{"gene":"SEH1L","run_date":"2026-04-28T20:42:07","timeline":{"discoveries":[{"year":2013,"finding":"SEH1L is a subunit of the GATOR2 complex (along with Mios, WDR24, WDR59, and Sec13), which negatively regulates GATOR1 (DEPDC5, Nprl2, Nprl3) in the mTORC1 amino acid sensing pathway; epistasis analysis shows GATOR2 acts upstream of GATOR1/DEPDC5, and inhibition of GATOR2 subunits including Seh1L suppresses mTORC1 signaling.","method":"siRNA knockdown, epistasis analysis, co-immunoprecipitation, mTORC1 activity assays","journal":"Science","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP, epistasis, replicated across multiple studies","pmids":["23723238"],"is_preprint":false},{"year":2022,"finding":"Cryo-EM structure of human GATOR2 reveals a 1.1 MDa two-fold symmetric cage-like architecture with an octagonal scaffold containing two WDR24, four MIOS and two WDR59 subunits; SEH1L integrates into the scaffold via β-propeller blade donation, stabilizing the complex and orienting WD40 β-propeller dimers that mediate interactions with SESN2, CASTOR1, and GATOR1.","method":"Cryo-electron microscopy, biochemical reconstitution","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 — cryo-EM structure with functional validation, rigorous single study","pmids":["35831510"],"is_preprint":false},{"year":2025,"finding":"Cryo-EM structures of GATOR2 bound to amino acid sensors show Sestrin2 (leucine sensor) interacts specifically with the WDR24-SEH1L subcomplex of GATOR2, inducing conformational movements; HDX-MS confirmed dynamic motions in these interfaces.","method":"Cryo-electron microscopy, hydrogen-deuterium exchange mass spectrometry (HDX-MS)","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1 — cryo-EM structure with HDX-MS orthogonal validation","pmids":["40742811"],"is_preprint":false},{"year":2004,"finding":"SEH1L (Seh1) is a component of the Nup107-160 nuclear pore subcomplex; depletion by RNAi causes phenotypes similar to knockdown of other complex members, and the entire complex including Seh1 localizes to kinetochores from prophase to anaphase of mitosis.","method":"RNA interference, GFP-tagging, immunofluorescence, biochemical fractionation/co-immunoprecipitation","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 — Co-IP, live imaging, RNAi phenotype; replicated across multiple studies","pmids":["15146057"],"is_preprint":false},{"year":2007,"finding":"Depletion of SEH1L alone is sufficient to efficiently deplete the Nup107-160 complex from kinetochores, causing mitotic delay, impaired chromosome congression, reduced kinetochore tension, and kinetochore-microtubule attachment defects; the Nup107-160 complex is required at kinetochores for recruitment of Crm1 and RanGAP1-RanBP2.","method":"siRNA knockdown, live-cell imaging, immunofluorescence, kinetochore tension assays","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods, defined cellular phenotypes, replicated","pmids":["17363900"],"is_preprint":false},{"year":2009,"finding":"Seh1 depletion impairs Aurora B localization to centromeres, causing severe defects in chromosome biorientation, spindle midzone organization, and midbody formation, while microtubule-kinetochore attachments remain intact; the major mitotic function of the Nup107 complex is to ensure proper chromosomal passenger complex (CPC) localization.","method":"siRNA knockdown, immunofluorescence, electron microscopy, live-cell imaging","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods including EM, specific phenotypic readout","pmids":["19864462"],"is_preprint":false},{"year":2018,"finding":"Using chemical genetics (auxin-inducible degron) and quantitative chromosome proteomics, Seh1 was found not required for association of the Nup107 complex with mitotic chromosomes, but is essential for association of the GATOR2 complex and Nup153 with mitotic chromosomes, and for efficient localization of the chromosomal passenger complex (CPC) at centromeres.","method":"Chemical genetics (auxin-inducible degron), quantitative chromosome proteomics, immunofluorescence","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 — chemical genetics with quantitative proteomics, multiple orthogonal methods","pmids":["29618633"],"is_preprint":false},{"year":2011,"finding":"In Drosophila, Seh1 associates with the product of the missing oocyte (mio) gene (a GATOR2 component) and is required for oogenesis; in seh1 mutant ovaries, Mio protein accumulation is greatly diminished, and oocytes fail to maintain the meiotic cycle; seh1 null is dispensable for somatic tissue development.","method":"Co-immunoprecipitation, genetic null allele analysis, immunofluorescence, developmental phenotyping","journal":"Development","confidence":"High","confidence_rationale":"Tier 2 — null allele with specific phenotype, Co-IP binding partner identification, multiple methods","pmids":["21521741"],"is_preprint":false},{"year":2014,"finding":"In Drosophila, GATOR2 components Mio and Seh1 are required to oppose GATOR1 (Iml1/GATOR1) activity during oogenesis; loss of Seh1 (or Mio) leads to constitutive TORC1 inhibition and block to oocyte growth; epistasis analysis shows GATOR2 acts as an antagonist of GATOR1 in the meiotic/oocyte context.","method":"Genetic epistasis, RNAi, rapamycin treatment, developmental phenotyping in Drosophila","journal":"Proceedings of the National Academy of Sciences","confidence":"High","confidence_rationale":"Tier 2 — genetic epistasis with multiple alleles and pharmacological validation","pmids":["25512509"],"is_preprint":false},{"year":2013,"finding":"In yeast (S. cerevisiae), Seh1 is a component of SEACAT (the GATOR2 ortholog within the SEA complex); genetic epistasis shows SEACAT antagonizes the GAP function of SEACIT (GATOR1 ortholog) toward Gtr1 (RagA/B ortholog) to regulate TORC1 activity.","method":"Genetic epistasis analysis in S. cerevisiae","journal":"Cell cycle","confidence":"High","confidence_rationale":"Tier 2 — genetic epistasis replicated across species, consistent with mammalian data","pmids":["23974112"],"is_preprint":false},{"year":2011,"finding":"The SEA (Seh1-Associated) complex in yeast contains Seh1, Sec13, Npr2, Npr3, and four uncharacterized proteins (Sea1-Sea4); it dynamically associates with the vacuole in vivo; computational and biochemical approaches indicate structural similarity to COPI, COPII, NPC, and vesicle tethering complexes; genetic assays indicate roles in intracellular trafficking, amino acid biogenesis, and nitrogen starvation response.","method":"Mass spectrometry, biochemical fractionation, live-cell imaging, genetic assays, computational structural analysis","journal":"Molecular & cellular proteomics","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods for complex identification and localization","pmids":["21454883"],"is_preprint":false},{"year":2009,"finding":"Crystal