{"gene":"RAE1","run_date":"2026-06-10T06:43:36","timeline":{"discoveries":[{"year":1995,"finding":"S. pombe Rae1 is required for nuclear export of poly(A)+ RNA; temperature-sensitive rae1-1 mutant accumulates poly(A)+ RNA in the nucleus within 30 min at restrictive temperature. Rae1 encodes a WD40-repeat protein, and loss of function also causes actin/tubulin disorganization and irreversible cell cycle arrest, with cells being particularly vulnerable during G2/M.","method":"Fluorescence in situ hybridization (FISH) to detect poly(A)+ RNA localization; complementation cloning; temperature-shift experiments","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct genetic identification in fission yeast with orthogonal readouts (poly(A)+ RNA export, cytoskeletal phenotype, cell cycle arrest), replicated in multiple follow-up studies","pmids":["7706287"],"is_preprint":false},{"year":1996,"finding":"S. cerevisiae Gle2 (ortholog of RAE1) associates with nuclear pore complexes and is required for poly(A)+ RNA export but not nuclear protein import; gle2 mutants show severe NPC and nuclear envelope structural perturbations. Two-hybrid interactions with Srp1p (NLS receptor) and Rip1p (NES-interacting protein) were detected.","method":"Indirect immunofluorescence; NPC fractionation; colony-sectoring genetic screen; thin-section electron microscopy; two-hybrid assay","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (IF, fractionation, EM, genetics), foundational study replicated across organisms","pmids":["8970155"],"is_preprint":false},{"year":1997,"finding":"Human RAE1 is a functional homolog of S. pombe rae1; human RAE1 cDNA partially suppresses the temperature-sensitivity and poly(A)+ RNA export defect of the rae1-1 mutant. Epitope-tagged human Rae1 localizes to both nucleus and cytoplasm in HeLa cells.","method":"Cross-species complementation in S. pombe; FISH for poly(A)+ RNA; immunofluorescence in HeLa cells","journal":"Gene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional rescue plus localization, single lab, partial suppression only","pmids":["9370289"],"is_preprint":false},{"year":1997,"finding":"S. pombe Rae1 is required for cell cycle progression through mitosis independent of mRNA export; rae1-loss cells arrest with elevated Cdc2p kinase before spindle formation and without spindle pole body separation. Rae1p localizes to the nuclear periphery.","method":"Temperature-shift cell cycle analysis; Cdc2p kinase assay; immunofluorescence localization","journal":"Yeast","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cell cycle kinetics plus kinase assay and localization, single lab","pmids":["9301023"],"is_preprint":false},{"year":1999,"finding":"Mammalian RAE1 binds directly to a GLEBS-like motif within NUP98 at the nuclear pore complex through multiple domains including WD-repeats and a C-terminal non-WD extension. RAE1 shuttles between nucleus and cytoplasm in a temperature-dependent, RanGTP-independent manner. NE docking of RAE1 requires new mRNA synthesis. Overexpression of the GLEBS-like motif inhibits NE binding of RAE1 and induces nuclear poly(A)+ RNA accumulation, effects reversed by RAE1 overexpression.","method":"In vitro binding studies; chemical cross-linking; microinjection in Xenopus oocytes; overexpression/dominant-negative experiments; FISH for poly(A)+ RNA","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution of direct binding, cross-linking, functional oocyte microinjection, multiple orthogonal methods","pmids":["10209021"],"is_preprint":false},{"year":2000,"finding":"Ct-RAE1 (Chironomus tentans ortholog) does not associate with mRNPs co-transcriptionally or in the nucleoplasm; instead, it interacts with exported BR RNP particles specifically at the nuclear pore complex. RAE1 is not found on the cytoplasmic side of the RNP in transit, suggesting it remains anchored at the nuclear face of the NPC or is rapidly released.","method":"Immunoelectron microscopy on Balbiani ring RNP particles","journal":"RNA","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct ultrastructural localization, single lab, single method","pmids":["11105759"],"is_preprint":false},{"year":2003,"finding":"Mammalian Rae1 haploinsufficiency causes mitotic checkpoint defects and chromosome missegregation in vivo; Rae1-null mice are embryonic lethal. Overexpression of Rae1 can rescue both Rae1 and Bub3 haploinsufficiency. Combined Rae1/Bub3 haploinsufficiency greatly amplifies premature sister chromatid separation. Rae1 and Bub3 have essential, overlapping roles in the mitotic checkpoint. Cells from Rae1/Bub3-null mice show no detectable defect in mRNA nuclear export.","method":"Knockout mouse generation; cytogenetic analysis; spindle checkpoint assays; mRNA export assays; overexpression rescue experiments","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo genetic knockout with multiple orthogonal functional readouts, reproduced across genotypes","pmids":["12551952"],"is_preprint":false},{"year":2003,"finding":"Rae1, Nup98, and TAP form a ternary complex at the nuclear pore. Gle2/Rae1 requires two sites within TAP for stable interaction. TAP has highest affinity for a specific region within the GLFG domain of Nup98. When Rae1 is bound to Nup98, it no longer interacts directly with TAP, suggesting a mechanism where Rae1 may deliver TAP to Nup98.","method":"In vitro binding assays; definition of binary and ternary complexes by pull-down and competition experiments","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct in vitro binding with competition, single lab, multiple binary pairs tested","pmids":["12637516"],"is_preprint":false},{"year":2005,"finding":"VSV matrix (M) protein inhibits host mRNA nuclear export by binding the mRNA export factor Rae1/mrnp41. A M protein mutant defective in Rae1 binding cannot inhibit mRNA export. Overexpression of Rae1 fully reverses M protein-mediated inhibition of mRNA export. Rae1 is induced by interferon-gamma.","method":"Co-immunoprecipitation; dominant-negative M protein mutant; mRNA export assay; overexpression rescue; IFN-gamma treatment","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — binding mapped to M protein domain, rescued by Rae1 overexpression, mutant validation, multiple orthogonal methods","pmids":["15629720"],"is_preprint":false},{"year":2005,"finding":"Rae1 is a microtubule-associated protein and spindle assembly factor regulated by the RanGTP/importin-beta pathway. Rae1 binds directly to importin beta. Depletion of Rae1 from Xenopus egg extracts or cells severely inhibits mitotic spindle assembly. A purified Rae1-containing ribonucleoprotein complex stabilizes microtubules in a RanGTP/importin beta-regulated manner, and this activity requires RNA.","method":"Activity-based biochemical purification from Xenopus egg extracts; immunodepletion; in vitro microtubule stabilization assay; direct binding assay with importin beta","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — biochemical purification, reconstitution in egg extracts, immunodepletion with specific phenotype, direct binding assay, multiple orthogonal methods","pmids":["15851029"],"is_preprint":false},{"year":2005,"finding":"Rae1 and Nup98 form a complex with Cdh1-activated APC (APC(Cdh1)) in early mitosis and specifically inhibit APC(Cdh1)-mediated ubiquitination of securin, preventing premature securin degradation until the metaphase/anaphase transition. Combined Rae1/Nup98 haploinsufficiency in mice results in premature sister chromatid separation, severe aneuploidy, and untimely securin degradation.","method":"Co-immunoprecipitation of APC(Cdh1) complex; ubiquitination assay; haploinsufficient mouse genetics; cytogenetic analysis; securin degradation timing assay","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro ubiquitination assay, co-IP, in vivo mouse genetics, multiple orthogonal methods in single rigorous study","pmids":["16355229"],"is_preprint":false},{"year":2006,"finding":"The Rae1-Nup98 complex also forms a complex with securin in prometaphase. This complex does not prevent APC(Cdh1) from binding securin, but instead prevents ubiquitination of APC(Cdh1)-bound securin, priming rapid securin degradation after dissociation of Rae1-Nup98 at the metaphase/anaphase transition.","method":"Co-immunoprecipitation; cell cycle timing analysis; genetic mouse models","journal":"Cell cycle","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP evidence with mechanistic interpretation, single lab, supported by existing mouse