{"gene":"SEH1L","run_date":"2026-06-10T07:46:30","timeline":{"discoveries":[{"year":2013,"finding":"SEH1L (Seh1L) is a subunit of the GATOR2 complex (together with Mios, WDR24, WDR59, and Sec13), which positively regulates mTORC1 signaling. Inhibition of GATOR2 subunits including Seh1L suppresses mTORC1 signaling; epistasis analysis shows GATOR2 negatively regulates DEPDC5 (a GATOR1 subunit), placing GATOR2 upstream of GATOR1 in the amino acid-sensing pathway to mTORC1.","method":"siRNA knockdown, epistasis analysis, co-immunoprecipitation, mTORC1 activity assays (phospho-S6K)","journal":"Science","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, epistasis, multiple orthogonal methods, replicated across multiple subsequent 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. SEH1L and SEC13 are integrated into the octagonal scaffold through β-propeller blade donation (blade insertion), which stabilizes the GATOR2 complex and reveals an evolutionary relationship to the nuclear pore and membrane-coating complexes. The scaffold orients WD40 β-propeller dimers that mediate interactions with SESN2, CASTOR1, and GATOR1.","method":"Cryo-electron microscopy (cryo-EM) structure determination","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 / Strong — cryo-EM structure at near-atomic resolution with functional validation of subunit integration mechanism","pmids":["35831510"],"is_preprint":false},{"year":2025,"finding":"Cryo-EM structures of GATOR2 in inhibitory states (CASTOR1-bound, Sestrin2-bound, and dual-bound) show that Sestrin2 (leucine sensor) interacts specifically with the WDR24-Seh1L subcomplex of GATOR2, inducing conformational movements. HDX-MS confirmed dynamic motions in apo-GATOR2 and its complexes with amino acid sensors.","method":"Cryo-electron microscopy (cryo-EM), hydrogen-deuterium exchange mass spectrometry (HDX-MS)","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1 / Moderate — cryo-EM structure with HDX-MS validation, single study with multiple orthogonal methods","pmids":["40742811"],"is_preprint":false},{"year":2004,"finding":"Seh1 is identified as a member of the Nup107-160 nuclear pore subcomplex in vertebrates. RNAi-mediated depletion of Seh1 leads to phenotypes similar to knockdown of other Nup107-160 constituents. Seh1, along with all other Nup107-160 complex members, is targeted to kinetochores from prophase to anaphase of mitosis.","method":"Co-immunoprecipitation, RNAi knockdown, GFP live-cell imaging, immunofluorescence","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, RNAi phenotype, live imaging, replicated in multiple subsequent studies","pmids":["15146057"],"is_preprint":false},{"year":2007,"finding":"Depletion of Seh1 alone is sufficient to efficiently remove the Nup107-160 complex from kinetochores, causing mitotic delay, impaired chromosome congression, reduced kinetochore tension, and kinetochore-microtubule attachment defects. The presence of the Nup107-160 complex at kinetochores (dependent on Seh1) is required for the recruitment of Crm1 and RanGAP1-RanBP2 to kinetochores.","method":"siRNA knockdown, immunofluorescence, live-cell imaging, mitotic phenotype analysis","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean siRNA depletion with multiple specific phenotypic readouts and downstream pathway placement, replicated across labs","pmids":["17363900"],"is_preprint":false},{"year":2009,"finding":"Seh1 depletion impairs Aurora B localization to centromeres (the chromosomal passenger complex, CPC), resulting in defects in biorientation and organization of the spindle midzone and midbody. Seh1 regulates chromosome alignment and segregation by controlling centromeric localization of Aurora B; microtubule-kinetochore attachments (assessed by EM) are intact in Seh1-depleted cells.","method":"siRNA knockdown, immunofluorescence, electron microscopy, live-cell imaging","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean KD with specific mechanistic readout (Aurora B mislocalization), electron microscopy structural validation, multiple methods","pmids":["19864462"],"is_preprint":false},{"year":2018,"finding":"Using chemical genetics (auxin-inducible degron) and quantitative chromosome proteomics, Seh1 is shown to be dispensable for association of the Nup107 complex with mitotic chromosomes, but essential for the association of the GATOR2 complex and nucleoporin Nup153 with mitotic chromosomes. Seh1 is also required at human centromeres for efficient localization of the chromosomal passenger complex (CPC).","method":"Auxin-inducible degron (chemical genetics), quantitative mass spectrometry-based chromosome proteomics, immunofluorescence","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Strong — rapid inducible depletion with quantitative proteomics, multiple orthogonal methods, clean mechanistic distinction from Nup107 complex function","pmids":["29618633"],"is_preprint":false},{"year":2011,"finding":"In Drosophila, Seh1 (SEH1L ortholog) associates with the product of the missing oocyte (mio) gene (a GATOR2 component). Loss of seh1 in the female germline causes failure of oocytes to maintain the meiotic cycle (pseudo-nurse cell development), phenocopying mio mutants. Mio protein accumulation is greatly diminished in seh1 mutant background, indicating Seh1 stabilizes Mio. Seh1 is dispensable for development of somatic tissues.","method":"Genetic null allele, co-immunoprecipitation, immunofluorescence, genetic interaction analysis","journal":"Development","confidence":"High","confidence_rationale":"Tier 2 / Strong — null allele with specific germline phenotype, Co-IP demonstrating physical interaction, protein stability assay","pmids":["21521741"],"is_preprint":false},{"year":2014,"finding":"In Drosophila, GATOR2 components Mio and Seh1 are required to oppose Iml1/GATOR1 activity to prevent constitutive inhibition of