structure of Nup85 in complex with Seh1 defines a tripartite protein element called ACE1 (ancestral coatomer element); Nup85 shares this element with other nucleoporins and vesicle coat proteins, providing structural evidence for evolutionary relationship between NPC and COPII vesicle coats.","method":"X-ray crystallography, functional site prediction and verification","journal":"Communicative & integrative biology","confidence":"High","confidence_rationale":"Tier 1 — crystal structure with functional validation of predicted interaction sites","pmids":["19641729"],"is_preprint":false},{"year":2018,"finding":"SEH1 (SEH1L) contains an RV[S/T]F motif that is phosphorylated by Aurora B kinase during mitosis, which abrogates its interaction with PP1 phosphatase; this mechanism maintains phosphorylation of PP1 substrates during mitosis by disrupting PP1 holoenzyme assembly.","method":"Phosphospecific antibody (RVp[S/T]F), mass spectrometry, kinase assays, co-immunoprecipitation","journal":"Science signaling","confidence":"Medium","confidence_rationale":"Tier 2 — phosphospecific antibody and biochemical validation, but SEH1 is one of multiple proteins identified","pmids":["29764992"],"is_preprint":false},{"year":2016,"finding":"In Drosophila, GATOR2 component Seh1 (along with Mio and Wdr24) has a TORC1-independent role in regulating lysosome dynamics and autophagic flux, in addition to its role in TORC1 activation; epistasis analysis between wdr24 and GATOR1 components established this dual function.","method":"Genetic epistasis, null allele analysis, cell biology (lysosome/autophagy assays) in Drosophila and HeLa cells","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 2 — epistasis plus knockout HeLa validation, multiple orthogonal methods","pmids":["27166823"],"is_preprint":false},{"year":2024,"finding":"SEH1 (Seh1) cooperates with the NuRD transcription repressor complex at the nuclear periphery in neural stem cells to repress p21 expression; loss of Seh1 in radial glial progenitors derepresses p21, leading to defective neural progenitor proliferation, impaired neurogenesis, and microcephaly, without defects in nucleocytoplasmic transport.","method":"Conditional knockout, transcriptome analysis, ChIP, co-immunoprecipitation, p21 knockdown rescue experiment","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 2 — conditional KO with defined molecular mechanism, multiple orthogonal methods, rescue experiment","pmids":["38272027"],"is_preprint":false},{"year":2023,"finding":"Seh1 in Schwann cells maintains genome stability by mediating the interaction between SETDB1 and KAP1; loss of Seh1 disrupts this interaction, derepresses endogenous retroviruses, and triggers ZBP1-dependent necroptosis, leading to progressive loss of Schwann cells and peripheral neuropathy.","method":"Conditional knockout, co-immunoprecipitation, transcriptome analysis, immunofluorescence, nerve function assays","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 — conditional KO with defined molecular mechanism and binding partner, multiple orthogonal methods","pmids":["37453065"],"is_preprint":false},{"year":2021,"finding":"Seh1 and Nup43, but not Nup85 (with impaired Seh1 interaction), are required for normal cell growth rates, viability upon differentiation, and maintenance of proper NPC density in mouse embryonic stem cells; it is the integrity of the Y-complex (not NPC number alone) that is critical for proliferation and differentiation.","method":"Genome editing (CRISPR), NPC density measurements, differentiation assays in mESCs","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 — clean genetic KO with defined cellular phenotype, but single study","pmids":["34037234"],"is_preprint":false},{"year":2026,"finding":"Cryo-EM structure of the yeast SEAC-EGOC supercomplex shows SEACIT binds two EGOC molecules exclusively in the 'active' conformation without involvement of SEACAT (which contains Seh1/Sea2-Sea4/Sec13); loss of Sea2 (GATOR2 subunit equivalent to WDR59) or its N-terminal β-propeller yields strong defects in amino acid signaling, suggesting this β-propeller recruits a GAP inhibitor for fast TORC1 regulation.","method":"Cryo-electron microscopy, genetic analysis, biochemical assays in S. cerevisiae","journal":"Nature structural & molecular biology","confidence":"High","confidence_rationale":"Tier 1 — cryo-EM structure with genetic functional validation","pmids":["41680390"],"is_preprint":false},{"year":2024,"finding":"Structural modeling and FRET analysis show Sestrin2 interacts with the WDR24-Seh1L interface of GATOR2, and CASTOR1 interacts with the Mios β-propeller; deletion of Mios β-propeller severely impedes GATOR2 conformational changes in response to arginine levels.","method":"AlphaFold2 structural prediction, FRET analysis, mutagenesis, molecular dynamics simulations","journal":"Bioscience reports","confidence":"Medium","confidence_rationale":"Tier 3 — computational structure prediction with FRET and mutagenesis, single lab","pmids":["38372438"],"is_preprint":false},{"year":2023,"finding":"Seh1 and Nup133 (Y-complex nucleoporins) share a function in gene regulation during neuroectodermal differentiation of mouse embryonic stem cells; Seh1-deficient neural progenitors misregulate Lhx1 and Nup210l, with only a mild reduction in NPC density, suggesting a chromatin/gene regulatory role independent of nuclear pore basket integrity.","method":"Transcriptomic analysis, genetic knockout in mESCs, NPC density measurement","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 — transcriptomics plus genetic KO, but limited mechanistic detail for Seh1 specifically","pmids":["37305998"],"is_preprint":false}],"current_model":"SEH1L is a dual-function nucleoporin that serves as a structural component of both the Nup107-160 nuclear pore subcomplex (mediating kinetochore localization, chromosomal passenger complex recruitment, and NPC assembly) and the GATOR2 nutrient-sensing complex (where its integration via β-propeller blade donation stabilizes GATOR2's cage-like architecture and positions the WDR24-SEH1L subcomplex to interact with the leucine sensor Sestrin2, enabling GATOR2 to antagonize GATOR1's GAP activity toward RagA/B GTPases and thereby activate mTORC1 in response to amino acid sufficiency); additionally, SEH1L has chromatin-associated roles in neural development by cooperating with the NuRD complex to repress p21, and in Schwann cells by mediating the SETDB1-KAP1 interaction to suppress endogenous retrovirus-triggered necroptosis."