellular level is regulated by parkin-mediated ubiquitination, VPS35-dependent lysosomal clearance, O-GlcNAcylation, and HK2-mediated autophagic degradation, while an oncogenic splice variant lacking exon 2 (AIMP2-DX2) antagonizes these tumor-suppressive functions by competing for binding to p53, TRAF2, and other partners, and is itself stabilized by HSP70 blocking Siah1-mediated ubiquitination.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"AIMP2 (JTV1/p38) is a structural scaffold of the multi-tRNA synthetase complex (MSC) that doubles as a stress-activated tumor suppressor and pro-apoptotic effector. As an MSC component, two AIMP2 N-terminal peptides form an antiparallel scaffold that holds two LysRS dimers, keeping all four catalytic subunits accessible for tRNA recognition, while its GST domain mediates conventional GST-type heterodimerization with EPRS and a strong contact with DRS that depends on AIMP2 Ser156 [#11, #12]. Diverse stress signals — DNA damage, oxidative stress, and TGFβ (via S156 phosphorylation) — trigger AIMP2 dissociation from the MSC and nuclear translocation, where it executes several pro-death programs: it binds p53 to block MDM2-mediated ubiquitination, the p53 transactivation domain 1 docking onto the AIMP2 GST domain [#1, #15]; it co-activates FBP/FUBP1-dependent transcription of the deubiquitinase USP29 to further stabilize p53 [#4]; it enhances Smurf2-mediated ubiquitination of FBP to suppress c-Myc [#8]; it competes with AXIN to inhibit Wnt/β-catenin signaling [#9]; and it binds TRAF2 to promote its c-IAP1-dependent degradation, sensitizing cells to TNFα-induced apoptosis [#2]. Consistent with these activities AIMP2 behaves as a haploinsufficient tumor suppressor [#3]. In dopaminergic neurons, accumulated AIMP2 directly associates with PARP1 in the nucleus to drive parthanatos, and also self-aggregates and seeds α-synuclein fibrillization, linking it to Parkinson's-relevant neurodegeneration [#6, #14]. AIMP2 abundance is tightly controlled by parkin-mediated proteasomal degradation, VPS35/Lamp2a-dependent lysosomal clearance, HK2-driven autophagic degradation, and O-GlcNAcylation that stabilizes and aggregates it [#0, #10, #16, #20]. An exon-2-deleted splice variant, AIMP2-DX2, antagonizes these tumor-suppressive functions by competing for p53, TRAF2, and PARP1 and by stabilizing KRAS against Smurf2-mediated degradation; DX2 itself is stabilized by HSP70, which shields it from Siah1-mediated ubiquitination [#5, #13, #18, #21]. An AIMP2 nonsense mutation (Y35X) causes hypomyelinating leukodystrophy 17 through Golgi mislocalization and caspase-2-dependent oligodendroglial differentiation failure [#17].\",\n  \"teleology\": [\n    {\n      \"year\": 2005,\n      \"claim\": \"Established that AIMP2 abundance is degradation-controlled and that its accumulation is neurotoxic, framing AIMP2 as a parkin substrate relevant to dopaminergic survival.\",\n      \"evidence\": \"Co-IP, ubiquitination assay, parkin-knockout mice, and overexpression-induced catecholaminergic cell death rescued by wild-type but not R42P parkin\",\n      \"pmids\": [\"16135753\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define how accumulated AIMP2 kills neurons\", \"Mechanism downstream of AIMP2 buildup unresolved at this stage\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Answered how stress converts AIMP2 from a cytoplasmic scaffold into a nuclear apoptotic effector, defining the p53-stabilization axis.\",\n      \"evidence\": \"Co-IP, nuclear fractionation, MDM2 ubiquitination assay, and interaction-disrupting mutagenesis in AIMP2-deficient cells after genotoxic stress\",\n      \"pmids\": [\"18695251\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Phosphorylation site driving dissociation not mapped here\", \"Did not address other stress inputs\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Showed AIMP2 also enforces apoptosis through a p53-independent route by destabilizing TRAF2 and dampening NF-κB.\",\n      \"evidence\": \"Reciprocal Co-IP of AIMP2-TRAF2 and TRAF2-c-IAP1, NF-κB reporters, and AIMP2 knockdown/knockout in TNFα-treated cells\",\n      \"pmids\": [\"19584093\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How AIMP2 promotes c-IAP1-TRAF2 association mechanistically unclear\", \"Stress signal coupling to this pathway not defined\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Quantified the tumor-suppressive dosage of AIMP2, establishing it as haploinsufficient across multiple death/growth-arrest pathways.\",\n      \"evidence\": \"WT vs heterozygous vs homozygous AIMP2 cell comparison and carcinogen-induced tumorigenesis in heterozygous mice\",\n      \"pmids\": [\"19622630\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not separate contributions of individual downstream pathways\", \"Single lab\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Connected oxidative stress to p53 stabilization via a transcriptional arm, adding USP29-mediated p53 deubiquitination to AIMP2's repertoire.