{"gene":"AIMP1","run_date":"2026-06-09T22:02:42","timeline":{"discoveries":[{"year":2001,"finding":"The EMAPII cytokine domain of p43/AIMP1 is released from the multisynthetase complex after caspase-7 cleavage in vitro, and the released EMAPII domain can induce migration of human mononuclear phagocytes. The full-length p43/proEMAPII has strong tRNA binding capacity (KD = 0.2 µM), which is lost upon release of the EMAPII domain, suggesting cleavage limits tRNA availability for aminoacyl-tRNA synthetases in the complex.","method":"In vitro caspase-7 digestion assay, tRNA binding assay (Kd measurement), mononuclear phagocyte migration assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution of caspase-7 cleavage, quantitative tRNA binding, and functional migration assay in a single rigorous study","pmids":["11306575"],"is_preprint":false},{"year":2001,"finding":"Crystal structure of human EMAPII domain at 1.14 Å resolution reveals that it is a monomer consisting of an OB-fold (Trbp-like) domain and an extra domain related by degenerate 2-fold symmetry, mimicking the dimer interface of bacterial Trbp proteins, and generating a novel OB-fold-based tRNA-binding site.","method":"X-ray crystallography (1.14 Å resolution)","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1 / Strong — high-resolution crystal structure with structural validation and mechanistic interpretation","pmids":["11157763"],"is_preprint":false},{"year":2014,"finding":"Crystal structure of the ArgRS–GlnRS–AIMP1 ternary subcomplex shows that the N-terminal helix of AIMP1 forms a coiled-coil with the N-terminal domain of ArgRS and anchors the C-terminal core of GlnRS. Mutation of AIMP1's N-terminal helix destabilizes ArgRS's N-terminal domain and abrogates ArgRS catalytic activity; mutation of ArgRS's N-terminal helix liberates GlnRS. AIMP1 also anchors the ternary complex to AIMP2/p38.","method":"X-ray crystallography, site-directed mutagenesis, aminoacylation activity assay, co-immunoprecipitation","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure combined with mutagenesis and functional enzymatic assays in a single rigorous study","pmids":["25288775"],"is_preprint":false},{"year":2003,"finding":"AIMP1/p43 is an integral component of both the nuclear and cytosolic human multisynthetase complexes, isolated to near homogeneity; gel filtration and immunoblot analysis demonstrate that a major biological role for p43 is as a structural part of the multisynthetase complex.","method":"Biochemical fractionation, gel filtration chromatography, immunoblotting, electron microscopy (negative staining)","journal":"Protein science : a publication of the Protein Society","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal biochemical methods, single lab","pmids":["14500886"],"is_preprint":false},{"year":2006,"finding":"Structural domain mapping of secreted AIMP1 using deletion fragments established three functionally distinct extracellular domains: aa 101–114 mediates pro-apoptotic activity toward endothelial cells (caspase-3 activation), aa 6–46 mediates fibroblast proliferation, and aa 114–192 mediates endothelial cell migration.","method":"Deletion fragment generation, endothelial cell death/caspase-3 assay, fibroblast proliferation assay, endothelial migration assay; elastase 2 cleavage","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — systematic deletion mapping with multiple functional readouts, single lab","pmids":["16472771"],"is_preprint":false},{"year":2012,"finding":"CD23 (low-affinity IgE receptor) was identified as the functional receptor for AIMP1 that mediates TNF-α secretion from THP-1 monocytic cells and primary human PBMCs. CD23 knockdown attenuated AIMP1 binding and AIMP1-induced TNF-α secretion. AIMP1-induced TNF-α secretion via CD23 involves ERK1/2 activation. Notably, the C-terminal EMAP II fragment of AIMP1 cannot bind CD23 or activate ERK1/2.","method":"Screen of 499 soluble receptors, co-immunoprecipitation, CD23 knockdown (siRNA), TNF-α ELISA, ERK1/2 phosphorylation assay, binding assay","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Strong — receptor screen plus reciprocal binding validation, functional knockdown, and signaling pathway identification in multiple cell types","pmids":["22767513"],"is_preprint":false},{"year":2010,"finding":"TLR4 activation by LPS induces phosphorylation of AIMP1 at serine-140 by JNK (via MyD88 pathway), causing dissociation of AIMP1 from gp96 and resulting in increased gp96 cell surface expression. Alanine mutation of serine-140 suppressed LPS-induced gp96 surface presentation.","method":"TLR4/LPS stimulation, JNK inhibitor experiments, site-directed mutagenesis (S140A), co-immunoprecipitation, flow cytometry for gp96 surface expression","journal":"Biochemical and biophysical research communications","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — mutagenesis of specific phosphorylation site combined with signaling pathway dissection and functional readout, single lab with multiple orthogonal methods","pmids":["20510162"],"is_preprint":false},{"year":2014,"finding":"AIMP1 negatively regulates TGF-β signaling by interacting directly with Smad2 and Smad3, as demonstrated by co-immunoprecipitation and luciferase reporter assay. AIMP1 downregulation by siRNA promotes Smad2/3 phosphorylation and restores chondrogenic differentiation in dedifferentiated and OA-derived degenerated chondrocytes.","method":"Co-immunoprecipitation, luciferase reporter assay, siRNA knockdown, Western blot for p-Smad2/3, in vivo mouse implantation model","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP and functional reporter combined with in vivo rescue, single lab","pmids":["26890138"],"is_preprint":false},{"year":2014,"finding":"HCV envelope protein E2 directly interacts with AIMP1/p43 (by GST pulldown and co-immunoprecipitation) and promotes its degradation via ubiquitin-dependent proteasome pathway. E2 also disrupts the stabilizing interaction between AIMP1 and the ER chaperone grp78, further reducing cellular AIMP1. Loss of AIMP1 caused by E2 results in upregulation of TGF-β signaling and increased surface expression of gp96.","method":"GST pulldown, co-immunoprecipitation, confocal immunofluorescence, proteasome inhibitor experiments, TGF-β signaling assay, flow cytometry for gp96 surface expression","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal biochemical methods (GST pulldown, co-IP, proteasome inhibition) with functional downstream readouts, single lab","pmids":["24816397"],"is_preprint":false},{"year":2006,"finding":"EMAP-II pre-treatment of human endothelial cells does not increase TNF-R1 protein expression but induces redistribution of TNF-R1 from Golgi storage pools to the cell membrane and mobilizes TRADD to the membrane (in separate vesicles from TNF-R1), thereby sensitizing endothelial cells to TNF-induced apoptosis.","method":"Flow cytometry, immunofluorescence co-staining, Western blot, apoptosis assay","journal":"Apoptosis : an international journal on programmed cell death","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — subcellular localization experiments with functional apoptosis readout, single lab, multiple imaging methods","pmids":["17051333"],"is_preprint":false},{"year":2000,"finding":"Recombinant EMAP-II upregulates TNF-R1 (but not TNF-R2) mRNA and protein expression in human umbilical vein endothelial cells ~4-6 fold within 2 h, and conditioned media from high-EMAP-II expressing cell lines upregulated TNF-R1 by up to 20-fold; effect was blocked by anti-EMAP-II antibody.","method":"Northern blot/RT-PCR, ELISA, neutralizing antibody blockade","journal":"Cytokine","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — functional receptor upregulation shown by multiple methods (mRNA, protein, antibody blockade), replicated across cell lines and in vivo","pmids":["10880244"],"is_preprint":false},{"year":2007,"finding":"RARS overexpression impairs AIMP1 secretion in HeLa and MCF7 cells, and proteasome inhibition impairs cleavage of AIMP1 to generate mature EMAP II, indicating that the proteasome is involved in proteolytic processing of AIMP1 to produce EMAP II.","method":"RARS overexpression, proteasome inhibitor treatment, AIMP1/EMAP II detection (Western blot/ELISA)","journal":"Journal of cellular physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological and overexpression approaches with biochemical readouts, single lab","pmids":["17443684"],"is_preprint":false},{"year":2014,"finding":"AIMP1 negatively regulates adipogenesis by directly interacting with the DNA-binding domain of PPARγ via co-immunoprecipitation, thereby inhibiting PPARγ transcriptional activity. AIMP1-deficient cells show augmented adipogenesis compared to controls.","method":"Co-immunoprecipitation, luciferase reporter assay, AIMP1 knockout/deficient cells, adipogenesis assay","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct protein-protein interaction with functional transcriptional readout and loss-of-function phenotype, single lab","pmids":["25146391"],"is_preprint":false},{"year":2011,"finding":"Exogenous AIMP1 decreases endothelial cell viability through an α5β1 integrin-dependent mechanism and inhibits cell adhesion. Affinity purification, pulldown, and co-immunoprecipitation demonstrate that AIMP1 interacts with four cytoskeletal proteins: filamin-A, α-tubulin, vinculin, and cingulin. α-Tubulin is phosphorylated upon AIMP1 treatment, and AIMP1 colocalizes with filamin-A and cingulin.","method":"Affinity purification, pulldown, co-immunoprecipitation, immunofluorescence, integrin-blocking antibody, cell viability and adhesion assays","journal":"Journal of cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — multiple orthogonal binding methods plus functional readouts, single lab","pmids":["21416500"],"is_preprint":false},{"year":2015,"finding":"AIMP1 promotes osteoclastogenesis and acts synergistically with RANKL; downregulation of CD23 (its receptor) abolishes AIMP1-mediated osteoclastogenesis, confirming that AIMP1 signals through CD23 to promote osteoclast differentiation.","method":"Osteoclastogenesis assay, CD23 knockdown, RANKL synergy assay, ELISA for serum AIMP1 in RA patients","journal":"Biomaterials","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CD23-dependent mechanism confirmed by knockdown with functional osteoclastogenesis readout, single lab","pmids":["25617125"],"is_preprint":false},{"year":2019,"finding":"AIMP1 binds and colocalizes with FSCN1 (fascin) in laryngeal squamous cell carcinoma cells, as validated by co-immunoprecipitation/Western blotting and immunofluorescence; knockdown of AIMP1 inhibits LSCC cell proliferation, migration, and invasion.","method":"Co-immunoprecipitation, mass spectrometry, immunofluorescence, siRNA knockdown with proliferation/migration/invasion assays","journal":"Proteomics","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — co-IP validated binding partner identified by MS, functional knockdown with phenotypic readout, single lab","pmids":["31287215"],"is_preprint":false},{"year":2022,"finding":"In multiple myeloma, AIMP1 interacts with ANP32A (acidic leucine-rich nuclear phosphoprotein 32A) to regulate histone H3 acetylation, increasing H3 acetylation enrichment at the GAREM2 locus, which promotes p-ERK1/2 (MAPK pathway activation). AIMP1 also promotes osteoclast differentiation by activating NFATc1.","method":"Protein chip assay, co-immunoprecipitation, ChIP-seq, RNA-seq, MTT assay, xenograft model, TRAC staining","journal":"Cancer communications (London, England)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — protein chip + co-IP to identify binding partner, ChIP-seq for epigenetic mechanism, multiple orthogonal methods, single lab","pmids":["36042007"],"is_preprint":false},{"year":2019,"finding":"AIMP1 regulates T cell responses by inhibiting TCR-dependent activation: AIMP1 reduces lipid raft association upon TCR engagement, decreases Ca2+ influx, and downregulates phosphorylation of PLCγ and PI3K in CD4+ T cells. AIMP1 also specifically enhances differentiation of regulatory T (Treg) cells without affecting Th1, Th2, or Th17 differentiation.","method":"T cell activation assay, Ca2+ influx measurement, microscopic lipid raft analysis, Western blot for p-PLCγ/p-PI3K, Treg differentiation flow cytometry","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal signaling measurements with functional differentiation readout, single lab","pmids":["31084930"],"is_preprint":false},{"year":2018,"finding":"AIMp1/p43 absence in bone marrow-derived dendritic cells impairs cytokine production, costimulatory molecule expression, p38 MAPK signaling, and TH1 polarization of co-cultured T cells. AIMp1-deficient DCs showed significantly compromised vaccine-mediated protection against melanoma in vivo, and AIMp1 in the host was critical for antiviral immunity against influenza.","method":"AIMp1 knockout BMDC, cytokine ELISA, flow cytometry for costimulatory molecules, p38 MAPK phosphorylation assay, T cell co-culture TH1 polarization assay, in vivo tumor and influenza models","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with multiple orthogonal readouts in vitro and in vivo, single lab","pmids":["29379495"],"is_preprint":false},{"year":2012,"finding":"AIMP1 deficiency in mice results in spontaneous airway hyperreactivity and TH2-biased immune responses; adoptive transfer of AIMP1-deficient CD4+ T cells to OVA-sensitized mice exacerbates airway inflammation. AIMP1-deficient mice show decreased serum IL-12p40, and AIMP1-deficient lung DCs show increased surface molecule expression, establishing AIMP1 as a negative regulator of TH2 responses in vivo.","method":"AIMP1-deficient mouse model, methacholine challenge (Penh values), adoptive transfer of CD4+ T cells, cytokine ELISA, histological analysis","journal":"Clinical immunology (Orlando, Fla.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with multiple functional in vivo readouts and adoptive transfer epistasis, single lab","pmids":["22472603"],"is_preprint":false},{"year":2024,"finding":"An AIMP1-derived peptide (TN41, aa 6–46) is generated by MMP1-mediated cleavage of AIMP1 secreted from Wnt-treated hair follicle stem cells, and this fragment activates dermal papilla cells by activating Akt and ERK, increasing β-catenin. TN41 promotes hair shaft elongation in cultured human hair follicles and enhances DPC spheroid hair-inducing activity. Deletion mapping identified aa 6–46 as the active region.","method":"Deletion mapping, MMP1 cleavage assay, Akt/ERK/β-catenin Western blot, hair follicle organ culture, DPC spheroid assay","journal":"International journal of biological sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — deletion mapping with functional readout and identified protease, multiple downstream signaling assays, single lab","pmids":["39494335"],"is_preprint":false},{"year":2025,"finding":"AIMP1 derived from dopaminergic neurons is elevated in PD; Aimp1 knockout or knockdown improves DA neuron viability and reduces microglial activation in MPTP-induced PD mouse model. RNA-seq analysis revealed AIMP1 promotes microglial inflammatory response. AIMP1-induced microglial activation is CD23-dependent.","method":"MPTP mouse model, Aimp1 KO/KD, immunofluorescence for TH and microglia markers, RNA-seq, ELISA, in vitro MPP+ cell model","journal":"CNS neuroscience & therapeutics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO in vivo model with RNA-seq and CD23-dependence established, single lab","pmids":["40522094"],"is_preprint":false},{"year":2025,"finding":"EMAP-II packaged in macrophage-derived extracellular vesicles (from OGD/R-activated macrophages) is transferred to neutrophils, where it suppresses PI3K/AKT signaling, induces mitochondrial oxidative stress (mtROS), and drives pathological NETs formation in lung ischemia/reperfusion injury. shRNA-mediated EMAP-II knockdown in macrophages abolished OGD/R-EV-induced mtROS and NETs formation and mitigated pulmonary inflammation in mice.","method":"Proteomic profiling of EVs, shRNA EMAP-II knockdown, PI3K/AKT pharmacological inhibition, mtROS measurement, NETs assay, mouse LIRI model","journal":"Redox biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — proteomic EV identification + shRNA KD + pharmacological inhibition + in vivo model, single lab with multiple orthogonal methods","pmids":["40616949"],"is_preprint":false},{"year":2025,"finding":"AIMP1 functions as a limiter of autophagy, at least in part by uncoupling mTORC1 activity, while minimally affecting protein synthesis. Depletion of Aimp1 in murine myeloid cells impairs innate