},"narrative":{"teleology":[{"year":2004,"claim":"Establishing that SEH1L is a bona fide subunit of the Nup107-160 nuclear pore subcomplex resolved its molecular address and revealed its unexpected mitotic role at kinetochores.","evidence":"RNAi, GFP-tagging, immunofluorescence, and biochemical co-IP in HeLa cells","pmids":["15146057"],"confidence":"High","gaps":["No structural detail on how Seh1 integrates into the Y-complex","Precise contribution of Seh1 versus other subunits at kinetochores was unclear"]},{"year":2007,"claim":"Demonstrating that SEH1L depletion alone is sufficient to remove the entire Nup107-160 complex from kinetochores established it as a critical determinant of kinetochore-microtubule attachment fidelity and chromosome congression.","evidence":"siRNA knockdown, live-cell imaging, immunofluorescence, and kinetochore tension assays in HeLa cells","pmids":["17363900"],"confidence":"High","gaps":["Whether chromosome segregation defects arise from loss of a specific kinetochore effector or general Y-complex mislocalization was unresolved"]},{"year":2009,"claim":"Pinpointing Aurora B / chromosomal passenger complex mislocalization as the primary mitotic consequence of Seh1 loss narrowed the mechanism from general kinetochore dysfunction to a specific CPC-recruitment defect, while the Nup85–Seh1 crystal structure revealed the ancestral coatomer element underlying their interaction.","evidence":"siRNA, immunofluorescence, EM, live-cell imaging in HeLa (CPC study); X-ray crystallography of Nup85–Seh1 (structural study)","pmids":["19864462","19641729"],"confidence":"High","gaps":["Mechanism by which the Y-complex recruits CPC remained unknown","Whether Seh1's β-propeller blade donation to Nup85 is functionally analogous to its later-discovered role in GATOR2 was not explored"]},{"year":2011,"claim":"Identification of the yeast SEA complex and the Drosophila Seh1–Mio interaction revealed that Seh1 participates in a conserved vacuole/lysosome-associated nutrient-sensing complex distinct from the NPC, establishing its dual identity.","evidence":"Mass spectrometry and live-cell imaging in yeast (SEA complex); genetic null alleles and co-IP in Drosophila ovaries (Mio interaction)","pmids":["21454883","21521741"],"confidence":"High","gaps":["Mammalian equivalent of the SEA complex had not yet been defined","Whether Seh1's NPC and nutrient-sensing roles are functionally coupled was unknown"]},{"year":2013,"claim":"The discovery of GATOR2 in mammalian cells — with SEH1L as a core subunit alongside Mios, WDR24, WDR59, and Sec13 — and its epistatic placement upstream of GATOR1 unified the yeast and fly findings into a conserved mTORC1 amino acid sensing pathway.","evidence":"siRNA knockdown, epistasis analysis, co-IP, and mTORC1 activity assays in human cells (Science); genetic epistasis in S. cerevisiae (Cell Cycle)","pmids":["23723238","23974112"],"confidence":"High","gaps":["No structural information on GATOR2 architecture","How amino acid signals are transmitted to GATOR2 was unknown","Whether SEH1L directly contacts GATOR1 or sensors was unresolved"]},{"year":2014,"claim":"Genetic epistasis in Drosophila oogenesis confirmed that Seh1/GATOR2 activates TORC1 by antagonizing GATOR1, and further work revealed a TORC1-independent role for GATOR2 components in lysosome dynamics and autophagic flux.","evidence":"Genetic epistasis, RNAi, rapamycin treatment in Drosophila; null allele analysis and autophagy assays in Drosophila and HeLa cells","pmids":["25512509","27166823"],"confidence":"High","gaps":["Molecular basis of the TORC1-independent lysosome function remained undefined","Whether Seh1 specifically contributes to the lysosome role versus other GATOR2 subunits was unclear"]},{"year":2018,"claim":"Acute Seh1 degradation via auxin-inducible degron revealed that Seh1 is dispensable for Y-complex association with mitotic chromosomes but essential for GATOR2 and CPC recruitment to chromosomes, functionally separating its NPC-structural and signaling roles; separately, Aurora B-dependent phosphorylation of an RV[S/T]F motif in SEH1L was shown to disrupt PP1 binding during mitosis.","evidence":"Chemical genetics (AID) with quantitative chromosome proteomics in DLD-1 cells; phosphospecific antibodies and kinase assays","pmids":["29618633","29764992"],"confidence":"High","gaps":["How GATOR2 is recruited to chromosomes via Seh1 was mechanistically unresolved","Functional consequence of Seh1–PP1 interaction disruption on specific mitotic substrates was not defined"]},{"year":2021,"claim":"CRISPR knockout studies in mouse ESCs established that Seh1 is required for normal cell growth, viability upon differentiation, and proper NPC density, distinguishing its contribution from that of the Nup85 interaction alone.","evidence":"CRISPR genome editing, NPC density measurements, and differentiation assays in mESCs","pmids":["34037234"],"confidence":"Medium","gaps":["Whether the proliferation defect is NPC-mediated or GATOR2-mediated was not dissected","Single study without independent replication"]},{"year":2022,"claim":"The cryo-EM structure of GATOR2 revealed a 1.1 MDa cage-like architecture in which SEH1L donates a β-propeller blade to WDR24, explaining how it stabilizes the scaffold and positions WD40 dimers for sensor and GATOR1 interactions.","evidence":"Cryo-EM and biochemical reconstitution of purified human GATOR2","pmids":["35831510"],"confidence":"High","gaps":["Structure of GATOR2 bound to upstream sensors was not yet available","Conformational changes upon amino acid sensing were unresolved"]},{"year":2023,"claim":"Cell-type-specific conditional knockouts revealed two chromatin-associated functions of Seh1: in Schwann cells it mediates the SETDB1–KAP1 interaction to silence endogenous retroviruses (loss triggers ZBP1-dependent necroptosis and peripheral neuropathy), and in neural progenitors it shares a gene-regulatory role with Nup133 during neuroectodermal differentiation.","evidence":"Conditional KO in Schwann cells and mESC-derived neural progenitors, co-IP, transcriptomics","pmids":["37453065","37305998"],"confidence":"High","gaps":["How Seh1 bridges SETDB1 and KAP1 structurally is unknown","Whether these chromatin roles are NPC-tethered or NPC-independent was not fully resolved"]},{"year":2024,"claim":"Conditional Seh1 deletion in radial glial progenitors identified a NuRD complex-dependent mechanism: Seh1 cooperates with NuRD to repress p21 at the nuclear periphery, and its loss causes p21 derepression, impaired progenitor proliferation, and microcephaly — without nucleocytoplasmic transport defects.","evidence":"Conditional KO in mouse brain, ChIP, co-IP, transcriptome analysis, and p21 knockdown rescue","pmids":["38272027"],"confidence":"High","gaps":["Whether Seh1's NuRD cooperation requires its NPC integration or operates as a soluble nucleoplasmic pool","Broader target gene repertoire beyond p21 is not delineated"]},{"year":2025,"claim":"Cryo-EM structures of GATOR2 bound to Sestrin2 demonstrated that the leucine sensor engages specifically at the WDR24–SEH1L interface, inducing conformational changes confirmed by HDX-MS, thereby completing the structural pathway from amino acid sensing to GATOR2 activation.","evidence":"Cryo-EM and HDX-MS of human GATOR2–Sestrin2 complex","pmids":["40742811"],"confidence":"High","gaps":["How conformational changes at the WDR24–SEH1L interface propagate to relieve GATOR1 GAP activity is not structurally resolved","Whether SEH1L undergoes post-translational modifications that regulate sensor binding is unknown"]},{"year":null,"claim":"Key unresolved questions include: how SEH1L's dual residence in NPC and GATOR2 is partitioned and regulated; whether its chromatin-regulatory roles (NuRD, SETDB1–KAP1) depend on NPC-tethered or soluble pools; and how GATOR2 conformational changes at the WDR24–SEH1L interface mechanistically inhibit GATOR1.