\",\n      \"evidence\": \"Co-IP with FBP/FUBP1, fractionation, USP29 luciferase reporter, and USP29 deubiquitination assay on p53\",\n      \"pmids\": [\"21285945\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How AIMP2 activates FBP transcriptionally not fully defined\", \"Relation to direct p53 binding not integrated\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Identified the oncogenic exon-2-deleted variant AIMP2-DX2 as a dominant antagonist that competes for p53 binding.\",\n      \"evidence\": \"Competitive Co-IP with p53, colony formation, cell death assays, and carcinogen-induced tumorigenesis in transgenic mice\",\n      \"pmids\": [\"21483803\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How DX2 splicing is regulated in cancer not addressed\", \"DX2 effects on non-p53 partners not yet explored here\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Defined the mechanism of AIMP2-driven dopaminergic neurodegeneration as DNA-damage-independent PARP1 overactivation (parthanatos).\",\n      \"evidence\": \"AIMP2 transgenic mice, nuclear AIMP2-PARP1 Co-IP, and PARP1 genetic deletion/inhibitor rescue with behavioral and neuron-count readouts\",\n      \"pmids\": [\"23974709\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How AIMP2 activates PARP1 structurally unresolved\", \"Trigger for AIMP2 nuclear accumulation in neurons not defined\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Revealed a proviral function in which AIMP2 stabilizes influenza M1 by switching its modification from ubiquitination to SUMOylation.\",\n      \"evidence\": \"Yeast two-hybrid, GST pulldown, Co-IP with NS2, K242 mutagenesis, modification assays, and viral replication readout\",\n      \"pmids\": [\"25320310\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How AIMP2 directs the ubiquitin-to-SUMO switch mechanistically unclear\", \"Relevance to MSC dissociation not addressed\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Mapped the TGFβ-responsive phospho-switch (S156) and showed AIMP2 suppresses c-Myc through Smurf2-mediated FBP ubiquitination.\",\n      \"evidence\": \"Phosphorylation mapping, fractionation, Co-IP of AIMP2-Smurf2 and Smurf2-FBP, FBP ubiquitination, S156 mutagenesis, and in vivo tumorigenesis\",\n      \"pmids\": [\"27197155\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Kinase responsible for S156 phosphorylation not identified\", \"Interplay with FBP's role in USP29 transcription not reconciled\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Added a Wnt-suppressive role, showing AIMP2 competes with AXIN for DVL1 to restrain intestinal stem-cell expansion and adenoma formation.\",\n      \"evidence\": \"Competitive Co-IP of AXIN-DVL1, Aimp2 hemizygous mice, ApcMin/+ crosses, and intestinal organoids\",\n      \"pmids\": [\"27262173\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How nuclear vs cytoplasmic AIMP2 pools are partitioned among pathways unclear\", \"Stress dependence of Wnt suppression not defined\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Provided structural definition of AIMP2's scaffolding role within the MSC and the basis for disease-causing LysRS release.\",\n      \"evidence\": \"1.88 Å crystal structure of LysRS-AIMP2 plus gel filtration, Co-IP, and disease-mutation mapping; and crystal structure of the DRS-AIMP2GST-EPRSGST subcomplex with S156 mutagenesis\",\n      \"pmids\": [\"30733335\", \"31576228\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural transition accompanying stress-induced MSC dissociation not captured\", \"Conformation of nuclear AIMP2 unknown\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Explained how the oncogenic DX2 variant accumulates, identifying HSP70 as a chaperone that blocks Siah1-mediated DX2 degradation.\",\n      \"evidence\": \"Interactome analysis, X-ray crystallography, NMR, Co-IP, Siah1 ubiquitination assay, in vivo progression, and a DX2-HSP70 small-molecule inhibitor\",\n      \"pmids\": [\"31792442\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether HSP70 similarly affects full-length AIMP2 not resolved\", \"In vivo therapeutic window of the inhibitor not defined\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Demonstrated AIMP2 self-aggregation and direct α-synuclein seeding, linking AIMP2 to proteinopathy in Parkinson's-relevant models.\",\n      \"evidence\": \"In vitro aggregation and binding assays, co-expression cell and mouse models, and AIMP2 knockdown rescue of fibril-/6-OHDA-induced death\",\n      \"pmids\": [\"33177178\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural determinants of AIMP2 amyloid-like oligomerization not defined\", \"Relation between aggregation and PARP1 activation not integrated\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Resolved the structural basis for p53 recognition, mapping p53 TAD1 binding to the AIMP2 GST domain shared with DX2.\",\n      \"evidence\": \"NMR chemical-shift perturbation, transferred-NOE structure determination, and computational docking\",\n      \"pmids\": [\"32448505\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Docking component is computational\", \"Affinity comparison with MDM2-bound p53 not quantified in cells\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Connected post-translational modification to AIMP2 stability and aggregation, showing O-GlcNAcylation drives PARP1 activation in hepatic steatosis.