immunity kinetics, revealing that Aimp1's redundancy for protein synthesis allows it to reinforce autophagic activity.","method":"Gene essentiality genomics analysis, Aimp1 depletion in murine myeloid cells, transcriptomics, mTORC1 activity assays, innate immunity kinetics assay","journal":"Communications biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Aimp1 depletion with mTORC1 and transcriptomic readouts, single lab, multiple methods","pmids":["41862581"],"is_preprint":false},{"year":2011,"finding":"AIMP1 upregulates TLR2 protein expression in bone marrow-derived DCs in a time- and dose-dependent manner via NF-κB activation (blocked by BAY11-7082), and enhances TLR2-mediated IL-6 and IL-12 production and costimulatory molecule expression when combined with TLR2 agonists.","method":"Flow cytometry, RT-PCR, NF-κB inhibitor (BAY11-7082), ELISA for IL-6/IL-12, costimulatory molecule expression assay","journal":"Immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological inhibition of NF-κB confirming pathway, multiple functional readouts, single lab","pmids":["21711348"],"is_preprint":false},{"year":2025,"finding":"AIMP1 downregulates the tight junction protein ZO-1 in brain microvascular endothelial cells, increasing blood-brain barrier permeability. siRNA knockdown of AIMP1 restored ZO-1 protein levels and reduced BBB permeability. The miRNA let-7f-5p directly targets AIMP1 (validated by luciferase reporter assay) and overexpression of let-7f-5p suppresses AIMP1 and partially rescues ZO-1 levels.","method":"siRNA knockdown, Western blot, luciferase reporter assay, Na-F permeability assay, TEER measurement","journal":"Clinical and experimental immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA KD with functional barrier readout and validated miRNA regulatory interaction, single lab","pmids":["41316924"],"is_preprint":false},{"year":2020,"finding":"HLD3-associated frameshift mutant AIMP1 proteins (292CA) localize predominantly to lysosomes where they form aggregates and specifically interact with actin to block actin fiber formation; Q39X mutant also aggregates in lysosomes but without actin interaction. Both 292CA and Q39X mutants inhibit neuronal differentiation in N1E-115 cells; ibuprofen treatment reverses mutant-induced inhibitory differentiation and lysosomal localization.","method":"Immunofluorescence (lysosome/organelle localization), immunoprecipitation, actin fiber formation assay, neuronal differentiation assay, ibuprofen treatment","journal":"Medicines (Basel, Switzerland)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — subcellular localization, protein-protein interaction by IP, functional differentiation readout, pharmacological rescue, single lab","pmids":["32384815"],"is_preprint":false}],"current_model":"AIMP1/p43 is a multifunctional auxiliary component of the multisynthetase complex (MSC) that structurally scaffolds the MSC by forming a coiled-coil with ArgRS and anchoring GlnRS (crystal structure established); it binds tRNA with high affinity and undergoes caspase-7 cleavage during apoptosis to release the inflammatory cytokine EMAP II, which signals extracellularly through CD23 on monocytes (activating ERK1/2 and TNF-α secretion), redistributes TNF-R1 and TRADD to the plasma membrane in endothelial cells, and acts on distinct structural domains for endothelial apoptosis (aa 101–114), fibroblast proliferation (aa 6–46), and endothelial migration (aa 114–192); intracellularly, AIMP1 is phosphorylated by JNK at Ser-140 downstream of TLR4-MyD88 signaling, causing dissociation from gp96 and its surface translocation, inhibits PPARγ transcriptional activity to suppress adipogenesis, negatively regulates TGF-β signaling via Smad2/3 interaction, and limits mTORC1-coupled autophagy in myeloid cells, while its degradation by HCV E2 through ubiquitin-proteasomal and grp78-displacement mechanisms de-represses both TGF-β signaling and gp96 surface expression."},"narrative":{"mechanistic_narrative":"AIMP1 (p43/proEMAP II) is a multifunctional auxiliary component of the tRNA multisynthetase complex (MSC) that doubles as the precursor of the secreted inflammatory cytokine EMAP II [PMID:11306575, PMID:14500886]. Structurally, AIMP1 scaffolds the MSC: its N-terminal helix forms a coiled-coil with the N-terminal domain of ArgRS, an interaction required for ArgRS catalytic activity, while it anchors GlnRS and bridges the ternary subcomplex to AIMP2/p38 [PMID:25288775]. Full-length proEMAP II binds tRNA with high affinity through an OB-fold-based site, and caspase-7 cleavage liberates the C-terminal EMAP II domain, abolishing tRNA binding and releasing the cytokine [PMID:11306575, PMID:11157763]; proteasome-dependent processing also contributes to mature EMAP II generation [PMID:17443684]. As a secreted factor, AIMP1 acts through distinct structural domains for endothelial apoptosis (aa 101–114), fibroblast proliferation (aa 6–46), and endothelial migration (aa 114–192) [PMID:16472771], and signals through the receptor CD23 to drive ERK1/2 activation and TNF-α secretion in monocytes and to promote osteoclastogenesis [PMID:22767513, PMID:25617125]. Intracellularly, AIMP1 is phosphorylated at Ser-140 by JNK downstream of TLR4–MyD88, triggering its dissociation from gp96 and increased gp96 surface presentation [PMID:20510162], and it acts as a broad negative regulator of signaling—binding Smad2/3 to restrain TGF-β signaling [PMID:26890138], binding the PPARγ DNA-binding domain to suppress adipogenesis [PMID:25146391], and limiting mTORC1-coupled autophagy in myeloid cells [PMID:41862581]. Genetically, frameshift mutant AIMP1 proteins associated with hypomyelinating leukodystrophy (HLD3) mislocalize to lysosomes, form aggregates, sequester actin, and impair neuronal differentiation [PMID:32384815].","teleology":[{"year":2001,"claim":"Established that AIMP1 is a tRNA-binding precursor whose proteolytic cleavage couples loss of synthetase-complex function to release of a phagocyte-recruiting cytokine.","evidence":"In vitro caspase-7 digestion, quantitative tRNA binding (KD = 0.2 µM), and mononuclear phagocyte migration assay","pmids":["11306575"],"confidence":"High","gaps":["Did not define the receptor mediating phagocyte migration","In vivo trigger for caspase-7 cleavage not established"]},{"year":2001,"claim":"Defined the atomic architecture of the EMAP II cytokine domain, showing how an OB-fold creates a novel tRNA-binding surface.","evidence":"1.14 Å X-ray crystallography of the human EMAP II domain","pmids":["11157763"],"confidence":"High","gaps":["Structure of the full-length protein and its MSC contacts not solved here","Does not address how cleavage abolishes tRNA binding"]},{"year":2003,"claim":"Confirmed AIMP1 as an integral structural subunit of both nuclear and cytosolic MSC, framing its synthetase-scaffolding role.","evidence":"Biochemical fractionation, gel filtration, immunoblotting, and electron microscopy","pmids":["14500886"],"confidence":"Medium","gaps":["Did not resolve specific synthetase contacts","Functional distinction between nuclear and cytosolic pools unclear"]},{"year":2014,"claim":"Resolved the molecular logic of AIMP1's scaffolding role: its N-terminal helix stabilizes ArgRS and anchors GlnRS, linking AIMP1 structure to synthetase catalytic activity.","evidence":"Crystal structure of the ArgRS–GlnRS–AIMP1 subcomplex with mutagenesis and aminoacylation assays","pmids":["25288775"],"confidence":"High","gaps":["Full MSC assembly architecture beyond the ternary core not resolved","How cytokine release reshapes the complex not addressed"]},{"year":2006,"claim":"Mapped distinct extracellular functions of secreted AIMP1 to separate structural domains, explaining its pleiotropic activity on different cell types.","evidence":"Deletion fragment mapping with endothelial apoptosis, fibroblast proliferation, and migration assays plus elastase 2 cleavage","pmids":["16472771"],"confidence":"Medium","gaps":["Receptors for each domain not all identified","Physiological proteases generating each fragment in vivo unclear"]},{"year":2012,"claim":"Identified CD23 as a functional AIMP1 receptor driving ERK1/2-dependent TNF-α secretion, providing a defined extracellular signaling axis.","evidence":"Soluble-receptor screen, reciprocal binding, CD23 siRNA knockdown, and