genetics","pmids":["16479161"],"is_preprint":false},{"year":2006,"finding":"Rae1 interacts with the nuclear mitotic apparatus protein NuMA in a mitosis-specific manner. A specific binding site for Rae1 on NuMA was mapped. This interaction is required for bipolar spindle formation; reducing Rae1 or increasing NuMA causes spindle abnormalities. Coupling NuMA overexpression with Rae1 overexpression, or depleting both simultaneously, prevents aberrant spindle formation. Overexpression of the Rae1-binding domain of NuMA in HeLa cells causes aberrant spindles.","method":"Co-immunoprecipitation; domain mapping; siRNA knockdown and overexpression in HeLa cells; spindle morphology analysis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal genetic rescue, domain mapping, multiple cell biology readouts, single lab with multiple orthogonal approaches","pmids":["17172455"],"is_preprint":false},{"year":2008,"finding":"Retinoic acid downregulates Rae1 expression in human SH-SY5Y neuroblastoma cells, thereby facilitating APC(Cdh1)-mediated Skp2 degradation, p27 stabilization, and neuroblastoma differentiation. Rae1 overexpression promotes Skp2 accumulation and prevents retinoic acid-induced cell cycle arrest; Rae1 inhibition accelerates differentiation.","method":"Western blotting; siRNA knockdown; overexpression; cell cycle analysis; measurement of Skp2 and p27 levels","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA knockdown and rescue with defined molecular readouts, single lab","pmids":["18212744"],"is_preprint":false},{"year":2010,"finding":"Crystal structure of human Rae1 in complex with the Nup98 GLEBS motif determined at 1.65 Å resolution. Rae1 forms a seven-bladed beta-propeller. The Nup98 GLEBS motif forms an ~50 Å-long hairpin binding to an invariant hydrophobic surface on the top face of Rae1. The C-terminal arm of the GLEBS hairpin is necessary and sufficient for Rae1 binding; a tandem glutamate element in this arm is critical. The Rae1-Nup98 complex possesses single-stranded RNA-binding capability via a conserved basic patch.","method":"X-ray crystallography at 1.65 Å; mutagenesis of GLEBS motif; in vitro RNA-binding assay","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — high-resolution crystal structure plus mutagenesis and biochemical validation of RNA binding","pmids":["20498086"],"is_preprint":false},{"year":2011,"finding":"RNAi knockdown of NUP98 in human cells disrupts RAE1 expression and localization (but not HDAC1). Rescue experiments show that the RAE1-NUP98 complex orchestrates proper chromosome segregation. In NUP98-HOXA9-transfected cells, RAE1 protein is reduced and mis-localized. This is confirmed in NUP98-HOXA9 transgenic mice and AML patient samples.","method":"RNAi knockdown; rescue experiments; immunofluorescence localization; chromosome segregation assays; transgenic mouse analysis; patient sample analysis","journal":"Cell cycle","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional rescue and multiple cellular readouts, single lab","pmids":["21467841"],"is_preprint":false},{"year":2011,"finding":"Drosophila Rae1 is a component of the Highwire (Hiw)/Fsn E3 ubiquitin ligase complex in post-mitotic neurons. Rae1 physically and genetically interacts with Hiw. Loss of Rae1 in neurons produces NMJ morphological defects similar to hiw mutants. Rae1 is necessary and sufficient to promote Hiw protein abundance by binding Hiw and protecting it from autophagy-mediated degradation.","method":"Tandem affinity purification; co-immunoprecipitation; genetic epistasis; loss-of-function neuronal phenotype analysis; autophagy inhibitor experiments","journal":"Nature neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — TAP identification, co-IP, genetic epistasis, multiple orthogonal methods establishing mechanism of Hiw stabilization","pmids":["21874015"],"is_preprint":false},{"year":2012,"finding":"VSV M protein forms multiple distinct complexes with Rae1 and Nup98 (high, intermediate, and low molecular weight). The intermediate MW complexes containing Nup98 interact most efficiently with M protein. Silencing Rae1 reduces VSV's ability to inhibit host transcription but does not affect nuclear mRNA accumulation or inhibition of translation. M protein-Rae1-Nup98 complexes associate with the chromatin fraction, suggesting a role in inhibiting host transcription.","method":"Size exclusion chromatography; sedimentation velocity analysis; siRNA silencing; mRNA export assay; translation assay; chromatin fractionation","journal":"PLoS pathogens","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — biochemical complex characterization plus functional siRNA data, single lab","pmids":["23028327"],"is_preprint":false},{"year":2013,"finding":"Drosophila Rae1 localizes to the nuclear envelope and is required for normal male meiosis: rae1 mutants display defects in primary spermatocyte nuclear integrity, meiotic chromosome condensation, segregation, and spindle morphology, leading to failure to complete meiosis. GFP-RAE1 dynamically localizes to the nuclear envelope, chromatin, and other structures during spermatogenesis.","method":"Genetic mutant analysis; immunofluorescence; GFP-RAE1 live imaging; RNAi","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — defined genetic loss-of-function with specific cytological phenotype and live imaging, single lab","pmids":["23788425"],"is_preprint":false},{"year":2014,"finding":"Crystal structure of VSV M protein in complex with Rae1 and Nup98 at 3.15 Å resolution. M protein contacts the Rae1-Nup98 heterodimer via two protrusions (finger and thumb). The conserved Met51 of M inserts into a deep hydrophobic pocket on the Rae1 beta-propeller; flanking acidic residues bond to a basic groove on Rae1. M protein competes with oligonucleotides for binding to Rae1-Nup98 in vitro. A synthetic peptide corresponding to the finger competes for nucleic acid binding, suggesting Rae1 binds the phosphate backbone of any nucleic acid and M mimics this ligand.","method":"X-ray crystallography at 3.15 Å; in vitro nucleic acid competition binding assay; synthetic peptide competition","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — high-resolution crystal structure, in vitro competition assay, structural rationalization of mechanism","pmids":["24927547"],"is_preprint":false},{"year":2016,"finding":"The Hippo pathway targets Rae1 for degradation downstream of Warts/Lats. In proliferating cells, Rae1 loss restricts cyclin B levels and organ size; Rae1 overexpression increases cyclin B and organ size. Reducing Rae1 blocks cyclin B accumulation and suppresses overgrowth caused by Hippo pathway loss. Rae1 also acts in a feedback circuit to increase protein levels of Merlin, Hippo, and Warts and to reduce Yki/YAP levels.","method":"Genetic epistasis in Drosophila tissues and cells; biochemical studies; mammalian cell overexpression/knockdown; cyclin B and organ size measurements","journal":"PLoS genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic and biochemical evidence in two systems, single lab","pmids":["27494403"],"is_preprint":false},{"year":2018,"finding":"USP11 is a deubiquitinating enzyme for RAE1; USP11 controls RAE1 ubiquitination at the mitotic spindle. USP11 localizes to the mitotic spindle and its knockdown (or RAE1 knockdown) reduces cell proliferation and increases multipolar spindle formation. USP11 does not regulate spindle assembly checkpoint inactivation but modulates RAE1's interaction with NuMA.","method":"Lentiviral knockdown; co-immunoprecipitation; ubiquitination assay; spindle morphology analysis; localization by immunofluorescence","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — deubiquitination assay plus functional spindle phenotype and NuMA interaction modulation, single lab","pmids":["29293652"],"is_preprint":false},{"year":2019,"finding":"RAE1 directly binds to the promoter region of the EMT transcription factor ZEB1 in breast cancer cells, mediating its upregulation. RAE1 overexpression induces EMT and invasive/migratory behavior; ZEB1 knockdown in RAE1-overexpressing cells suppresses invasiveness and restores epithelial markers.","method":"ChIP (promoter binding assay); siRNA knockdown of ZEB1 in RAE1-overexpressing cells; 3D culture; xenograft models; invasion/migration assays","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct promoter binding demonstrated, epistatic rescue, in vivo xenograft, single lab","pmids":["30814639"],"is_preprint":false},{"year":2021,"finding":"SARS-CoV-2 ORF6 blocks nuclear mRNA export and inhibits nuclear