\",\n      \"evidence\": \"LC-MS proteomics, O-GlcNAcase knockout mice, OGT overexpression/OGA inhibition, and PARP1 activation assay\",\n      \"pmids\": [\"34817071\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"O-GlcNAc site(s) on AIMP2 not mapped\", \"Tissue specificity beyond liver not tested\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Linked AIMP2 to a Mendelian disease, showing the Y35X nonsense mutation causes HLD17 via Golgi mislocalization and caspase-2-dependent myelination failure.\",\n      \"evidence\": \"Immunofluorescence localization, caspase-2 activity assay, oligodendroglial differentiation phenotype, and CASP2 knockdown rescue\",\n      \"pmids\": [\"34523057\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How a truncated protein reaches the Golgi mechanistically unclear\", \"Relationship to MSC scaffolding loss not addressed\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Expanded DX2 oncogenicity to RAS signaling, showing DX2 stabilizes pre-farnesylation KRAS by blocking Smurf2 access.\",\n      \"evidence\": \"Co-IP and domain mapping of DX2-KRAS, Smurf2 competition, in vitro binding, a DX2-KRAS inhibitor, and xenografts\",\n      \"pmids\": [\"35546148\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether full-length AIMP2 also engages KRAS not established\", \"Effect on downstream RAS effector pathways not detailed\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Placed AIMP2 in an ALS pathway, showing mutant SOD1 binding to KARS1 releases AIMP2 to trigger TRAF2 degradation and neuronal death, antagonized by DX2.\",\n      \"evidence\": \"Co-IP of mutant SOD1-KARS1-AIMP2, TRAF2 degradation assay, ALS mouse model, and AAV-DX2 intrathecal rescue\",\n      \"pmids\": [\"36242734\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct contribution of free AIMP2 vs other factors to motor neuron death not isolated\", \"Single lab\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Added a cancer-relevant degradation route, showing HK2-driven autophagic clearance of AIMP2 confers radio-resistance in hepatocellular carcinoma.\",\n      \"evidence\": \"HK2-AIMP2 Co-IP, autophagy inhibition, HK2 knockdown with apoptosis readout, and xenografts\",\n      \"pmids\": [\"37524692\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How HK2 routes AIMP2 to autophagy mechanistically unclear\", \"Interplay with other AIMP2 degradation systems not compared\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Revised the DX2-PARP1 relationship, showing DX2 outcompetes AIMP2 for PARP1 to inhibit parthanatos, with therapeutic benefit in a Parkinson's model.\",\n      \"evidence\": \"Comparative Co-IP of AIMP2 vs DX2 with PARP1, nuclear translocation imaging, PARP1 activation assay, and AAV-DX2 rescue in 6-OHDA mice\",\n      \"pmids\": [\"38172953\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How DX2's higher PARP1 affinity arises structurally not defined\", \"Long-term safety of DX2 delivery not addressed\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Generalized AIMP2's Smurf2-recruiting activity to antiviral defense, showing it degrades the EV71 3D polymerase.\",\n      \"evidence\": \"Co-IP of AIMP2-3D polymerase and AIMP2-SMURF2, ubiquitination assay, and viral replication with knockdown/overexpression\",\n      \"pmids\": [\"38945214\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How AIMP2 distinguishes viral substrates for Smurf2 recruitment unclear\", \"Single lab\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how a single scaffold partitions among its many mutually exclusive nuclear functions (p53, FBP/USP29, Smurf2/FBP, AXIN, TRAF2, PARP1) and what structural state AIMP2 adopts upon stress-induced MSC release and aggregation.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structure of stress-released or nuclear AIMP2\", \"Determinants selecting among competing partners undefined\", \"Kinases/signals targeting each modification not fully mapped\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [1, 2, 4, 8, 9, 11]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [11, 12]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1, 2, 6, 18]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [4, 8]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [1, 4, 6, 8]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [1, 4, 18]},\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [17]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [1, 2, 6]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [11, 12]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [8, 9]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [6, 14, 17, 18]}\n    ],\n    \"complexes\": [\"multi-tRNA synthetase complex (MSC)\"],\n    \"partners\": [\"TP53\", \"TRAF2\", \"PARP1\", \"FUBP1\", \"SMURF2\", \"KARS1\", \"VPS35\", \"SNCA\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}