TNF-α/ERK readouts in monocytes","pmids":["22767513"],"confidence":"High","gaps":["Structural basis of AIMP1–CD23 binding unknown","Why the EMAP II fragment cannot engage CD23 not explained"]},{"year":2010,"claim":"Linked TLR4 signaling to AIMP1 post-translational control, showing JNK phosphorylation at Ser-140 governs gp96 surface presentation.","evidence":"LPS/TLR4 stimulation, JNK inhibition, S140A mutagenesis, co-IP, and flow cytometry for surface gp96","pmids":["20510162"],"confidence":"High","gaps":["Downstream consequence of surface gp96 for immunity not defined here","Whether Ser-140 phosphorylation affects MSC association unknown"]},{"year":2014,"claim":"Established AIMP1 as an intracellular brake on signaling through direct Smad2/3 and PPARγ interactions, controlling TGF-β output and adipogenesis.","evidence":"Co-IP, luciferase reporters, siRNA/knockout cells with chondrogenic and adipogenesis readouts","pmids":["26890138","25146391"],"confidence":"Medium","gaps":["Structural mode of Smad and PPARγ binding not determined","Whether these functions require free or MSC-bound AIMP1 unclear"]},{"year":2014,"claim":"Showed viral hijacking of AIMP1 stability by HCV E2, connecting AIMP1 degradation to de-repression of TGF-β signaling and gp96 surface expression.","evidence":"GST pulldown, co-IP, proteasome inhibition, grp78-displacement analysis, and downstream signaling readouts","pmids":["24816397"],"confidence":"Medium","gaps":["E3 ligase mediating AIMP1 ubiquitination not identified","Relevance to HCV pathogenesis in vivo not established"]},{"year":2006,"claim":"Clarified how secreted EMAP II sensitizes endothelium to apoptosis by trafficking TNF-R1 and TRADD to the membrane rather than altering receptor levels.","evidence":"Flow cytometry, immunofluorescence co-staining, and apoptosis assays in endothelial cells","pmids":["17051333","10880244"],"confidence":"Medium","gaps":["Receptor mediating EMAP II uptake/signaling not defined","Reconciliation of transcriptional vs. trafficking effects across studies"]},{"year":2011,"claim":"Extended AIMP1's extracellular targets to the cytoskeleton and integrins, linking it to endothelial viability and adhesion control.","evidence":"Affinity purification, pulldown, co-IP, immunofluorescence, and α5β1 integrin blockade with viability/adhesion assays","pmids":["21416500"],"confidence":"Medium","gaps":["Direct vs. indirect cytoskeletal interactions not separated","Functional significance of α-tubulin phosphorylation unclear"]},{"year":2018,"claim":"Defined AIMP1 as a regulator of adaptive and innate immunity in vivo, shaping dendritic cell function, T-cell polarization, and antiviral/antitumor protection.","evidence":"AIMP1-knockout/deficient mice, BMDC and T-cell assays, and in vivo tumor, influenza, and airway models","pmids":["29379495","22472603","31084930","21711348"],"confidence":"Medium","gaps":["Whether immune phenotypes reflect intracellular or secreted AIMP1 not resolved","Receptors mediating each immune effect not uniformly defined"]},{"year":2022,"claim":"Revealed disease-context AIMP1 partnerships in cancer, including ANP32A-dependent histone acetylation and fascin binding that drive proliferation and invasion.","evidence":"Protein chip, co-IP, mass spectrometry, ChIP-seq, and knockdown phenotyping in myeloma and laryngeal carcinoma","pmids":["36042007","31287215"],"confidence":"Medium","gaps":["Generality of these interactions beyond specific tumors unknown","Direct vs. complex-mediated nature of ANP32A effect on chromatin unclear"]},{"year":2025,"claim":"Identified an autophagy-limiting function for AIMP1 via mTORC1 uncoupling, distinguishing it from its synthetase role and tying it to innate immune kinetics.","evidence":"Gene-essentiality analysis, Aimp1 depletion in murine myeloid cells, mTORC1 assays, and transcriptomics","pmids":["41862581"],"confidence":"Medium","gaps":["Molecular link between AIMP1 and mTORC1 not defined","Whether autophagy role requires MSC dissociation unknown"]},{"year":2020,"claim":"Connected HLD3 leukodystrophy mutations to a cellular defect: mutant AIMP1 mislocalizes to lysosomes, aggregates, sequesters actin, and blocks neuronal differentiation.","evidence":"Immunofluorescence localization, immunoprecipitation, actin fiber and neuronal differentiation assays with ibuprofen rescue","pmids":["32384815"],"confidence":"Medium","gaps":["Mechanism by which mutants are routed to lysosomes unclear","Whether loss of MSC function contributes to leukodystrophy not addressed"]},{"year":null,"claim":"How AIMP1 partitions between its MSC-scaffolding role and its diverse secreted-cytokine and intracellular-regulatory functions, and what governs the switch, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model linking MSC residence, cleavage, and secretion","Receptor identity for several extracellular activities undefined","Structural basis of CD23, Smad, and PPARγ binding unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[0,1]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[2,3]},{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[5,14]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[7,12]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[2]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[3]},{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[4,5]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[3]},{"term_id":"GO:0005764","term_label":"lysosome","supporting_discovery_ids":[26]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[2,3]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[5,6,18,19]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[7,12]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[23]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[9,4]}],"complexes":["multisynthetase complex (MSC)"],"partners":["RARS","QARS","AIMP2","CD23","SMAD2","SMAD3","PPARG","GP96"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q12904","full_name":"Aminoacyl tRNA synthase complex-interacting multifunctional protein 1","aliases":["Multisynthase complex auxiliary component p43"],"length_aa":312,"mass_kda":34.4,"function":"Non-catalytic component of the multisynthase complex. Stimulates the catalytic activity of cytoplasmic arginyl-tRNA synthase (PubMed:10358004). Binds tRNA. Possesses inflammatory cytokine activity (PubMed:11306575). Negatively regulates TGF-beta signaling through stabilization of SMURF2 by binding to SMURF2 and inhibiting its SMAD7-mediated degradation (By similarity). Involved in glucose homeostasis through induction of glucagon secretion at low glucose levels (By similarity). Promotes dermal fibroblast proliferation and wound repair (PubMed:16472771). Regulates KDELR1-mediated retention of HSP90B1/gp96 in the endoplasmic reticulum (By similarity). Plays a role in angiogenesis by inducing endothelial cell migration at low concentrations and endothelial cell apoptosis at high concentrations (PubMed:12237313). Induces maturation of dendritic cells and monocyte cell adhesion (PubMed:11818442). Modulates endothelial cell responses by degrading HIF-1A through interaction with PSMA7 (PubMed:19362550)","subcellular_location":"Nucleus; Cytoplasm, cytosol; Secreted; Endoplasmic reticulum; Golgi apparatus","url":"https://www.uniprot.org/uniprotkb/Q12904/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/AIMP1","classification":"Not 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blood-brain barrier dysfunction in neuromyelitis optica spectrum disorders.","date":"2025","source":"Clinical and experimental immunology","url":"https://pubmed.ncbi.nlm.nih.gov/41316924","citation_count":0,"is_preprint":false},{"pmid":"41862581","id":"PMC_41862581","title":"The redundant protein synthesis gene Aimp1 challenges the canonical inverse relationship between translation and autophagy.","date":"2026","source":"Communications biology","url":"https://pubmed.ncbi.nlm.nih.gov/41862581","citation_count":0,"is_preprint":false},{"pmid":"39726207","id":"PMC_39726207","title":"Hereditary Spastic Paraplegia Linked to Abnormal Splicing From an AIMP1 Missense Variant.","date":"2024","source":"Clinical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/39726207","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.03.13.643116","title":"Response to anti-angiogenic therapy is affected by AIMP protein family activity in glioblastoma and lower-grade gliomas","date":"2025-03-14","source":"bioRxiv","url":"https://doi.org/10.1101/2025.03.13.643116","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":40788,"output_tokens":7120,"usd":0.114582,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":32612,"output_tokens":11547,"usd":0.32839,"resynth_parse_fail":true,"stage2_stop_reason":"end_turn"},"total_usd":0.442972,"stage1_batch_id":"msgbatch_0179Z2pxRYBsXi2xADneafRw","stage2_batch_id":"msgbatch_01LaY9ZaVdgjWArcZo9eqQE5","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2001,\n      \"finding\": \"The EMAPII cytokine domain of p43/AIMP1 is released from the multisynthetase complex after caspase-7 cleavage in vitro, and the released EMAPII domain can induce migration of human mononuclear phagocytes. The full-length p43/proEMAPII has strong tRNA binding capacity (KD = 0.2 µM), which is lost upon release of the EMAPII domain, suggesting cleavage limits tRNA availability for aminoacyl-tRNA synthetases in the complex.