import of host proteins by co-purifying with Rae1 and Nup98. Interactions map to the C terminus of ORF6 and a single mutation at Met58 abolishes binding. Overexpression of Rae1 restores reporter expression suppressed by ORF6. SARS-CoV-2 ORF6 more strongly copurifies with Rae1 and Nup98 than SARS-CoV ORF6.","method":"Co-immunoprecipitation; site-directed mutagenesis (Met58); reporter assay; nuclear mRNA accumulation assay; overexpression rescue","journal":"mBio","confidence":"High","confidence_rationale":"Tier 2 / Strong — binding mapped by mutagenesis, functional rescue by Rae1 overexpression, multiple orthogonal methods, comparator SARS-CoV-1 vs SARS-CoV-2","pmids":["33849972"],"is_preprint":false},{"year":2022,"finding":"Crystal structures of both SARS-CoV-2 and SARS-CoV-1 ORF6 C-termini in complex with the Rae1-Nup98 heterodimer were determined. ORF6 occupies the same potential mRNA-binding groove of the Rae1-Nup98 complex as VSV M protein. The conserved Met58 of ORF6 is critical for complex formation and competitive inhibition of RNA binding to Rae1-Nup98.","method":"X-ray crystallography; biochemical binding assays; site-directed mutagenesis; RNA competition binding assay","journal":"Frontiers in molecular biosciences","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structures for both viral orthologs, mutagenesis of critical residue, biochemical validation, multiple orthogonal methods","pmids":["35096974"],"is_preprint":false},{"year":2023,"finding":"NUP98 and RAE1 are highly expressed in epidermal progenitors and form a distinct nucleoplasmic complex. Reduction of NUP98 or RAE1 abolishes progenitor regenerative capacity, inhibiting proliferation and inducing premature terminal differentiation. NUP98 binds chromatin near transcription start sites of key epigenetic regulators (DNMT1, UHRF1, EZH2) co-occupied by HDAC1. HDAC inhibition diminishes NUP98 chromatin binding and induces NUP98 and RAE1 to relocalize interdependently to the nucleolus.","method":"siRNA knockdown; ChIP; immunofluorescence fractionation; HDAC inhibitor treatment; proliferation and differentiation assays","journal":"Communications biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and functional knockdown with defined readouts, HDAC inhibitor mechanistic dissection, single lab","pmids":["37353594"],"is_preprint":false},{"year":2024,"finding":"Rae1 is required to position SARS-CoV-2 ORF6 within the NPC to inhibit nucleocytoplasmic transport. Loss of Rae1 suppresses ORF6's transport inhibitory activity. Rae1 alone is not necessary for p-STAT1 import or poly(A) RNA export under normal conditions. Rae1 is also required for normal viral protein production during SARS-CoV-2 infection, presumably through supporting ORF6 function.","method":"siRNA knockdown of Rae1; nuclear transport assays (p-STAT1 import, poly(A) RNA export); SARS-CoV-2 infection; viral protein production assay","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional knockdown with specific transport readouts, epistatic relationship with ORF6 established, single lab","pmids":["38507240"],"is_preprint":false},{"year":2023,"finding":"RAE1 regulates PPARα mRNA stability in esophageal epithelial cells; RAE1 knockdown causes G2/M cell cycle blockade and reduced lipid accumulation, phenocopied by PPARα downregulation. RAE1 overexpression promotes malignant transformation by maintaining PPARα mRNA stability.","method":"siRNA knockdown; overexpression; mRNA stability assay; cell cycle analysis; xenograft tumor model","journal":"Ecotoxicology and environmental safety","confidence":"Low","confidence_rationale":"Tier 3 / Weak — mRNA stability linkage inferred from knockdown/overexpression without direct biochemical demonstration of binding or decay mechanism, single lab","pmids":["37774541"],"is_preprint":false}],"current_model":"RAE1 (Gle2/Mnrp41) is a conserved WD40/beta-propeller protein that functions at the nuclear pore complex as a direct binding partner of NUP98 (via the GLEBS motif), where the Rae1–Nup98 complex binds single-stranded RNA to facilitate mRNA export; in mitosis, Rae1 moonlights as a spindle assembly factor that associates with microtubules through a RanGTP/importin-beta-regulated ribonucleoprotein complex, interacts with NuMA to support bipolar spindle formation, and inhibits APC(Cdh1)-mediated ubiquitination of securin to prevent premature anaphase onset, while in post-mitotic neurons it stabilizes the Highwire E3 ubiquitin ligase by protecting it from autophagy, and its RNA-binding groove on the Rae1–Nup98 complex surface is exploited by multiple viruses (VSV M protein, SARS-CoV-2 ORF6) through a conserved methionine-containing motif that competitively displaces RNA cargo to block host mRNA export."},"narrative":{"mechanistic_narrative":"RAE1 (Gle2/Mnrp41) is an evolutionarily conserved WD40 protein that folds into a seven-bladed beta-propeller and functions both at the nuclear pore complex in mRNA export and as a moonlighting regulator of mitotic spindle assembly and chromosome segregation [PMID:7706287, PMID:15851029, PMID:20498086]. At the NPC, RAE1 binds directly to a GLEBS-like motif of NUP98 through its WD-repeats and a C-terminal extension, and this docking — which depends on ongoing mRNA synthesis — is required for nuclear export of poly(A)+ RNA [PMID:10209021, PMID:8970155]. The 1.65 Å crystal structure shows the Nup98 GLEBS motif binding as an extended hairpin to the propeller's top face, and reveals that the Rae1–Nup98 complex acquires single-stranded RNA-binding capability through a conserved basic patch [PMID:20498086]. RAE1 also bridges NUP98 to the export receptor TAP within a ternary complex, consistent with a role in delivering cargo at the pore [PMID:12637516]. Independent of export, RAE1 acts as a microtubule-associated spindle assembly factor: a RanGTP/importin-β–regulated, RNA-containing RAE1 ribonucleoprotein stabilizes microtubules, RAE1 binds importin-β directly, and it interacts mitosis-specifically with NuMA to support bipolar spindle formation [PMID:15851029, PMID:17172455]. RAE1, together with NUP98, restrains APC(Cdh1) by blocking ubiquitination of APC(Cdh1)-bound securin until the metaphase/anaphase transition, and RAE1 cooperates genetically with BUB3 in the mitotic checkpoint; haploinsufficiency causes premature sister-chromatid separation, aneuploidy, and embryonic lethality in mice [PMID:12551952, PMID:16355229, PMID:16479161]. RAE1 abundance at the spindle is set by ubiquitination opposed by the deubiquitinase USP11 [PMID:29293652]. Beyond proliferating cells, Drosophila RAE1 is a component of the Highwire/Fsn E3 ligase complex in post-mitotic neurons, where it binds and stabilizes Highwire by protecting it from autophagy [PMID:21874015]. The Rae1–Nup98 RNA-binding groove is a recurrent viral target: VSV matrix protein and SARS-CoV-2 ORF6 dock through a conserved methionine-containing motif (M Met51, ORF6 Met58) that competitively displaces nucleic acid to block host mRNA export, with RAE1 also positioning ORF6 within the NPC [PMID:15629720, PMID:24927547, PMID:33849972, PMID:35096974, PMID:38507240].","teleology":[{"year":1995,"claim":"Established RAE1 as an essential factor for nuclear export of poly(A)+ RNA, defining its core cellular role and its identity as a WD40-repeat protein.","evidence":"Temperature-sensitive rae1-1 mutant analysis with FISH for poly(A)+ RNA and complementation cloning in S. pombe","pmids":["7706287"],"confidence":"High","gaps":["Molecular partners at the pore not yet identified","Cytoskeletal and cell-cycle phenotypes left mechanistically unexplained"]},{"year":1996,"claim":"Localized the ortholog (Gle2) physically to nuclear pore complexes and showed its loss perturbs NPC/nuclear envelope architecture, tying export function to the pore itself.","evidence":"Immunofluorescence, NPC fractionation, EM and genetic screening in S. cerevisiae","pmids":["8970155"],"confidence":"High","gaps":["Direct NPC anchoring partner not defined","Mechanism of structural perturbation unresolved"]},{"year":1997,"claim":"Demonstrated functional conservation to human RAE1 and separated its mitotic role from mRNA export in yeast, hinting at a moonlighting function.","evidence":"Cross-species complementation in S. pombe and Cdc2p kinase/cell-cycle analysis","pmids":["9370289","9301023"],"confidence":"Medium","gaps":["Partial suppression only","Mitotic mechanism unknown at this stage"]},{"year":1999,"claim":"Identified NUP98 as the direct NPC-docking partner via a GLEBS-like motif and tied RAE1 docking