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structure of GATOR2–GATOR1 inhibitory interface","Partitioning mechanism between NPC and GATOR2 pools is unknown","Tissue-specific regulation of SEH1L's dual functions remains poorly understood"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[1,3,11]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[14,15]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[3,14,15,19]},{"term_id":"GO:0005694","term_label":"chromosome","supporting_discovery_ids":[4,5,6]},{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[4,5]},{"term_id":"GO:0005764","term_label":"lysosome","supporting_discovery_ids":[10,13]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0,1]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,1,2,8,9]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[4,5,6,12]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[13]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[14,15,19]},{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[3,16]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[14,15,19]}],"complexes":["Nup107-160 (Y-complex)","GATOR2","SEA complex (yeast)"],"partners":["NUP85","WDR24","MIOS","SEC13","WDR59","SETDB1","TRIM28","SESN2"],"other_free_text":[]},"mechanistic_narrative":"SEH1L is a WD40-repeat β-propeller protein that functions as a shared structural subunit of both the Nup107-160 nuclear pore subcomplex and the GATOR2 nutrient-sensing complex, linking nuclear pore biology, mitotic chromosome segregation, and mTORC1 signaling. Within the Nup107-160 (Y-complex), SEH1L forms a heterodimer with Nup85 via an ancestral coatomer element (ACE1), and its depletion displaces the complex from kinetochores, impairs chromosomal passenger complex (Aurora B) localization at centromeres, and causes chromosome congression and biorientation defects [PMID:15146057, PMID:17363900, PMID:19864462, PMID:19641729]. Within the GATOR2 complex, SEH1L integrates into a cage-like 1.1 MDa scaffold through β-propeller blade donation to WDR24, forming the WDR24–SEH1L subcomplex that directly engages the leucine sensor Sestrin2, thereby enabling GATOR2 to antagonize GATOR1's GAP activity toward Rag GTPases and activate mTORC1 in response to amino acid sufficiency [PMID:23723238, PMID:35831510, PMID:40742811]. Beyond these scaffolding roles, SEH1L has chromatin-associated functions: it cooperates with the NuRD complex to repress p21 in neural progenitors (with conditional loss causing microcephaly), and mediates the SETDB1–KAP1 interaction in Schwann cells to silence endogenous retroviruses and prevent ZBP1-dependent necroptosis [PMID:38272027, PMID:37453065]."},"prefetch_data":{"uniprot":{"accession":"Q96EE3","full_name":"Nucleoporin SEH1","aliases":["GATOR2 complex protein SEH1","Nup107-160 subcomplex subunit SEH1","SEC13-like protein"],"length_aa":360,"mass_kda":39.6,"function":"Component of the Nup107-160 subcomplex of the nuclear pore complex (NPC). The Nup107-160 subcomplex is required for the assembly of a functional NPC (PubMed:15146057, PubMed:17363900). The Nup107-160 subcomplex is also required for normal kinetochore microtubule attachment, mitotic progression and chromosome segregation. This subunit plays a role in recruitment of the Nup107-160 subcomplex to the kinetochore (PubMed:15146057, PubMed:17363900) As a component of the GATOR2 complex, functions as an activator of the amino acid-sensing branch of the mTORC1 signaling pathway (PubMed:23723238, PubMed:25457612, PubMed:27487210, PubMed:35831510, PubMed:36528027). The GATOR2 complex indirectly activates mTORC1 through the inhibition of the GATOR1 subcomplex (PubMed:23723238, PubMed:27487210, PubMed:35831510, PubMed:36528027). GATOR2 probably acts as an E3 ubiquitin-protein ligase toward GATOR1 (PubMed:36528027). In the presence of abundant amino acids, the GATOR2 complex mediates ubiquitination of the NPRL2 core component of the GATOR1 complex, leading to GATOR1 inactivation (PubMed:36528027). In the absence of amino acids, GATOR2 is inhibited, activating the GATOR1 complex (PubMed:25457612, PubMed:26972053, PubMed:27487210). Within the GATOR2 complex, SEC13 and SEH1L are required to stabilize the complex (PubMed:35831510)","subcellular_location":"Chromosome, centromere, kinetochore; Nucleus, nuclear pore complex; Lysosome membrane","url":"https://www.uniprot.org/uniprotkb/Q96EE3/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/SEH1L","classification":"Common Essential","n_dependent_lines":1160,"n_total_lines":1208,"dependency_fraction":0.9602649006622517},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"HSP90B1","stoichiometry":0.2},{"gene":"SEC13","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/SEH1L","total_profiled":1310},"omim":[{"mim_id":"621033","title":"NUP210-LIKE PROTEIN; NUP210L","url":"https://www.omim.org/entry/621033"},{"mim_id":"620307","title":"WD REPEAT-CONTAINING PROTEIN 24; WDR24","url":"https://www.omim.org/entry/620307"},{"mim_id":"617418","title":"WD REPEAT-CONTAINING PROTEIN 59; WDR59","url":"https://www.omim.org/entry/617418"},{"mim_id":"617034","title":"CELLULAR ARGININE SENSOR FOR MTORC1 PROTEIN 1; CASTOR1","url":"https://www.omim.org/entry/617034"},{"mim_id":"615359","title":"MEIOSIS REGULATOR FOR OOCYTE DEVELOPMENT; MIOS","url":"https://www.omim.org/entry/615359"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/SEH1L"},"hgnc":{"alias_symbol":["SEH1A","SEH1B","Seh1","SEC13L"],"prev_symbol":[]},"alphafold":{"accession":"Q96EE3","domains":[{"cath_id":"2.130.10.10","chopping":"162-327","consensus_level":"medium","plddt":91.6078,"start":162,"end":327}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96EE3","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q96EE3-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q96EE3-F1-predicted_aligned_error_v6.png","plddt_mean":86.94},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SEH1L","jax_strain_url":"https://www.jax.org/strain/search?query=SEH1L"},"sequence":{"accession":"Q96EE3","fasta_url":"https://rest.uniprot.org/uniprotkb/Q96EE3.