\",\n      \"method\": \"In vitro caspase-7 digestion assay, tRNA binding assay (Kd measurement), mononuclear phagocyte migration assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution of caspase-7 cleavage, quantitative tRNA binding, and functional migration assay in a single rigorous study\",\n      \"pmids\": [\"11306575\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Crystal structure of human EMAPII domain at 1.14 Å resolution reveals that it is a monomer consisting of an OB-fold (Trbp-like) domain and an extra domain related by degenerate 2-fold symmetry, mimicking the dimer interface of bacterial Trbp proteins, and generating a novel OB-fold-based tRNA-binding site.\",\n      \"method\": \"X-ray crystallography (1.14 Å resolution)\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — high-resolution crystal structure with structural validation and mechanistic interpretation\",\n      \"pmids\": [\"11157763\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Crystal structure of the ArgRS–GlnRS–AIMP1 ternary subcomplex shows that the N-terminal helix of AIMP1 forms a coiled-coil with the N-terminal domain of ArgRS and anchors the C-terminal core of GlnRS. Mutation of AIMP1's N-terminal helix destabilizes ArgRS's N-terminal domain and abrogates ArgRS catalytic activity; mutation of ArgRS's N-terminal helix liberates GlnRS. AIMP1 also anchors the ternary complex to AIMP2/p38.\",\n      \"method\": \"X-ray crystallography, site-directed mutagenesis, aminoacylation activity assay, co-immunoprecipitation\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure combined with mutagenesis and functional enzymatic assays in a single rigorous study\",\n      \"pmids\": [\"25288775\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"AIMP1/p43 is an integral component of both the nuclear and cytosolic human multisynthetase complexes, isolated to near homogeneity; gel filtration and immunoblot analysis demonstrate that a major biological role for p43 is as a structural part of the multisynthetase complex.\",\n      \"method\": \"Biochemical fractionation, gel filtration chromatography, immunoblotting, electron microscopy (negative staining)\",\n      \"journal\": \"Protein science : a publication of the Protein Society\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal biochemical methods, single lab\",\n      \"pmids\": [\"14500886\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Structural domain mapping of secreted AIMP1 using deletion fragments established three functionally distinct extracellular domains: aa 101–114 mediates pro-apoptotic activity toward endothelial cells (caspase-3 activation), aa 6–46 mediates fibroblast proliferation, and aa 114–192 mediates endothelial cell migration.\",\n      \"method\": \"Deletion fragment generation, endothelial cell death/caspase-3 assay, fibroblast proliferation assay, endothelial migration assay; elastase 2 cleavage\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — systematic deletion mapping with multiple functional readouts, single lab\",\n      \"pmids\": [\"16472771\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"CD23 (low-affinity IgE receptor) was identified as the functional receptor for AIMP1 that mediates TNF-α secretion from THP-1 monocytic cells and primary human PBMCs. CD23 knockdown attenuated AIMP1 binding and AIMP1-induced TNF-α secretion. AIMP1-induced TNF-α secretion via CD23 involves ERK1/2 activation. Notably, the C-terminal EMAP II fragment of AIMP1 cannot bind CD23 or activate ERK1/2.\",\n      \"method\": \"Screen of 499 soluble receptors, co-immunoprecipitation, CD23 knockdown (siRNA), TNF-α ELISA, ERK1/2 phosphorylation assay, binding assay\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — receptor screen plus reciprocal binding validation, functional knockdown, and signaling pathway identification in multiple cell types\",\n      \"pmids\": [\"22767513\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"TLR4 activation by LPS induces phosphorylation of AIMP1 at serine-140 by JNK (via MyD88 pathway), causing dissociation of AIMP1 from gp96 and resulting in increased gp96 cell surface expression. Alanine mutation of serine-140 suppressed LPS-induced gp96 surface presentation.\",\n      \"method\": \"TLR4/LPS stimulation, JNK inhibitor experiments, site-directed mutagenesis (S140A), co-immunoprecipitation, flow cytometry for gp96 surface expression\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — mutagenesis of specific phosphorylation site combined with signaling pathway dissection and functional readout, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"20510162\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"AIMP1 negatively regulates TGF-β signaling by interacting directly with Smad2 and Smad3, as demonstrated by co-immunoprecipitation and luciferase reporter assay. AIMP1 downregulation by siRNA promotes Smad2/3 phosphorylation and restores chondrogenic differentiation in dedifferentiated and OA-derived degenerated chondrocytes.\",\n      \"method\": \"Co-immunoprecipitation, luciferase reporter assay, siRNA knockdown, Western blot for p-Smad2/3, in vivo mouse implantation model\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP and functional reporter combined with in vivo rescue, single lab\",\n      \"pmids\": [\"26890138\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"HCV envelope protein E2 directly interacts with AIMP1/p43 (by GST pulldown and co-immunoprecipitation) and promotes its degradation via ubiquitin-dependent proteasome pathway. E2 also disrupts the stabilizing interaction between AIMP1 and the ER chaperone grp78, further reducing cellular AIMP1. Loss of AIMP1 caused by E2 results in upregulation of TGF-β signaling and increased surface expression of gp96.\",\n      \"method\": \"GST pulldown, co-immunoprecipitation, confocal immunofluorescence, proteasome inhibitor experiments, TGF-β signaling assay, flow cytometry for gp96 surface expression\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal biochemical methods (GST pulldown, co-IP, proteasome inhibition) with functional downstream readouts, single lab\",\n      \"pmids\": [\"24816397\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"EMAP-II pre-treatment of human endothelial cells does not increase TNF-R1 protein expression but induces redistribution of TNF-R1 from Golgi storage pools to the cell membrane and mobilizes TRADD to the membrane (in separate vesicles from TNF-R1), thereby sensitizing endothelial cells to TNF-induced apoptosis.\",\n      \"method\": \"Flow cytometry, immunofluorescence co-staining, Western blot, apoptosis assay\",\n      \"journal\": \"Apoptosis : an international journal on programmed cell death\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — subcellular localization experiments with functional apoptosis readout, single lab, multiple imaging methods\",\n      \"pmids\": [\"17051333\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Recombinant EMAP-II upregulates TNF-R1 (but not TNF-R2) mRNA and protein expression in human umbilical vein endothelial cells ~4-6 fold within 2 h, and conditioned media from high-EMAP-II expressing cell lines upregulated TNF-R1 by up to 20-fold; effect was blocked by anti-EMAP-II antibody.