to active mRNA synthesis, providing the molecular basis for export function.","evidence":"In vitro binding, cross-linking and Xenopus oocyte microinjection with dominant-negative GLEBS overexpression","pmids":["10209021"],"confidence":"High","gaps":["Structural basis of binding not yet resolved","How RNA cargo is engaged unclear"]},{"year":2003,"claim":"Resolved RAE1's in vivo function as a mitotic checkpoint factor cooperating with BUB3, showing chromosome-segregation roles can be genetically separated from mRNA export.","evidence":"Knockout/haploinsufficient mouse genetics with cytogenetics, checkpoint assays and mRNA export assays","pmids":["12551952"],"confidence":"High","gaps":["Biochemical mechanism linking RAE1 to checkpoint not defined","Relationship between BUB3 and NUP98 roles unclear"]},{"year":2003,"claim":"Placed RAE1 in a NUP98–TAP ternary complex, suggesting it functions as an adaptor that hands export cargo/receptor to NUP98.","evidence":"In vitro binary/ternary complex reconstitution with competition pull-downs","pmids":["12637516"],"confidence":"Medium","gaps":["Delivery model not directly demonstrated in cells","Single lab in vitro evidence"]},{"year":2005,"claim":"Defined the dual mitotic mechanisms: RAE1 as a RanGTP/importin-β–regulated, RNA-dependent microtubule-stabilizing RNP, and as an APC(Cdh1) inhibitor protecting securin from premature ubiquitination.","evidence":"Xenopus egg extract purification, immunodepletion, in vitro microtubule and ubiquitination assays, and haploinsufficient mouse genetics","pmids":["15851029","16355229"],"confidence":"High","gaps":["Identity of the RNA in the spindle RNP unknown","How RAE1 senses the metaphase/anaphase transition unresolved"]},{"year":2005,"claim":"Revealed RAE1 as a direct viral target, with VSV M protein binding it to block host mRNA export, establishing RAE1 as a host-pathogen interface.","evidence":"Co-immunoprecipitation, M-protein binding mutant and Rae1 overexpression rescue of export","pmids":["15629720"],"confidence":"High","gaps":["Structural basis of M–RAE1 interaction not yet defined","Whether NUP98 participates not established here"]},{"year":2006,"claim":"Refined the securin-protection mechanism and identified NuMA as the mitotic spindle partner mediating bipolar spindle assembly.","evidence":"Co-IP, domain mapping and reciprocal knockdown/overexpression rescue in HeLa cells; cell-cycle timing analyses","pmids":["16479161","17172455"],"confidence":"High","gaps":["How RAE1–NuMA binding is regulated within the cycle unclear","Securin-priming model rests on co-IP interpretation"]},{"year":2010,"claim":"Provided atomic resolution of the RAE1 beta-propeller bound to the Nup98 GLEBS hairpin and demonstrated the complex's intrinsic single-stranded RNA-binding via a basic patch, unifying the structural and functional pictures.","evidence":"1.65 Å X-ray crystallography with GLEBS mutagenesis and in vitro RNA-binding assay","pmids":["20498086"],"confidence":"High","gaps":["Sequence specificity of RNA binding not defined","Link between this RNA groove and spindle RNP unestablished"]},{"year":2011,"claim":"Extended RAE1 function into post-mitotic neurons as a Highwire E3-ligase component that stabilizes Highwire against autophagy, a role distinct from export and mitosis.","evidence":"Tandem affinity purification, co-IP, genetic epistasis and autophagy-inhibitor experiments in Drosophila","pmids":["21874015"],"confidence":"High","gaps":["Whether this neuronal role is conserved in mammals untested in corpus","Mechanism of autophagy protection unresolved"]},{"year":2011,"claim":"Showed NUP98 controls RAE1 expression and localization and that the complex governs chromosome segregation, with disruption in NUP98-HOXA9 leukemia.","evidence":"RNAi, rescue, IF localization and chromosome segregation assays with transgenic mouse and patient samples","pmids":["21467841"],"confidence":"Medium","gaps":["Direct contribution to leukemogenesis not isolated","Single lab"]},{"year":2014,"claim":"Defined the structural mechanism of viral hijacking: VSV M Met51 inserts into a hydrophobic pocket and competes with nucleic acid for the RAE1–Nup98 groove, establishing ligand mimicry.","evidence":"3.15 Å crystal structure with in vitro nucleic acid competition and synthetic peptide assays","pmids":["24927547"],"confidence":"High","gaps":["Physiological RNA ligand of the groove still undefined","Mechanism extrapolated to other viruses not yet tested here"]},{"year":2018,"claim":"Identified USP11 as the deubiquitinase setting RAE1 levels at the spindle and modulating its NuMA interaction, adding post-translational control of the mitotic function.","evidence":"Lentiviral knockdown, co-IP, ubiquitination assay and spindle morphology analysis","pmids":["29293652"],"confidence":"Medium","gaps":["E3 ligase opposing USP11 on RAE1 not identified","Single lab"]},{"year":2023,"claim":"Connected the RAE1–NUP98 complex to a nucleoplasmic, chromatin-associated role controlling epidermal progenitor proliferation versus differentiation via epigenetic regulator loci.","evidence":"siRNA knockdown, ChIP, fractionation and HDAC-inhibitor relocalization assays","pmids":["37353594"],"confidence":"Medium","gaps":["Direct RAE1 chromatin contacts vs. NUP98-mediated not separated","Single lab"]},{"year":2024,"claim":"Showed SARS-CoV-2 ORF6 hijacks the same RAE1–Nup98 groove (ORF6 Met58) to block transport and that RAE1 is required to position ORF6 within the NPC, completing the viral-mimicry paradigm across two virus families.","evidence":"Co-IP, Met58 mutagenesis, reporter and transport assays, crystallography of ORF6–Rae1–Nup98, and siRNA/SARS-CoV-2 infection assays","pmids":["33849972","35096974","38507240"],"confidence":"High","gaps":["Endogenous transport function of RAE1 partly dispensable under normal conditions, raising redundancy questions","Why RAE1 loss broadly disables ORF6 not fully mechanistically resolved"]},{"year":null,"claim":"The endogenous RNA ligand bound by the RAE1–Nup98 groove and the RNA species in the mitotic spindle RNP remain unidentified, leaving the link between RAE1's export and spindle functions unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No physiological RNA cargo defined","Mechanistic unification of NPC versus spindle roles incomplete"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[9,14,19]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[7,4]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[9,12]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[10,11,16]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[2,25]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[2]},{"term_id":"GO:0005730","term_label":"nucleolus","supporting_discovery_ids":[25]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of 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zhi","url":"https://pubmed.ncbi.nlm.nih.gov/17490545","citation_count":0,"is_preprint":false},{"pmid":"12545745","id":"PMC_12545745","title":"[Establishment of rat alveolar type II epithelial cell line RAE-1 and its biological characteristics].","date":"2002","source":"Wei sheng yan jiu = Journal of hygiene research","url":"https://pubmed.ncbi.nlm.nih.gov/12545745","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.06.04.657793","title":"The endoribonuclease Rae1 from  <i>Bacillus subtilis</i>  cleaves mRNA upstream of stalled ribosomes","date":"2025-06-04","source":"bioRxiv","url":"https://doi.org/10.1101/2025.06.04.657793","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.04.09.647954","title":"The leader proteins of Theiler’s virus and Boone cardiovirus use a combination of Short Linear Motifs (SLiMs) to target RSK kinases to the nuclear pore 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Rae1 encodes a WD40-repeat protein, and loss of function also causes actin/tubulin disorganization and irreversible cell cycle arrest, with cells being particularly vulnerable during G2/M.\",\n      \"method\": \"Fluorescence in situ hybridization (FISH) to detect poly(A)+ RNA localization; complementation cloning; temperature-shift experiments\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct genetic identification in fission yeast with orthogonal readouts (poly(A)+ RNA export, cytoskeletal phenotype, cell cycle arrest), replicated in multiple follow-up studies\",\n      \"pmids\": [\"7706287\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"S. cerevisiae Gle2 (ortholog of RAE1) associates with nuclear pore complexes and is required for poly(A)+ RNA export but not nuclear protein import; gle2 mutants show severe NPC and nuclear envelope structural perturbations. Two-hybrid interactions with Srp1p (NLS receptor) and Rip1p (NES-interacting protein) were detected.