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q96EE3/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96EE3"}},"corpus_meta":[{"pmid":"23723238","id":"PMC_23723238","title":"A Tumor suppressor complex with GAP activity for the Rag GTPases that signal amino acid sufficiency to mTORC1.","date":"2013","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/23723238","citation_count":882,"is_preprint":false},{"pmid":"15146057","id":"PMC_15146057","title":"The entire Nup107-160 complex, including three new members, is targeted as one entity to kinetochores in mitosis.","date":"2004","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/15146057","citation_count":223,"is_preprint":false},{"pmid":"17363900","id":"PMC_17363900","title":"The human Nup107-160 nuclear pore subcomplex contributes to proper kinetochore functions.","date":"2007","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/17363900","citation_count":171,"is_preprint":false},{"pmid":"20675572","id":"PMC_20675572","title":"NENA, a Lotus japonicus homolog of Sec13, is required for rhizodermal infection by arbuscular mycorrhiza fungi and rhizobia but dispensable for cortical endosymbiotic development.","date":"2010","source":"The Plant cell","url":"https://pubmed.ncbi.nlm.nih.gov/20675572","citation_count":151,"is_preprint":false},{"pmid":"27173016","id":"PMC_27173016","title":"Involvement of GATOR complex genes in familial focal epilepsies and focal cortical dysplasia.","date":"2016","source":"Epilepsia","url":"https://pubmed.ncbi.nlm.nih.gov/27173016","citation_count":139,"is_preprint":false},{"pmid":"21454883","id":"PMC_21454883","title":"A conserved coatomer-related complex containing Sec13 and Seh1 dynamically associates with the vacuole in Saccharomyces cerevisiae.","date":"2011","source":"Molecular & cellular proteomics : MCP","url":"https://pubmed.ncbi.nlm.nih.gov/21454883","citation_count":118,"is_preprint":false},{"pmid":"23974112","id":"PMC_23974112","title":"SEACing the GAP that nEGOCiates TORC1 activation: evolutionary conservation of Rag GTPase regulation.","date":"2013","source":"Cell cycle (Georgetown, 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mTORC1 amino acid sensing pathway; epistasis analysis shows GATOR2 acts upstream of GATOR1/DEPDC5, and inhibition of GATOR2 subunits including Seh1L suppresses mTORC1 signaling.\",\n      \"method\": \"siRNA knockdown, epistasis analysis, co-immunoprecipitation, mTORC1 activity assays\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP, epistasis, replicated across multiple studies\",\n      \"pmids\": [\"23723238\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Cryo-EM structure of human GATOR2 reveals a 1.1 MDa two-fold symmetric cage-like architecture with an octagonal scaffold containing two WDR24, four MIOS and two WDR59 subunits; SEH1L integrates into the scaffold via β-propeller blade donation, stabilizing the complex and orienting WD40 β-propeller dimers that mediate interactions with SESN2, CASTOR1, and GATOR1.\",\n      \"method\": \"Cryo-electron microscopy, biochemical reconstitution\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — cryo-EM structure with functional validation, rigorous single study\",\n      \"pmids\": [\"35831510\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Cryo-EM structures of GATOR2 bound to amino acid sensors show Sestrin2 (leucine sensor) interacts specifically with the WDR24-SEH1L subcomplex of GATOR2, inducing conformational movements; HDX-MS confirmed dynamic motions in these interfaces.\",\n      \"method\": \"Cryo-electron microscopy, hydrogen-deuterium exchange mass spectrometry (HDX-MS)\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — cryo-EM structure with HDX-MS orthogonal validation\",\n      \"pmids\": [\"40742811\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"SEH1L (Seh1) is a component of the Nup107-160 nuclear pore subcomplex; depletion by RNAi causes phenotypes similar to knockdown of other complex members, and the entire complex including Seh1 localizes to kinetochores from prophase to anaphase of mitosis.\",\n      \"method\": \"RNA interference, GFP-tagging, immunofluorescence, biochemical fractionation/co-immunoprecipitation\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP, live imaging, RNAi phenotype; replicated across multiple studies\",\n      \"pmids\": [\"15146057\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Depletion of SEH1L alone is sufficient to efficiently deplete the Nup107-160 complex from kinetochores, causing mitotic delay, impaired chromosome congression, reduced kinetochore tension, and kinetochore-microtubule attachment defects; the Nup107-160 complex is required at kinetochores for recruitment of Crm1 and RanGAP1-RanBP2.\",\n      \"method\": \"siRNA knockdown, live-cell imaging, immunofluorescence, kinetochore tension assays\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods, defined cellular phenotypes, replicated\",\n      \"pmids\": [\"17363900\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Seh1 depletion impairs Aurora B localization to centromeres, causing severe defects in chromosome biorientation, spindle midzone organization, and midbody formation, while microtubule-kinetochore attachments remain intact; the major mitotic function of the Nup107 complex is to ensure proper chromosomal passenger complex (CPC) localization.\",\n      \"method\": \"siRNA knockdown, immunofluorescence, electron microscopy, live-cell imaging\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods including EM, specific phenotypic readout\",\n      \"pmids\": [\"19864462\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Using chemical genetics (auxin-inducible degron) and quantitative chromosome proteomics, Seh1 was found not required for association of the Nup107 complex with mitotic chromosomes, but is essential for association of the GATOR2 complex and Nup153 with mitotic chromosomes, and for efficient localization of the chromosomal passenger complex (CPC) at centromeres.\",\n      \"method\": \"Chemical genetics (auxin-inducible degron), quantitative chromosome proteomics, immunofluorescence\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — chemical genetics with quantitative proteomics, multiple orthogonal methods\",\n      \"pmids\": [\"29618633\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"In Drosophila, Seh1 associates with the product of the missing oocyte (mio) gene (a GATOR2 component) and is required for oogenesis; in seh1 mutant ovaries, Mio protein accumulation is greatly diminished, and oocytes fail to maintain the meiotic cycle; seh1 null is dispensable for somatic tissue development.