\",\n      \"method\": \"Northern blot/RT-PCR, ELISA, neutralizing antibody blockade\",\n      \"journal\": \"Cytokine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — functional receptor upregulation shown by multiple methods (mRNA, protein, antibody blockade), replicated across cell lines and in vivo\",\n      \"pmids\": [\"10880244\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"RARS overexpression impairs AIMP1 secretion in HeLa and MCF7 cells, and proteasome inhibition impairs cleavage of AIMP1 to generate mature EMAP II, indicating that the proteasome is involved in proteolytic processing of AIMP1 to produce EMAP II.\",\n      \"method\": \"RARS overexpression, proteasome inhibitor treatment, AIMP1/EMAP II detection (Western blot/ELISA)\",\n      \"journal\": \"Journal of cellular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological and overexpression approaches with biochemical readouts, single lab\",\n      \"pmids\": [\"17443684\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"AIMP1 negatively regulates adipogenesis by directly interacting with the DNA-binding domain of PPARγ via co-immunoprecipitation, thereby inhibiting PPARγ transcriptional activity. AIMP1-deficient cells show augmented adipogenesis compared to controls.\",\n      \"method\": \"Co-immunoprecipitation, luciferase reporter assay, AIMP1 knockout/deficient cells, adipogenesis assay\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct protein-protein interaction with functional transcriptional readout and loss-of-function phenotype, single lab\",\n      \"pmids\": [\"25146391\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Exogenous AIMP1 decreases endothelial cell viability through an α5β1 integrin-dependent mechanism and inhibits cell adhesion. Affinity purification, pulldown, and co-immunoprecipitation demonstrate that AIMP1 interacts with four cytoskeletal proteins: filamin-A, α-tubulin, vinculin, and cingulin. α-Tubulin is phosphorylated upon AIMP1 treatment, and AIMP1 colocalizes with filamin-A and cingulin.\",\n      \"method\": \"Affinity purification, pulldown, co-immunoprecipitation, immunofluorescence, integrin-blocking antibody, cell viability and adhesion assays\",\n      \"journal\": \"Journal of cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — multiple orthogonal binding methods plus functional readouts, single lab\",\n      \"pmids\": [\"21416500\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"AIMP1 promotes osteoclastogenesis and acts synergistically with RANKL; downregulation of CD23 (its receptor) abolishes AIMP1-mediated osteoclastogenesis, confirming that AIMP1 signals through CD23 to promote osteoclast differentiation.\",\n      \"method\": \"Osteoclastogenesis assay, CD23 knockdown, RANKL synergy assay, ELISA for serum AIMP1 in RA patients\",\n      \"journal\": \"Biomaterials\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CD23-dependent mechanism confirmed by knockdown with functional osteoclastogenesis readout, single lab\",\n      \"pmids\": [\"25617125\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"AIMP1 binds and colocalizes with FSCN1 (fascin) in laryngeal squamous cell carcinoma cells, as validated by co-immunoprecipitation/Western blotting and immunofluorescence; knockdown of AIMP1 inhibits LSCC cell proliferation, migration, and invasion.\",\n      \"method\": \"Co-immunoprecipitation, mass spectrometry, immunofluorescence, siRNA knockdown with proliferation/migration/invasion assays\",\n      \"journal\": \"Proteomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — co-IP validated binding partner identified by MS, functional knockdown with phenotypic readout, single lab\",\n      \"pmids\": [\"31287215\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"In multiple myeloma, AIMP1 interacts with ANP32A (acidic leucine-rich nuclear phosphoprotein 32A) to regulate histone H3 acetylation, increasing H3 acetylation enrichment at the GAREM2 locus, which promotes p-ERK1/2 (MAPK pathway activation). AIMP1 also promotes osteoclast differentiation by activating NFATc1.\",\n      \"method\": \"Protein chip assay, co-immunoprecipitation, ChIP-seq, RNA-seq, MTT assay, xenograft model, TRAC staining\",\n      \"journal\": \"Cancer communications (London, England)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — protein chip + co-IP to identify binding partner, ChIP-seq for epigenetic mechanism, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"36042007\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"AIMP1 regulates T cell responses by inhibiting TCR-dependent activation: AIMP1 reduces lipid raft association upon TCR engagement, decreases Ca2+ influx, and downregulates phosphorylation of PLCγ and PI3K in CD4+ T cells. AIMP1 also specifically enhances differentiation of regulatory T (Treg) cells without affecting Th1, Th2, or Th17 differentiation.\",\n      \"method\": \"T cell activation assay, Ca2+ influx measurement, microscopic lipid raft analysis, Western blot for p-PLCγ/p-PI3K, Treg differentiation flow cytometry\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal signaling measurements with functional differentiation readout, single lab\",\n      \"pmids\": [\"31084930\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"AIMp1/p43 absence in bone marrow-derived dendritic cells impairs cytokine production, costimulatory molecule expression, p38 MAPK signaling, and TH1 polarization of co-cultured T cells. AIMp1-deficient DCs showed significantly compromised vaccine-mediated protection against melanoma in vivo, and AIMp1 in the host was critical for antiviral immunity against influenza.\",\n      \"method\": \"AIMp1 knockout BMDC, cytokine ELISA, flow cytometry for costimulatory molecules, p38 MAPK phosphorylation assay, T cell co-culture TH1 polarization assay, in vivo tumor and influenza models\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with multiple orthogonal readouts in vitro and in vivo, single lab\",\n      \"pmids\": [\"29379495\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"AIMP1 deficiency in mice results in spontaneous airway hyperreactivity and TH2-biased immune responses; adoptive transfer of AIMP1-deficient CD4+ T cells to OVA-sensitized mice exacerbates airway inflammation. AIMP1-deficient mice show decreased serum IL-12p40, and AIMP1-deficient lung DCs show increased surface molecule expression, establishing AIMP1 as a negative regulator of TH2 responses in vivo.\",\n      \"method\": \"AIMP1-deficient mouse model, methacholine challenge (Penh values), adoptive transfer of CD4+ T cells, cytokine ELISA, histological analysis\",\n      \"journal\": \"Clinical immunology (Orlando, Fla.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with multiple functional in vivo readouts and adoptive transfer epistasis, single lab\",\n      \"pmids\": [\"22472603\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"An AIMP1-derived peptide (TN41, aa 6–46) is generated by MMP1-mediated cleavage of AIMP1 secreted from Wnt-treated hair follicle stem cells, and this fragment activates dermal papilla cells by activating Akt and ERK, increasing β-catenin. TN41 promotes hair shaft elongation in cultured human hair follicles and enhances DPC spheroid hair-inducing activity. Deletion mapping identified aa 6–46 as the active region.\",\n      \"method\": \"Deletion mapping, MMP1 cleavage assay, Akt/ERK/β-catenin Western blot, hair follicle organ culture, DPC spheroid assay\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — deletion mapping with functional readout and identified protease, multiple downstream signaling assays, single lab\",\n      \"pmids\": [\"39494335\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"AIMP1 derived from dopaminergic neurons is elevated in PD; Aimp1 knockout or knockdown improves DA neuron viability and reduces microglial activation in MPTP-induced PD mouse model. RNA-seq analysis revealed AIMP1 promotes microglial inflammatory response. AIMP1-induced microglial activation is CD23-dependent.