\",\n      \"method\": \"Indirect immunofluorescence; NPC fractionation; colony-sectoring genetic screen; thin-section electron microscopy; two-hybrid assay\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (IF, fractionation, EM, genetics), foundational study replicated across organisms\",\n      \"pmids\": [\"8970155\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"Human RAE1 is a functional homolog of S. pombe rae1; human RAE1 cDNA partially suppresses the temperature-sensitivity and poly(A)+ RNA export defect of the rae1-1 mutant. Epitope-tagged human Rae1 localizes to both nucleus and cytoplasm in HeLa cells.\",\n      \"method\": \"Cross-species complementation in S. pombe; FISH for poly(A)+ RNA; immunofluorescence in HeLa cells\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional rescue plus localization, single lab, partial suppression only\",\n      \"pmids\": [\"9370289\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"S. pombe Rae1 is required for cell cycle progression through mitosis independent of mRNA export; rae1-loss cells arrest with elevated Cdc2p kinase before spindle formation and without spindle pole body separation. Rae1p localizes to the nuclear periphery.\",\n      \"method\": \"Temperature-shift cell cycle analysis; Cdc2p kinase assay; immunofluorescence localization\",\n      \"journal\": \"Yeast\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cell cycle kinetics plus kinase assay and localization, single lab\",\n      \"pmids\": [\"9301023\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Mammalian RAE1 binds directly to a GLEBS-like motif within NUP98 at the nuclear pore complex through multiple domains including WD-repeats and a C-terminal non-WD extension. RAE1 shuttles between nucleus and cytoplasm in a temperature-dependent, RanGTP-independent manner. NE docking of RAE1 requires new mRNA synthesis. Overexpression of the GLEBS-like motif inhibits NE binding of RAE1 and induces nuclear poly(A)+ RNA accumulation, effects reversed by RAE1 overexpression.\",\n      \"method\": \"In vitro binding studies; chemical cross-linking; microinjection in Xenopus oocytes; overexpression/dominant-negative experiments; FISH for poly(A)+ RNA\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution of direct binding, cross-linking, functional oocyte microinjection, multiple orthogonal methods\",\n      \"pmids\": [\"10209021\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Ct-RAE1 (Chironomus tentans ortholog) does not associate with mRNPs co-transcriptionally or in the nucleoplasm; instead, it interacts with exported BR RNP particles specifically at the nuclear pore complex. RAE1 is not found on the cytoplasmic side of the RNP in transit, suggesting it remains anchored at the nuclear face of the NPC or is rapidly released.\",\n      \"method\": \"Immunoelectron microscopy on Balbiani ring RNP particles\",\n      \"journal\": \"RNA\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct ultrastructural localization, single lab, single method\",\n      \"pmids\": [\"11105759\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Mammalian Rae1 haploinsufficiency causes mitotic checkpoint defects and chromosome missegregation in vivo; Rae1-null mice are embryonic lethal. Overexpression of Rae1 can rescue both Rae1 and Bub3 haploinsufficiency. Combined Rae1/Bub3 haploinsufficiency greatly amplifies premature sister chromatid separation. Rae1 and Bub3 have essential, overlapping roles in the mitotic checkpoint. Cells from Rae1/Bub3-null mice show no detectable defect in mRNA nuclear export.\",\n      \"method\": \"Knockout mouse generation; cytogenetic analysis; spindle checkpoint assays; mRNA export assays; overexpression rescue experiments\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo genetic knockout with multiple orthogonal functional readouts, reproduced across genotypes\",\n      \"pmids\": [\"12551952\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Rae1, Nup98, and TAP form a ternary complex at the nuclear pore. Gle2/Rae1 requires two sites within TAP for stable interaction. TAP has highest affinity for a specific region within the GLFG domain of Nup98. When Rae1 is bound to Nup98, it no longer interacts directly with TAP, suggesting a mechanism where Rae1 may deliver TAP to Nup98.\",\n      \"method\": \"In vitro binding assays; definition of binary and ternary complexes by pull-down and competition experiments\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct in vitro binding with competition, single lab, multiple binary pairs tested\",\n      \"pmids\": [\"12637516\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"VSV matrix (M) protein inhibits host mRNA nuclear export by binding the mRNA export factor Rae1/mrnp41. A M protein mutant defective in Rae1 binding cannot inhibit mRNA export. Overexpression of Rae1 fully reverses M protein-mediated inhibition of mRNA export. Rae1 is induced by interferon-gamma.\",\n      \"method\": \"Co-immunoprecipitation; dominant-negative M protein mutant; mRNA export assay; overexpression rescue; IFN-gamma treatment\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — binding mapped to M protein domain, rescued by Rae1 overexpression, mutant validation, multiple orthogonal methods\",\n      \"pmids\": [\"15629720\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Rae1 is a microtubule-associated protein and spindle assembly factor regulated by the RanGTP/importin-beta pathway. Rae1 binds directly to importin beta. Depletion of Rae1 from Xenopus egg extracts or cells severely inhibits mitotic spindle assembly. A purified Rae1-containing ribonucleoprotein complex stabilizes microtubules in a RanGTP/importin beta-regulated manner, and this activity requires RNA.\",\n      \"method\": \"Activity-based biochemical purification from Xenopus egg extracts; immunodepletion; in vitro microtubule stabilization assay; direct binding assay with importin beta\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — biochemical purification, reconstitution in egg extracts, immunodepletion with specific phenotype, direct binding assay, multiple orthogonal methods\",\n      \"pmids\": [\"15851029\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Rae1 and Nup98 form a complex with Cdh1-activated APC (APC(Cdh1)) in early mitosis and specifically inhibit APC(Cdh1)-mediated ubiquitination of securin, preventing premature securin degradation until the metaphase/anaphase transition. Combined Rae1/Nup98 haploinsufficiency in mice results in premature sister chromatid separation, severe aneuploidy, and untimely securin degradation.\",\n      \"method\": \"Co-immunoprecipitation of APC(Cdh1) complex; ubiquitination assay; haploinsufficient mouse genetics; cytogenetic analysis; securin degradation timing assay\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro ubiquitination assay, co-IP, in vivo mouse genetics, multiple orthogonal methods in single rigorous study\",\n      \"pmids\": [\"16355229\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"The Rae1-Nup98 complex also forms a complex with securin in prometaphase. This complex does not prevent APC(Cdh1) from binding securin, but instead prevents ubiquitination of APC(Cdh1)-bound securin, priming rapid securin degradation after dissociation of Rae1-Nup98 at the metaphase/anaphase transition.\",\n      \"method\": \"Co-immunoprecipitation; cell cycle timing analysis; genetic mouse models\",\n      \"journal\": \"Cell cycle\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP evidence with mechanistic interpretation, single lab, supported by existing mouse genetics\",\n      \"pmids\": [\"16479161\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Rae1 interacts with the nuclear mitotic apparatus protein NuMA in a mitosis-specific manner. A specific binding site for Rae1 on NuMA was mapped. This interaction is required for bipolar spindle formation; reducing Rae1 or increasing NuMA causes spindle abnormalities. Coupling NuMA overexpression with Rae1 overexpression, or depleting both simultaneously, prevents aberrant spindle formation. Overexpression of the Rae1-binding domain of NuMA in HeLa cells causes aberrant spindles.