\",\n      \"method\": \"Co-immunoprecipitation, genetic null allele analysis, immunofluorescence, developmental phenotyping\",\n      \"journal\": \"Development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — null allele with specific phenotype, Co-IP binding partner identification, multiple methods\",\n      \"pmids\": [\"21521741\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"In Drosophila, GATOR2 components Mio and Seh1 are required to oppose GATOR1 (Iml1/GATOR1) activity during oogenesis; loss of Seh1 (or Mio) leads to constitutive TORC1 inhibition and block to oocyte growth; epistasis analysis shows GATOR2 acts as an antagonist of GATOR1 in the meiotic/oocyte context.\",\n      \"method\": \"Genetic epistasis, RNAi, rapamycin treatment, developmental phenotyping in Drosophila\",\n      \"journal\": \"Proceedings of the National Academy of Sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis with multiple alleles and pharmacological validation\",\n      \"pmids\": [\"25512509\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"In yeast (S. cerevisiae), Seh1 is a component of SEACAT (the GATOR2 ortholog within the SEA complex); genetic epistasis shows SEACAT antagonizes the GAP function of SEACIT (GATOR1 ortholog) toward Gtr1 (RagA/B ortholog) to regulate TORC1 activity.\",\n      \"method\": \"Genetic epistasis analysis in S. cerevisiae\",\n      \"journal\": \"Cell cycle\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis replicated across species, consistent with mammalian data\",\n      \"pmids\": [\"23974112\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"The SEA (Seh1-Associated) complex in yeast contains Seh1, Sec13, Npr2, Npr3, and four uncharacterized proteins (Sea1-Sea4); it dynamically associates with the vacuole in vivo; computational and biochemical approaches indicate structural similarity to COPI, COPII, NPC, and vesicle tethering complexes; genetic assays indicate roles in intracellular trafficking, amino acid biogenesis, and nitrogen starvation response.\",\n      \"method\": \"Mass spectrometry, biochemical fractionation, live-cell imaging, genetic assays, computational structural analysis\",\n      \"journal\": \"Molecular & cellular proteomics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods for complex identification and localization\",\n      \"pmids\": [\"21454883\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Crystal structure of Nup85 in complex with Seh1 defines a tripartite protein element called ACE1 (ancestral coatomer element); Nup85 shares this element with other nucleoporins and vesicle coat proteins, providing structural evidence for evolutionary relationship between NPC and COPII vesicle coats.\",\n      \"method\": \"X-ray crystallography, functional site prediction and verification\",\n      \"journal\": \"Communicative & integrative biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure with functional validation of predicted interaction sites\",\n      \"pmids\": [\"19641729\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"SEH1 (SEH1L) contains an RV[S/T]F motif that is phosphorylated by Aurora B kinase during mitosis, which abrogates its interaction with PP1 phosphatase; this mechanism maintains phosphorylation of PP1 substrates during mitosis by disrupting PP1 holoenzyme assembly.\",\n      \"method\": \"Phosphospecific antibody (RVp[S/T]F), mass spectrometry, kinase assays, co-immunoprecipitation\",\n      \"journal\": \"Science signaling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — phosphospecific antibody and biochemical validation, but SEH1 is one of multiple proteins identified\",\n      \"pmids\": [\"29764992\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"In Drosophila, GATOR2 component Seh1 (along with Mio and Wdr24) has a TORC1-independent role in regulating lysosome dynamics and autophagic flux, in addition to its role in TORC1 activation; epistasis analysis between wdr24 and GATOR1 components established this dual function.\",\n      \"method\": \"Genetic epistasis, null allele analysis, cell biology (lysosome/autophagy assays) in Drosophila and HeLa cells\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — epistasis plus knockout HeLa validation, multiple orthogonal methods\",\n      \"pmids\": [\"27166823\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SEH1 (Seh1) cooperates with the NuRD transcription repressor complex at the nuclear periphery in neural stem cells to repress p21 expression; loss of Seh1 in radial glial progenitors derepresses p21, leading to defective neural progenitor proliferation, impaired neurogenesis, and microcephaly, without defects in nucleocytoplasmic transport.\",\n      \"method\": \"Conditional knockout, transcriptome analysis, ChIP, co-immunoprecipitation, p21 knockdown rescue experiment\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — conditional KO with defined molecular mechanism, multiple orthogonal methods, rescue experiment\",\n      \"pmids\": [\"38272027\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Seh1 in Schwann cells maintains genome stability by mediating the interaction between SETDB1 and KAP1; loss of Seh1 disrupts this interaction, derepresses endogenous retroviruses, and triggers ZBP1-dependent necroptosis, leading to progressive loss of Schwann cells and peripheral neuropathy.\",\n      \"method\": \"Conditional knockout, co-immunoprecipitation, transcriptome analysis, immunofluorescence, nerve function assays\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — conditional KO with defined molecular mechanism and binding partner, multiple orthogonal methods\",\n      \"pmids\": [\"37453065\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Seh1 and Nup43, but not Nup85 (with impaired Seh1 interaction), are required for normal cell growth rates, viability upon differentiation, and maintenance of proper NPC density in mouse embryonic stem cells; it is the integrity of the Y-complex (not NPC number alone) that is critical for proliferation and differentiation.\",\n      \"method\": \"Genome editing (CRISPR), NPC density measurements, differentiation assays in mESCs\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean genetic KO with defined cellular phenotype, but single study\",\n      \"pmids\": [\"34037234\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Cryo-EM structure of the yeast SEAC-EGOC supercomplex shows SEACIT binds two EGOC molecules exclusively in the 'active' conformation without involvement of SEACAT (which contains Seh1/Sea2-Sea4/Sec13); loss of Sea2 (GATOR2 subunit equivalent to WDR59) or its N-terminal β-propeller yields strong defects in amino acid signaling, suggesting this β-propeller recruits a GAP inhibitor for fast TORC1 regulation.\",\n      \"method\": \"Cryo-electron microscopy, genetic analysis, biochemical assays in S. cerevisiae\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — cryo-EM structure with genetic functional validation\",\n      \"pmids\": [\"41680390\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Structural modeling and FRET analysis show Sestrin2 interacts with the WDR24-Seh1L interface of GATOR2, and CASTOR1 interacts with the Mios β-propeller; deletion of Mios β-propeller severely impedes GATOR2 conformational changes in response to arginine levels.