\",\n      \"method\": \"MPTP mouse model, Aimp1 KO/KD, immunofluorescence for TH and microglia markers, RNA-seq, ELISA, in vitro MPP+ cell model\",\n      \"journal\": \"CNS neuroscience & therapeutics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO in vivo model with RNA-seq and CD23-dependence established, single lab\",\n      \"pmids\": [\"40522094\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"EMAP-II packaged in macrophage-derived extracellular vesicles (from OGD/R-activated macrophages) is transferred to neutrophils, where it suppresses PI3K/AKT signaling, induces mitochondrial oxidative stress (mtROS), and drives pathological NETs formation in lung ischemia/reperfusion injury. shRNA-mediated EMAP-II knockdown in macrophages abolished OGD/R-EV-induced mtROS and NETs formation and mitigated pulmonary inflammation in mice.\",\n      \"method\": \"Proteomic profiling of EVs, shRNA EMAP-II knockdown, PI3K/AKT pharmacological inhibition, mtROS measurement, NETs assay, mouse LIRI model\",\n      \"journal\": \"Redox biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — proteomic EV identification + shRNA KD + pharmacological inhibition + in vivo model, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"40616949\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"AIMP1 functions as a limiter of autophagy, at least in part by uncoupling mTORC1 activity, while minimally affecting protein synthesis. Depletion of Aimp1 in murine myeloid cells impairs innate immunity kinetics, revealing that Aimp1's redundancy for protein synthesis allows it to reinforce autophagic activity.\",\n      \"method\": \"Gene essentiality genomics analysis, Aimp1 depletion in murine myeloid cells, transcriptomics, mTORC1 activity assays, innate immunity kinetics assay\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Aimp1 depletion with mTORC1 and transcriptomic readouts, single lab, multiple methods\",\n      \"pmids\": [\"41862581\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"AIMP1 upregulates TLR2 protein expression in bone marrow-derived DCs in a time- and dose-dependent manner via NF-κB activation (blocked by BAY11-7082), and enhances TLR2-mediated IL-6 and IL-12 production and costimulatory molecule expression when combined with TLR2 agonists.\",\n      \"method\": \"Flow cytometry, RT-PCR, NF-κB inhibitor (BAY11-7082), ELISA for IL-6/IL-12, costimulatory molecule expression assay\",\n      \"journal\": \"Immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological inhibition of NF-κB confirming pathway, multiple functional readouts, single lab\",\n      \"pmids\": [\"21711348\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"AIMP1 downregulates the tight junction protein ZO-1 in brain microvascular endothelial cells, increasing blood-brain barrier permeability. siRNA knockdown of AIMP1 restored ZO-1 protein levels and reduced BBB permeability. The miRNA let-7f-5p directly targets AIMP1 (validated by luciferase reporter assay) and overexpression of let-7f-5p suppresses AIMP1 and partially rescues ZO-1 levels.\",\n      \"method\": \"siRNA knockdown, Western blot, luciferase reporter assay, Na-F permeability assay, TEER measurement\",\n      \"journal\": \"Clinical and experimental immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA KD with functional barrier readout and validated miRNA regulatory interaction, single lab\",\n      \"pmids\": [\"41316924\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"HLD3-associated frameshift mutant AIMP1 proteins (292CA) localize predominantly to lysosomes where they form aggregates and specifically interact with actin to block actin fiber formation; Q39X mutant also aggregates in lysosomes but without actin interaction. Both 292CA and Q39X mutants inhibit neuronal differentiation in N1E-115 cells; ibuprofen treatment reverses mutant-induced inhibitory differentiation and lysosomal localization.\",\n      \"method\": \"Immunofluorescence (lysosome/organelle localization), immunoprecipitation, actin fiber formation assay, neuronal differentiation assay, ibuprofen treatment\",\n      \"journal\": \"Medicines (Basel, Switzerland)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — subcellular localization, protein-protein interaction by IP, functional differentiation readout, pharmacological rescue, single lab\",\n      \"pmids\": [\"32384815\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"AIMP1/p43 is a multifunctional auxiliary component of the multisynthetase complex (MSC) that structurally scaffolds the MSC by forming a coiled-coil with ArgRS and anchoring GlnRS (crystal structure established); it binds tRNA with high affinity and undergoes caspase-7 cleavage during apoptosis to release the inflammatory cytokine EMAP II, which signals extracellularly through CD23 on monocytes (activating ERK1/2 and TNF-α secretion), redistributes TNF-R1 and TRADD to the plasma membrane in endothelial cells, and acts on distinct structural domains for endothelial apoptosis (aa 101–114), fibroblast proliferation (aa 6–46), and endothelial migration (aa 114–192); intracellularly, AIMP1 is phosphorylated by JNK at Ser-140 downstream of TLR4-MyD88 signaling, causing dissociation from gp96 and its surface translocation, inhibits PPARγ transcriptional activity to suppress adipogenesis, negatively regulates TGF-β signaling via Smad2/3 interaction, and limits mTORC1-coupled autophagy in myeloid cells, while its degradation by HCV E2 through ubiquitin-proteasomal and grp78-displacement mechanisms de-represses both TGF-β signaling and gp96 surface expression.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"AIMP1 (p43/proEMAP II) is a multifunctional auxiliary component of the tRNA multisynthetase complex (MSC) that doubles as the precursor of the secreted inflammatory cytokine EMAP II [#0, #3]. Structurally, AIMP1 scaffolds the MSC: its N-terminal helix forms a coiled-coil with the N-terminal domain of ArgRS, an interaction required for ArgRS catalytic activity, while it anchors GlnRS and bridges the ternary subcomplex to AIMP2/p38 [#2]. Full-length proEMAP II binds tRNA with high affinity through an OB-fold-based site, and caspase-7 cleavage liberates the C-terminal EMAP II domain, abolishing tRNA binding and releasing the cytokine [#0, #1]; proteasome-dependent processing also contributes to mature EMAP II generation [#11]. As a secreted factor, AIMP1 acts through distinct structural domains for endothelial apoptosis (aa 101\\u2013114), fibroblast proliferation (aa 6\\u201346), and endothelial migration (aa 114\\u2013192) [#4], and signals through the receptor CD23 to drive ERK1/2 activation and TNF-\\u03b1 secretion in monocytes and to promote osteoclastogenesis [#5, #14]. Intracellularly, AIMP1 is phosphorylated at Ser-140 by JNK downstream of TLR4\\u2013MyD88, triggering its dissociation from gp96 and increased gp96 surface presentation [#6], and it acts as a broad negative regulator of signaling\\u2014binding Smad2/3 to restrain TGF-\\u03b2 signaling [#7], binding the PPAR\\u03b3 DNA-binding domain to suppress adipogenesis [#12], and limiting mTORC1-coupled autophagy in myeloid cells [#23]. Genetically, frameshift mutant AIMP1 proteins associated with hypomyelinating leukodystrophy (HLD3) mislocalize to lysosomes, form aggregates, sequester actin, and impair neuronal differentiation [#26].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Established that AIMP1 is a tRNA-binding precursor whose proteolytic cleavage couples loss of synthetase-complex function to release of a phagocyte-recruiting cytokine.\",\n      \"evidence\": \"In vitro caspase-7 digestion, quantitative tRNA binding (KD = 0.2 \\u00b5M), and mononuclear phagocyte migration assay\",\n      \"pmids\": [\"11306575\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the receptor mediating phagocyte migration\", \"In vivo trigger for caspase-7 cleavage not established\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Defined the atomic architecture of the EMAP II cytokine domain, showing how an OB-fold creates a novel tRNA-binding surface.\",\n      \"evidence\": \"1.14 \\u00c5 X-ray crystallography of the human EMAP II domain\",\n      \"pmids\": [\"11157763\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structure of the full-length protein and its MSC contacts not solved here\", \"Does not address how cleavage abolishes tRNA binding\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Confirmed AIMP1 as an integral structural subunit of both nuclear and cytosolic MSC, framing its synthetase-scaffolding role.