\",\n      \"method\": \"Co-immunoprecipitation; domain mapping; siRNA knockdown and overexpression in HeLa cells; spindle morphology analysis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal genetic rescue, domain mapping, multiple cell biology readouts, single lab with multiple orthogonal approaches\",\n      \"pmids\": [\"17172455\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Retinoic acid downregulates Rae1 expression in human SH-SY5Y neuroblastoma cells, thereby facilitating APC(Cdh1)-mediated Skp2 degradation, p27 stabilization, and neuroblastoma differentiation. Rae1 overexpression promotes Skp2 accumulation and prevents retinoic acid-induced cell cycle arrest; Rae1 inhibition accelerates differentiation.\",\n      \"method\": \"Western blotting; siRNA knockdown; overexpression; cell cycle analysis; measurement of Skp2 and p27 levels\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA knockdown and rescue with defined molecular readouts, single lab\",\n      \"pmids\": [\"18212744\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Crystal structure of human Rae1 in complex with the Nup98 GLEBS motif determined at 1.65 Å resolution. Rae1 forms a seven-bladed beta-propeller. The Nup98 GLEBS motif forms an ~50 Å-long hairpin binding to an invariant hydrophobic surface on the top face of Rae1. The C-terminal arm of the GLEBS hairpin is necessary and sufficient for Rae1 binding; a tandem glutamate element in this arm is critical. The Rae1-Nup98 complex possesses single-stranded RNA-binding capability via a conserved basic patch.\",\n      \"method\": \"X-ray crystallography at 1.65 Å; mutagenesis of GLEBS motif; in vitro RNA-binding assay\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — high-resolution crystal structure plus mutagenesis and biochemical validation of RNA binding\",\n      \"pmids\": [\"20498086\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"RNAi knockdown of NUP98 in human cells disrupts RAE1 expression and localization (but not HDAC1). Rescue experiments show that the RAE1-NUP98 complex orchestrates proper chromosome segregation. In NUP98-HOXA9-transfected cells, RAE1 protein is reduced and mis-localized. This is confirmed in NUP98-HOXA9 transgenic mice and AML patient samples.\",\n      \"method\": \"RNAi knockdown; rescue experiments; immunofluorescence localization; chromosome segregation assays; transgenic mouse analysis; patient sample analysis\",\n      \"journal\": \"Cell cycle\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional rescue and multiple cellular readouts, single lab\",\n      \"pmids\": [\"21467841\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Drosophila Rae1 is a component of the Highwire (Hiw)/Fsn E3 ubiquitin ligase complex in post-mitotic neurons. Rae1 physically and genetically interacts with Hiw. Loss of Rae1 in neurons produces NMJ morphological defects similar to hiw mutants. Rae1 is necessary and sufficient to promote Hiw protein abundance by binding Hiw and protecting it from autophagy-mediated degradation.\",\n      \"method\": \"Tandem affinity purification; co-immunoprecipitation; genetic epistasis; loss-of-function neuronal phenotype analysis; autophagy inhibitor experiments\",\n      \"journal\": \"Nature neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — TAP identification, co-IP, genetic epistasis, multiple orthogonal methods establishing mechanism of Hiw stabilization\",\n      \"pmids\": [\"21874015\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"VSV M protein forms multiple distinct complexes with Rae1 and Nup98 (high, intermediate, and low molecular weight). The intermediate MW complexes containing Nup98 interact most efficiently with M protein. Silencing Rae1 reduces VSV's ability to inhibit host transcription but does not affect nuclear mRNA accumulation or inhibition of translation. M protein-Rae1-Nup98 complexes associate with the chromatin fraction, suggesting a role in inhibiting host transcription.\",\n      \"method\": \"Size exclusion chromatography; sedimentation velocity analysis; siRNA silencing; mRNA export assay; translation assay; chromatin fractionation\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — biochemical complex characterization plus functional siRNA data, single lab\",\n      \"pmids\": [\"23028327\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Drosophila Rae1 localizes to the nuclear envelope and is required for normal male meiosis: rae1 mutants display defects in primary spermatocyte nuclear integrity, meiotic chromosome condensation, segregation, and spindle morphology, leading to failure to complete meiosis. GFP-RAE1 dynamically localizes to the nuclear envelope, chromatin, and other structures during spermatogenesis.\",\n      \"method\": \"Genetic mutant analysis; immunofluorescence; GFP-RAE1 live imaging; RNAi\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — defined genetic loss-of-function with specific cytological phenotype and live imaging, single lab\",\n      \"pmids\": [\"23788425\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Crystal structure of VSV M protein in complex with Rae1 and Nup98 at 3.15 Å resolution. M protein contacts the Rae1-Nup98 heterodimer via two protrusions (finger and thumb). The conserved Met51 of M inserts into a deep hydrophobic pocket on the Rae1 beta-propeller; flanking acidic residues bond to a basic groove on Rae1. M protein competes with oligonucleotides for binding to Rae1-Nup98 in vitro. A synthetic peptide corresponding to the finger competes for nucleic acid binding, suggesting Rae1 binds the phosphate backbone of any nucleic acid and M mimics this ligand.\",\n      \"method\": \"X-ray crystallography at 3.15 Å; in vitro nucleic acid competition binding assay; synthetic peptide competition\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — high-resolution crystal structure, in vitro competition assay, structural rationalization of mechanism\",\n      \"pmids\": [\"24927547\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"The Hippo pathway targets Rae1 for degradation downstream of Warts/Lats. In proliferating cells, Rae1 loss restricts cyclin B levels and organ size; Rae1 overexpression increases cyclin B and organ size. Reducing Rae1 blocks cyclin B accumulation and suppresses overgrowth caused by Hippo pathway loss. Rae1 also acts in a feedback circuit to increase protein levels of Merlin, Hippo, and Warts and to reduce Yki/YAP levels.\",\n      \"method\": \"Genetic epistasis in Drosophila tissues and cells; biochemical studies; mammalian cell overexpression/knockdown; cyclin B and organ size measurements\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic and biochemical evidence in two systems, single lab\",\n      \"pmids\": [\"27494403\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"USP11 is a deubiquitinating enzyme for RAE1; USP11 controls RAE1 ubiquitination at the mitotic spindle. USP11 localizes to the mitotic spindle and its knockdown (or RAE1 knockdown) reduces cell proliferation and increases multipolar spindle formation. USP11 does not regulate spindle assembly checkpoint inactivation but modulates RAE1's interaction with NuMA.\",\n      \"method\": \"Lentiviral knockdown; co-immunoprecipitation; ubiquitination assay; spindle morphology analysis; localization by immunofluorescence\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — deubiquitination assay plus functional spindle phenotype and NuMA interaction modulation, single lab\",\n      \"pmids\": [\"29293652\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"RAE1 directly binds to the promoter region of the EMT transcription factor ZEB1 in breast cancer cells, mediating its upregulation. RAE1 overexpression induces EMT and invasive/migratory behavior; ZEB1 knockdown in RAE1-overexpressing cells suppresses invasiveness and restores epithelial markers.\",\n      \"method\": \"ChIP (promoter binding assay); siRNA knockdown of ZEB1 in RAE1-overexpressing cells; 3D culture; xenograft models; invasion/migration assays\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct promoter binding demonstrated, epistatic rescue, in vivo xenograft, single lab\",\n      \"pmids\": [\"30814639\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SARS-CoV-2 ORF6 blocks nuclear mRNA export and inhibits nuclear import of host proteins by co-purifying with Rae1 and Nup98. Interactions map to the C terminus of ORF6 and a single mutation at Met58 abolishes binding. Overexpression of Rae1 restores reporter expression suppressed by ORF6. SARS-CoV-2 ORF6 more strongly copurifies with Rae1 and Nup98 than SARS-CoV ORF6.