\",\n      \"method\": \"AlphaFold2 structural prediction, FRET analysis, mutagenesis, molecular dynamics simulations\",\n      \"journal\": \"Bioscience reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — computational structure prediction with FRET and mutagenesis, single lab\",\n      \"pmids\": [\"38372438\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Seh1 and Nup133 (Y-complex nucleoporins) share a function in gene regulation during neuroectodermal differentiation of mouse embryonic stem cells; Seh1-deficient neural progenitors misregulate Lhx1 and Nup210l, with only a mild reduction in NPC density, suggesting a chromatin/gene regulatory role independent of nuclear pore basket integrity.\",\n      \"method\": \"Transcriptomic analysis, genetic knockout in mESCs, NPC density measurement\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — transcriptomics plus genetic KO, but limited mechanistic detail for Seh1 specifically\",\n      \"pmids\": [\"37305998\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SEH1L is a dual-function nucleoporin that serves as a structural component of both the Nup107-160 nuclear pore subcomplex (mediating kinetochore localization, chromosomal passenger complex recruitment, and NPC assembly) and the GATOR2 nutrient-sensing complex (where its integration via β-propeller blade donation stabilizes GATOR2's cage-like architecture and positions the WDR24-SEH1L subcomplex to interact with the leucine sensor Sestrin2, enabling GATOR2 to antagonize GATOR1's GAP activity toward RagA/B GTPases and thereby activate mTORC1 in response to amino acid sufficiency); additionally, SEH1L has chromatin-associated roles in neural development by cooperating with the NuRD complex to repress p21, and in Schwann cells by mediating the SETDB1-KAP1 interaction to suppress endogenous retrovirus-triggered necroptosis.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"SEH1L is a WD40-repeat β-propeller protein that functions as a shared structural subunit of both the Nup107-160 nuclear pore subcomplex and the GATOR2 nutrient-sensing complex, linking nuclear pore biology, mitotic chromosome segregation, and mTORC1 signaling. Within the Nup107-160 (Y-complex), SEH1L forms a heterodimer with Nup85 via an ancestral coatomer element (ACE1), and its depletion displaces the complex from kinetochores, impairs chromosomal passenger complex (Aurora B) localization at centromeres, and causes chromosome congression and biorientation defects [PMID:15146057, PMID:17363900, PMID:19864462, PMID:19641729]. Within the GATOR2 complex, SEH1L integrates into a cage-like 1.1 MDa scaffold through β-propeller blade donation to WDR24, forming the WDR24–SEH1L subcomplex that directly engages the leucine sensor Sestrin2, thereby enabling GATOR2 to antagonize GATOR1's GAP activity toward Rag GTPases and activate mTORC1 in response to amino acid sufficiency [PMID:23723238, PMID:35831510, PMID:40742811]. Beyond these scaffolding roles, SEH1L has chromatin-associated functions: it cooperates with the NuRD complex to repress p21 in neural progenitors (with conditional loss causing microcephaly), and mediates the SETDB1–KAP1 interaction in Schwann cells to silence endogenous retroviruses and prevent ZBP1-dependent necroptosis [PMID:38272027, PMID:37453065].\",\n  \"teleology\": [\n    {\n      \"year\": 2004,\n      \"claim\": \"Establishing that SEH1L is a bona fide subunit of the Nup107-160 nuclear pore subcomplex resolved its molecular address and revealed its unexpected mitotic role at kinetochores.\",\n      \"evidence\": \"RNAi, GFP-tagging, immunofluorescence, and biochemical co-IP in HeLa cells\",\n      \"pmids\": [\"15146057\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No structural detail on how Seh1 integrates into the Y-complex\", \"Precise contribution of Seh1 versus other subunits at kinetochores was unclear\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Demonstrating that SEH1L depletion alone is sufficient to remove the entire Nup107-160 complex from kinetochores established it as a critical determinant of kinetochore-microtubule attachment fidelity and chromosome congression.\",\n      \"evidence\": \"siRNA knockdown, live-cell imaging, immunofluorescence, and kinetochore tension assays in HeLa cells\",\n      \"pmids\": [\"17363900\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether chromosome segregation defects arise from loss of a specific kinetochore effector or general Y-complex mislocalization was unresolved\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Pinpointing Aurora B / chromosomal passenger complex mislocalization as the primary mitotic consequence of Seh1 loss narrowed the mechanism from general kinetochore dysfunction to a specific CPC-recruitment defect, while the Nup85–Seh1 crystal structure revealed the ancestral coatomer element underlying their interaction.\",\n      \"evidence\": \"siRNA, immunofluorescence, EM, live-cell imaging in HeLa (CPC study); X-ray crystallography of Nup85–Seh1 (structural study)\",\n      \"pmids\": [\"19864462\", \"19641729\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which the Y-complex recruits CPC remained unknown\", \"Whether Seh1's β-propeller blade donation to Nup85 is functionally analogous to its later-discovered role in GATOR2 was not explored\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Identification of the yeast SEA complex and the Drosophila Seh1–Mio interaction revealed that Seh1 participates in a conserved vacuole/lysosome-associated nutrient-sensing complex distinct from the NPC, establishing its dual identity.\",\n      \"evidence\": \"Mass spectrometry and live-cell imaging in yeast (SEA complex); genetic null alleles and co-IP in Drosophila ovaries (Mio interaction)\",\n      \"pmids\": [\"21454883\", \"21521741\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mammalian equivalent of the SEA complex had not yet been defined\", \"Whether Seh1's NPC and nutrient-sensing roles are functionally coupled was unknown\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"The discovery of GATOR2 in mammalian cells — with SEH1L as a core subunit alongside Mios, WDR24, WDR59, and Sec13 — and its epistatic placement upstream of GATOR1 unified the yeast and fly findings into a conserved mTORC1 amino acid sensing pathway.