\",\n      \"evidence\": \"Biochemical fractionation, gel filtration, immunoblotting, and electron microscopy\",\n      \"pmids\": [\"14500886\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not resolve specific synthetase contacts\", \"Functional distinction between nuclear and cytosolic pools unclear\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Resolved the molecular logic of AIMP1's scaffolding role: its N-terminal helix stabilizes ArgRS and anchors GlnRS, linking AIMP1 structure to synthetase catalytic activity.\",\n      \"evidence\": \"Crystal structure of the ArgRS\\u2013GlnRS\\u2013AIMP1 subcomplex with mutagenesis and aminoacylation assays\",\n      \"pmids\": [\"25288775\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full MSC assembly architecture beyond the ternary core not resolved\", \"How cytokine release reshapes the complex not addressed\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Mapped distinct extracellular functions of secreted AIMP1 to separate structural domains, explaining its pleiotropic activity on different cell types.\",\n      \"evidence\": \"Deletion fragment mapping with endothelial apoptosis, fibroblast proliferation, and migration assays plus elastase 2 cleavage\",\n      \"pmids\": [\"16472771\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Receptors for each domain not all identified\", \"Physiological proteases generating each fragment in vivo unclear\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identified CD23 as a functional AIMP1 receptor driving ERK1/2-dependent TNF-\\u03b1 secretion, providing a defined extracellular signaling axis.\",\n      \"evidence\": \"Soluble-receptor screen, reciprocal binding, CD23 siRNA knockdown, and TNF-\\u03b1/ERK readouts in monocytes\",\n      \"pmids\": [\"22767513\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of AIMP1\\u2013CD23 binding unknown\", \"Why the EMAP II fragment cannot engage CD23 not explained\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Linked TLR4 signaling to AIMP1 post-translational control, showing JNK phosphorylation at Ser-140 governs gp96 surface presentation.\",\n      \"evidence\": \"LPS/TLR4 stimulation, JNK inhibition, S140A mutagenesis, co-IP, and flow cytometry for surface gp96\",\n      \"pmids\": [\"20510162\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream consequence of surface gp96 for immunity not defined here\", \"Whether Ser-140 phosphorylation affects MSC association unknown\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Established AIMP1 as an intracellular brake on signaling through direct Smad2/3 and PPAR\\u03b3 interactions, controlling TGF-\\u03b2 output and adipogenesis.\",\n      \"evidence\": \"Co-IP, luciferase reporters, siRNA/knockout cells with chondrogenic and adipogenesis readouts\",\n      \"pmids\": [\"26890138\", \"25146391\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural mode of Smad and PPAR\\u03b3 binding not determined\", \"Whether these functions require free or MSC-bound AIMP1 unclear\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Showed viral hijacking of AIMP1 stability by HCV E2, connecting AIMP1 degradation to de-repression of TGF-\\u03b2 signaling and gp96 surface expression.\",\n      \"evidence\": \"GST pulldown, co-IP, proteasome inhibition, grp78-displacement analysis, and downstream signaling readouts\",\n      \"pmids\": [\"24816397\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"E3 ligase mediating AIMP1 ubiquitination not identified\", \"Relevance to HCV pathogenesis in vivo not established\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Clarified how secreted EMAP II sensitizes endothelium to apoptosis by trafficking TNF-R1 and TRADD to the membrane rather than altering receptor levels.\",\n      \"evidence\": \"Flow cytometry, immunofluorescence co-staining, and apoptosis assays in endothelial cells\",\n      \"pmids\": [\"17051333\", \"10880244\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Receptor mediating EMAP II uptake/signaling not defined\", \"Reconciliation of transcriptional vs. trafficking effects across studies\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Extended AIMP1's extracellular targets to the cytoskeleton and integrins, linking it to endothelial viability and adhesion control.\",\n      \"evidence\": \"Affinity purification, pulldown, co-IP, immunofluorescence, and \\u03b15\\u03b21 integrin blockade with viability/adhesion assays\",\n      \"pmids\": [\"21416500\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs. indirect cytoskeletal interactions not separated\", \"Functional significance of \\u03b1-tubulin phosphorylation unclear\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Defined AIMP1 as a regulator of adaptive and innate immunity in vivo, shaping dendritic cell function, T-cell polarization, and antiviral/antitumor protection.\",\n      \"evidence\": \"AIMP1-knockout/deficient mice, BMDC and T-cell assays, and in vivo tumor, influenza, and airway models\",\n      \"pmids\": [\"29379495\", \"22472603\", \"31084930\", \"21711348\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether immune phenotypes reflect intracellular or secreted AIMP1 not resolved\", \"Receptors mediating each immune effect not uniformly defined\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Revealed disease-context AIMP1 partnerships in cancer, including ANP32A-dependent histone acetylation and fascin binding that drive proliferation and invasion.\",\n      \"evidence\": \"Protein chip, co-IP, mass spectrometry, ChIP-seq, and knockdown phenotyping in myeloma and laryngeal carcinoma\",\n      \"pmids\": [\"36042007\", \"31287215\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Generality of these interactions beyond specific tumors unknown\", \"Direct vs. complex-mediated nature of ANP32A effect on chromatin unclear\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified an autophagy-limiting function for AIMP1 via mTORC1 uncoupling, distinguishing it from its synthetase role and tying it to innate immune kinetics.\",\n      \"evidence\": \"Gene-essentiality analysis, Aimp1 depletion in murine myeloid cells, mTORC1 assays, and transcriptomics\",\n      \"pmids\": [\"41862581\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular link between AIMP1 and mTORC1 not defined\", \"Whether autophagy role requires MSC dissociation unknown\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Connected HLD3 leukodystrophy mutations to a cellular defect: mutant AIMP1 mislocalizes to lysosomes, aggregates, sequesters actin, and blocks neuronal differentiation.\",\n      \"evidence\": \"Immunofluorescence localization, immunoprecipitation, actin fiber and neuronal differentiation assays with ibuprofen rescue\",\n      \"pmids\": [\"32384815\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which mutants are routed to lysosomes unclear\", \"Whether loss of MSC function contributes to leukodystrophy not addressed\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How AIMP1 partitions between its MSC-scaffolding role and its diverse secreted-cytokine and intracellular-regulatory functions, and what governs the switch, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model linking MSC residence, cleavage, and secretion\", \"Receptor identity for several extracellular activities undefined\", \"Structural basis of CD23, Smad, and PPAR\\u03b3 binding unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [2, 3]},\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [5, 14]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [7, 12]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [4, 5]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"GO:0005764\", \"supporting_discovery_ids\": [26]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [2, 3]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [5, 6, 18, 19]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [7, 12]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [23]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [9, 4]}\n    ],\n    \"complexes\": [\n      \"multisynthetase complex (MSC)\"\n    ],\n    \"partners\": [\n      \"RARS\",\n      \"QARS\",\n      \"AIMP2\",\n      \"CD23\",\n      \"SMAD2\",\n      \"SMAD3\",\n      \"PPARG\",\n      \"gp96\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}