\",\n      \"method\": \"Co-immunoprecipitation; site-directed mutagenesis (Met58); reporter assay; nuclear mRNA accumulation assay; overexpression rescue\",\n      \"journal\": \"mBio\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — binding mapped by mutagenesis, functional rescue by Rae1 overexpression, multiple orthogonal methods, comparator SARS-CoV-1 vs SARS-CoV-2\",\n      \"pmids\": [\"33849972\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Crystal structures of both SARS-CoV-2 and SARS-CoV-1 ORF6 C-termini in complex with the Rae1-Nup98 heterodimer were determined. ORF6 occupies the same potential mRNA-binding groove of the Rae1-Nup98 complex as VSV M protein. The conserved Met58 of ORF6 is critical for complex formation and competitive inhibition of RNA binding to Rae1-Nup98.\",\n      \"method\": \"X-ray crystallography; biochemical binding assays; site-directed mutagenesis; RNA competition binding assay\",\n      \"journal\": \"Frontiers in molecular biosciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structures for both viral orthologs, mutagenesis of critical residue, biochemical validation, multiple orthogonal methods\",\n      \"pmids\": [\"35096974\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"NUP98 and RAE1 are highly expressed in epidermal progenitors and form a distinct nucleoplasmic complex. Reduction of NUP98 or RAE1 abolishes progenitor regenerative capacity, inhibiting proliferation and inducing premature terminal differentiation. NUP98 binds chromatin near transcription start sites of key epigenetic regulators (DNMT1, UHRF1, EZH2) co-occupied by HDAC1. HDAC inhibition diminishes NUP98 chromatin binding and induces NUP98 and RAE1 to relocalize interdependently to the nucleolus.\",\n      \"method\": \"siRNA knockdown; ChIP; immunofluorescence fractionation; HDAC inhibitor treatment; proliferation and differentiation assays\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and functional knockdown with defined readouts, HDAC inhibitor mechanistic dissection, single lab\",\n      \"pmids\": [\"37353594\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Rae1 is required to position SARS-CoV-2 ORF6 within the NPC to inhibit nucleocytoplasmic transport. Loss of Rae1 suppresses ORF6's transport inhibitory activity. Rae1 alone is not necessary for p-STAT1 import or poly(A) RNA export under normal conditions. Rae1 is also required for normal viral protein production during SARS-CoV-2 infection, presumably through supporting ORF6 function.\",\n      \"method\": \"siRNA knockdown of Rae1; nuclear transport assays (p-STAT1 import, poly(A) RNA export); SARS-CoV-2 infection; viral protein production assay\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional knockdown with specific transport readouts, epistatic relationship with ORF6 established, single lab\",\n      \"pmids\": [\"38507240\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"RAE1 regulates PPARα mRNA stability in esophageal epithelial cells; RAE1 knockdown causes G2/M cell cycle blockade and reduced lipid accumulation, phenocopied by PPARα downregulation. RAE1 overexpression promotes malignant transformation by maintaining PPARα mRNA stability.\",\n      \"method\": \"siRNA knockdown; overexpression; mRNA stability assay; cell cycle analysis; xenograft tumor model\",\n      \"journal\": \"Ecotoxicology and environmental safety\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — mRNA stability linkage inferred from knockdown/overexpression without direct biochemical demonstration of binding or decay mechanism, single lab\",\n      \"pmids\": [\"37774541\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"RAE1 (Gle2/Mnrp41) is a conserved WD40/beta-propeller protein that functions at the nuclear pore complex as a direct binding partner of NUP98 (via the GLEBS motif), where the Rae1–Nup98 complex binds single-stranded RNA to facilitate mRNA export; in mitosis, Rae1 moonlights as a spindle assembly factor that associates with microtubules through a RanGTP/importin-beta-regulated ribonucleoprotein complex, interacts with NuMA to support bipolar spindle formation, and inhibits APC(Cdh1)-mediated ubiquitination of securin to prevent premature anaphase onset, while in post-mitotic neurons it stabilizes the Highwire E3 ubiquitin ligase by protecting it from autophagy, and its RNA-binding groove on the Rae1–Nup98 complex surface is exploited by multiple viruses (VSV M protein, SARS-CoV-2 ORF6) through a conserved methionine-containing motif that competitively displaces RNA cargo to block host mRNA export.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"RAE1 (Gle2/Mnrp41) is an evolutionarily conserved WD40 protein that folds into a seven-bladed beta-propeller and functions both at the nuclear pore complex in mRNA export and as a moonlighting regulator of mitotic spindle assembly and chromosome segregation [#0, #9, #14]. At the NPC, RAE1 binds directly to a GLEBS-like motif of NUP98 through its WD-repeats and a C-terminal extension, and this docking — which depends on ongoing mRNA synthesis — is required for nuclear export of poly(A)+ RNA [#4, #1]. The 1.65 Å crystal structure shows the Nup98 GLEBS motif binding as an extended hairpin to the propeller's top face, and reveals that the Rae1–Nup98 complex acquires single-stranded RNA-binding capability through a conserved basic patch [#14]. RAE1 also bridges NUP98 to the export receptor TAP within a ternary complex, consistent with a role in delivering cargo at the pore [#7]. Independent of export, RAE1 acts as a microtubule-associated spindle assembly factor: a RanGTP/importin-β–regulated, RNA-containing RAE1 ribonucleoprotein stabilizes microtubules, RAE1 binds importin-β directly, and it interacts mitosis-specifically with NuMA to support bipolar spindle formation [#9, #12]. RAE1, together with NUP98, restrains APC(Cdh1) by blocking ubiquitination of APC(Cdh1)-bound securin until the metaphase/anaphase transition, and RAE1 cooperates genetically with BUB3 in the mitotic checkpoint; haploinsufficiency causes premature sister-chromatid separation, aneuploidy, and embryonic lethality in mice [#6, #10, #11]. RAE1 abundance at the spindle is set by ubiquitination opposed by the deubiquitinase USP11 [#21]. Beyond proliferating cells, Drosophila RAE1 is a component of the Highwire/Fsn E3 ligase complex in post-mitotic neurons, where it binds and stabilizes Highwire by protecting it from autophagy [#16]. The Rae1–Nup98 RNA-binding groove is a recurrent viral target: VSV matrix protein and SARS-CoV-2 ORF6 dock through a conserved methionine-containing motif (M Met51, ORF6 Met58) that competitively displaces nucleic acid to block host mRNA export, with RAE1 also positioning ORF6 within the NPC [#8, #19, #23, #24, #26].\",\n  \"teleology\": [\n    {\n      \"year\": 1995,\n      \"claim\": \"Established RAE1 as an essential factor for nuclear export of poly(A)+ RNA, defining its core cellular role and its identity as a WD40-repeat protein.\",\n      \"evidence\": \"Temperature-sensitive rae1-1 mutant analysis with FISH for poly(A)+ RNA and complementation cloning in S. pombe\",\n      \"pmids\": [\"7706287\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular partners at the pore not yet identified\", \"Cytoskeletal and cell-cycle phenotypes left mechanistically unexplained\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Localized the ortholog (Gle2) physically to nuclear pore complexes and showed its loss perturbs NPC/nuclear envelope architecture, tying export function to the pore itself.\",\n      \"evidence\": \"Immunofluorescence, NPC fractionation, EM and genetic screening in S. cerevisiae\",\n      \"pmids\": [\"8970155\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct NPC anchoring partner not defined\", \"Mechanism of structural perturbation unresolved\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Demonstrated functional conservation to human RAE1 and separated its mitotic role from mRNA export in yeast, hinting at a moonlighting function.\",\n      \"evidence\": \"Cross-species complementation in S. pombe and Cdc2p kinase/cell-cycle analysis\",\n      \"pmids\": [\"9370289\", \"9301023\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Partial suppression only\", \"Mitotic mechanism unknown at this stage\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Identified NUP98 as the direct NPC-docking partner via a GLEBS-like motif and tied RAE1 docking to active mRNA synthesis, providing the molecular basis for export function.