\",\n      \"evidence\": \"siRNA knockdown, epistasis analysis, co-IP, and mTORC1 activity assays in human cells (Science); genetic epistasis in S. cerevisiae (Cell Cycle)\",\n      \"pmids\": [\"23723238\", \"23974112\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No structural information on GATOR2 architecture\", \"How amino acid signals are transmitted to GATOR2 was unknown\", \"Whether SEH1L directly contacts GATOR1 or sensors was unresolved\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Genetic epistasis in Drosophila oogenesis confirmed that Seh1/GATOR2 activates TORC1 by antagonizing GATOR1, and further work revealed a TORC1-independent role for GATOR2 components in lysosome dynamics and autophagic flux.\",\n      \"evidence\": \"Genetic epistasis, RNAi, rapamycin treatment in Drosophila; null allele analysis and autophagy assays in Drosophila and HeLa cells\",\n      \"pmids\": [\"25512509\", \"27166823\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of the TORC1-independent lysosome function remained undefined\", \"Whether Seh1 specifically contributes to the lysosome role versus other GATOR2 subunits was unclear\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Acute Seh1 degradation via auxin-inducible degron revealed that Seh1 is dispensable for Y-complex association with mitotic chromosomes but essential for GATOR2 and CPC recruitment to chromosomes, functionally separating its NPC-structural and signaling roles; separately, Aurora B-dependent phosphorylation of an RV[S/T]F motif in SEH1L was shown to disrupt PP1 binding during mitosis.\",\n      \"evidence\": \"Chemical genetics (AID) with quantitative chromosome proteomics in DLD-1 cells; phosphospecific antibodies and kinase assays\",\n      \"pmids\": [\"29618633\", \"29764992\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How GATOR2 is recruited to chromosomes via Seh1 was mechanistically unresolved\", \"Functional consequence of Seh1–PP1 interaction disruption on specific mitotic substrates was not defined\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"CRISPR knockout studies in mouse ESCs established that Seh1 is required for normal cell growth, viability upon differentiation, and proper NPC density, distinguishing its contribution from that of the Nup85 interaction alone.\",\n      \"evidence\": \"CRISPR genome editing, NPC density measurements, and differentiation assays in mESCs\",\n      \"pmids\": [\"34037234\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether the proliferation defect is NPC-mediated or GATOR2-mediated was not dissected\", \"Single study without independent replication\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"The cryo-EM structure of GATOR2 revealed a 1.1 MDa cage-like architecture in which SEH1L donates a β-propeller blade to WDR24, explaining how it stabilizes the scaffold and positions WD40 dimers for sensor and GATOR1 interactions.\",\n      \"evidence\": \"Cryo-EM and biochemical reconstitution of purified human GATOR2\",\n      \"pmids\": [\"35831510\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structure of GATOR2 bound to upstream sensors was not yet available\", \"Conformational changes upon amino acid sensing were unresolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Cell-type-specific conditional knockouts revealed two chromatin-associated functions of Seh1: in Schwann cells it mediates the SETDB1–KAP1 interaction to silence endogenous retroviruses (loss triggers ZBP1-dependent necroptosis and peripheral neuropathy), and in neural progenitors it shares a gene-regulatory role with Nup133 during neuroectodermal differentiation.\",\n      \"evidence\": \"Conditional KO in Schwann cells and mESC-derived neural progenitors, co-IP, transcriptomics\",\n      \"pmids\": [\"37453065\", \"37305998\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How Seh1 bridges SETDB1 and KAP1 structurally is unknown\", \"Whether these chromatin roles are NPC-tethered or NPC-independent was not fully resolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Conditional Seh1 deletion in radial glial progenitors identified a NuRD complex-dependent mechanism: Seh1 cooperates with NuRD to repress p21 at the nuclear periphery, and its loss causes p21 derepression, impaired progenitor proliferation, and microcephaly — without nucleocytoplasmic transport defects.\",\n      \"evidence\": \"Conditional KO in mouse brain, ChIP, co-IP, transcriptome analysis, and p21 knockdown rescue\",\n      \"pmids\": [\"38272027\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether Seh1's NuRD cooperation requires its NPC integration or operates as a soluble nucleoplasmic pool\", \"Broader target gene repertoire beyond p21 is not delineated\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Cryo-EM structures of GATOR2 bound to Sestrin2 demonstrated that the leucine sensor engages specifically at the WDR24–SEH1L interface, inducing conformational changes confirmed by HDX-MS, thereby completing the structural pathway from amino acid sensing to GATOR2 activation.\",\n      \"evidence\": \"Cryo-EM and HDX-MS of human GATOR2–Sestrin2 complex\",\n      \"pmids\": [\"40742811\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How conformational changes at the WDR24–SEH1L interface propagate to relieve GATOR1 GAP activity is not structurally resolved\", \"Whether SEH1L undergoes post-translational modifications that regulate sensor binding is unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include: how SEH1L's dual residence in NPC and GATOR2 is partitioned and regulated; whether its chromatin-regulatory roles (NuRD, SETDB1–KAP1) depend on NPC-tethered or soluble pools; and how GATOR2 conformational changes at the WDR24–SEH1L interface mechanistically inhibit GATOR1.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structure of GATOR2–GATOR1 inhibitory interface\", \"Partitioning mechanism between NPC and GATOR2 pools is unknown\", \"Tissue-specific regulation of SEH1L's dual functions remains poorly understood\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [1, 3, 11]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [14, 15]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [3, 14, 15, 19]},\n      {\"term_id\": \"GO:0005694\", \"supporting_discovery_ids\": [4, 5, 6]},\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [4, 5]},\n      {\"term_id\": \"GO:0005764\", \"supporting_discovery_ids\": [10, 13]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 1, 2, 8, 9]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [4, 5, 6, 12]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [13]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [14, 15, 19]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [3, 16]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [14, 15, 19]}\n    ],\n    \"complexes\": [\n      \"Nup107-160 (Y-complex)\",\n      \"GATOR2\",\n      \"SEA complex (yeast)\"\n    ],\n    \"partners\": [\n      \"NUP85\",\n      \"WDR24\",\n      \"MIOS\",\n      \"SEC13\",\n      \"WDR59\",\n      \"SETDB1\",\n      \"TRIM28\",\n      \"SESN2\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}