\",\n      \"evidence\": \"In vitro binding, cross-linking and Xenopus oocyte microinjection with dominant-negative GLEBS overexpression\",\n      \"pmids\": [\"10209021\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of binding not yet resolved\", \"How RNA cargo is engaged unclear\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Resolved RAE1's in vivo function as a mitotic checkpoint factor cooperating with BUB3, showing chromosome-segregation roles can be genetically separated from mRNA export.\",\n      \"evidence\": \"Knockout/haploinsufficient mouse genetics with cytogenetics, checkpoint assays and mRNA export assays\",\n      \"pmids\": [\"12551952\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Biochemical mechanism linking RAE1 to checkpoint not defined\", \"Relationship between BUB3 and NUP98 roles unclear\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Placed RAE1 in a NUP98–TAP ternary complex, suggesting it functions as an adaptor that hands export cargo/receptor to NUP98.\",\n      \"evidence\": \"In vitro binary/ternary complex reconstitution with competition pull-downs\",\n      \"pmids\": [\"12637516\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Delivery model not directly demonstrated in cells\", \"Single lab in vitro evidence\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Defined the dual mitotic mechanisms: RAE1 as a RanGTP/importin-β–regulated, RNA-dependent microtubule-stabilizing RNP, and as an APC(Cdh1) inhibitor protecting securin from premature ubiquitination.\",\n      \"evidence\": \"Xenopus egg extract purification, immunodepletion, in vitro microtubule and ubiquitination assays, and haploinsufficient mouse genetics\",\n      \"pmids\": [\"15851029\", \"16355229\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the RNA in the spindle RNP unknown\", \"How RAE1 senses the metaphase/anaphase transition unresolved\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Revealed RAE1 as a direct viral target, with VSV M protein binding it to block host mRNA export, establishing RAE1 as a host-pathogen interface.\",\n      \"evidence\": \"Co-immunoprecipitation, M-protein binding mutant and Rae1 overexpression rescue of export\",\n      \"pmids\": [\"15629720\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of M–RAE1 interaction not yet defined\", \"Whether NUP98 participates not established here\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Refined the securin-protection mechanism and identified NuMA as the mitotic spindle partner mediating bipolar spindle assembly.\",\n      \"evidence\": \"Co-IP, domain mapping and reciprocal knockdown/overexpression rescue in HeLa cells; cell-cycle timing analyses\",\n      \"pmids\": [\"16479161\", \"17172455\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How RAE1–NuMA binding is regulated within the cycle unclear\", \"Securin-priming model rests on co-IP interpretation\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Provided atomic resolution of the RAE1 beta-propeller bound to the Nup98 GLEBS hairpin and demonstrated the complex's intrinsic single-stranded RNA-binding via a basic patch, unifying the structural and functional pictures.\",\n      \"evidence\": \"1.65 Å X-ray crystallography with GLEBS mutagenesis and in vitro RNA-binding assay\",\n      \"pmids\": [\"20498086\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Sequence specificity of RNA binding not defined\", \"Link between this RNA groove and spindle RNP unestablished\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Extended RAE1 function into post-mitotic neurons as a Highwire E3-ligase component that stabilizes Highwire against autophagy, a role distinct from export and mitosis.\",\n      \"evidence\": \"Tandem affinity purification, co-IP, genetic epistasis and autophagy-inhibitor experiments in Drosophila\",\n      \"pmids\": [\"21874015\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether this neuronal role is conserved in mammals untested in corpus\", \"Mechanism of autophagy protection unresolved\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Showed NUP98 controls RAE1 expression and localization and that the complex governs chromosome segregation, with disruption in NUP98-HOXA9 leukemia.\",\n      \"evidence\": \"RNAi, rescue, IF localization and chromosome segregation assays with transgenic mouse and patient samples\",\n      \"pmids\": [\"21467841\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct contribution to leukemogenesis not isolated\", \"Single lab\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Defined the structural mechanism of viral hijacking: VSV M Met51 inserts into a hydrophobic pocket and competes with nucleic acid for the RAE1–Nup98 groove, establishing ligand mimicry.\",\n      \"evidence\": \"3.15 Å crystal structure with in vitro nucleic acid competition and synthetic peptide assays\",\n      \"pmids\": [\"24927547\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological RNA ligand of the groove still undefined\", \"Mechanism extrapolated to other viruses not yet tested here\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identified USP11 as the deubiquitinase setting RAE1 levels at the spindle and modulating its NuMA interaction, adding post-translational control of the mitotic function.\",\n      \"evidence\": \"Lentiviral knockdown, co-IP, ubiquitination assay and spindle morphology analysis\",\n      \"pmids\": [\"29293652\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"E3 ligase opposing USP11 on RAE1 not identified\", \"Single lab\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Connected the RAE1–NUP98 complex to a nucleoplasmic, chromatin-associated role controlling epidermal progenitor proliferation versus differentiation via epigenetic regulator loci.\",\n      \"evidence\": \"siRNA knockdown, ChIP, fractionation and HDAC-inhibitor relocalization assays\",\n      \"pmids\": [\"37353594\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct RAE1 chromatin contacts vs. NUP98-mediated not separated\", \"Single lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Showed SARS-CoV-2 ORF6 hijacks the same RAE1–Nup98 groove (ORF6 Met58) to block transport and that RAE1 is required to position ORF6 within the NPC, completing the viral-mimicry paradigm across two virus families.\",\n      \"evidence\": \"Co-IP, Met58 mutagenesis, reporter and transport assays, crystallography of ORF6–Rae1–Nup98, and siRNA/SARS-CoV-2 infection assays\",\n      \"pmids\": [\"33849972\", \"35096974\", \"38507240\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Endogenous transport function of RAE1 partly dispensable under normal conditions, raising redundancy questions\", \"Why RAE1 loss broadly disables ORF6 not fully mechanistically resolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The endogenous RNA ligand bound by the RAE1–Nup98 groove and the RNA species in the mitotic spindle RNP remain unidentified, leaving the link between RAE1's export and spindle functions unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No physiological RNA cargo defined\", \"Mechanistic unification of NPC versus spindle roles incomplete\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [9, 14, 19]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [7, 4]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [9, 12]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [10, 11, 16]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005643\", \"supporting_discovery_ids\": [1, 4, 5]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [2, 25]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"GO:0005819\", \"supporting_discovery_ids\": [9, 12, 21]},\n      {\"term_id\": \"GO:0005730\", \"supporting_discovery_ids\": [25]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [0, 4, 14]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [6, 9, 10, 12]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [8, 19, 23, 24]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [4, 26]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [10, 16]}\n    ],\n    \"complexes\": [\n      \"Rae1-Nup98 complex\",\n      \"Rae1-Nup98-TAP ternary complex\",\n      \"APC(Cdh1)-Rae1-Nup98-securin complex\",\n      \"Highwire/Fsn E3 ubiquitin ligase complex\"\n    ],\n    \"partners\": [\n      \"NUP98\",\n      \"NuMA\",\n      \"importin-beta\",\n      \"TAP\",\n      \"BUB3\",\n      \"USP11\",\n      \"Highwire\",\n      \"securin\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":9,"faith_total":9,"faith_pct":100.0}}