TORC1, and their loss causes a block to oocyte growth and development. Epistasis analysis places GATOR2 (including Seh1) as an antagonist of GATOR1 in the TORC1 pathway during oogenesis.","method":"Genetic null alleles, epistasis analysis, rapamycin treatment, TORC1 activity assays","journal":"Proceedings of the National Academy of Sciences","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis with null alleles, pharmacological validation with rapamycin, replicated across organisms","pmids":["25512509"],"is_preprint":false},{"year":2011,"finding":"The SEA (Seh1-associated) complex in yeast contains Seh1 and Sec13 (along with Npr2, Npr3, and Sea1-Sea4). Combined computational and biochemical analysis indicates SEA complex proteins possess structural characteristics similar to membrane coating complexes (COPI, COPII, NPC). The SEA complex dynamically associates with the vacuole in vivo and functions in intracellular trafficking, amino acid biogenesis, and response to nitrogen starvation.","method":"Affinity purification/mass spectrometry, computational structural prediction, live-cell fluorescence microscopy, genetic assays","journal":"Molecular & cellular proteomics","confidence":"High","confidence_rationale":"Tier 2 / Strong — biochemical complex purification, MS identification, live imaging, genetic validation, multiple orthogonal methods","pmids":["21454883"],"is_preprint":false},{"year":2013,"finding":"In yeast, SEACAT (the GATOR2 equivalent subcomplex containing Seh1, Sea2-4, and Sec13) antagonizes the GAP function of SEACIT (GATOR1 equivalent) toward Gtr1 (RagA ortholog), as demonstrated by genetic epistasis. Loss of SEACAT subunits suppresses TORC1 activity downstream of amino acid signaling.","method":"Genetic epistasis analysis, TORC1 activity assays","journal":"Cell cycle","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis analysis in yeast, single lab, consistent with mammalian findings","pmids":["23974112"],"is_preprint":false},{"year":2016,"finding":"In Drosophila, Seh1 (GATOR2 component) has a TORC1-independent role in the regulation of lysosome function and autophagic flux, in addition to its role in TORC1 activation. This TORC1-independent lysosome function is shared with other GATOR2 members Mio and Wdr24.","method":"Genetic null alleles, epistasis analysis with GATOR1 components, lysosome acidification assays, autophagy flux assays","journal":"PLoS genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis with null alleles, cell biological assays, single study","pmids":["27166823"],"is_preprint":false},{"year":2009,"finding":"The crystal structure of Nup85 in complex with Seh1 defines a new tripartite protein element (ancestral coatomer element ACE1) shared with other nucleoporins and vesicle coat proteins. Seh1 forms the short arm of the Y-shaped Nup84 complex together with Nup85. Functional sites predicted by analogy to COPII coat interactions were verified experimentally.","method":"Crystal structure determination, mutagenesis, functional interaction assays","journal":"Communicative & integrative biology","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — crystal structure with functional mutagenesis, single study","pmids":["19641729"],"is_preprint":false},{"year":2023,"finding":"Seh1 (SEH1L) maintains Schwann cell homeostasis by safeguarding genome stability through mediating the interaction between SETDB1 and KAP1. Loss of Seh1 disrupts this interaction, derepresses endogenous retroviruses, and triggers ZBP1-dependent necroptosis in Schwann cells, leading to progressive reduction of non-myelinating Schwann cells and neural fiber degeneration.","method":"Conditional knockout, co-immunoprecipitation, transcriptome analysis, immunofluorescence, necroptosis assays","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO with specific mechanistic follow-up (Co-IP of SETDB1/KAP1 interaction), single lab study","pmids":["37453065"],"is_preprint":false},{"year":2024,"finding":"Seh1 cooperates with the NuRD transcription repressor complex at the nuclear periphery to repress p21 expression in neural stem cells. Depletion of Seh1 in radial glial progenitors derepresses p21, leading to defective neural progenitor proliferation and differentiation, impaired neurogenesis, and microcephaly. This function is independent of nucleocytoplasmic transport defects.","method":"Conditional knockout, transcriptome analysis, p21 knockdown rescue experiment, co-localization/nuclear periphery association assays","journal":"Developmental cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO with transcriptomic and functional rescue (p21 knockdown), mechanistic pathway placement, single lab","pmids":["38272027"],"is_preprint":false},{"year":2021,"finding":"Seh1 and Nup43 are dispensable in pluripotent mouse embryonic stem cells but required for normal cell growth rates and viability upon neuroectodermal differentiation, as well as maintenance of proper nuclear pore complex density. An N-terminally truncated Nup85 mutation that greatly impairs interaction with Seh1 reduces NPC density but does not affect proliferation or differentiation, indicating Y-complex integrity (not NPC number per se) is critical.","method":"CRISPR/Cas9 genome editing, cell viability assays, NPC density quantification by electron microscopy/immunofluorescence, differentiation assays","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean genetic KO with specific functional readouts and mechanistic distinction, single lab","pmids":["34037234"],"is_preprint":false},{"year":2004,"finding":"In S. pombe, Seh1 (ortholog) is localized at the nuclear envelope as part of the conserved Nup107-120 complex. Deletion of Nup107-120 complex members causes mRNA export defects and cell division defects (abnormal septa, mitotic spindles, chromosome missegregation) at restrictive temperature; genetic interaction with the Ran GTPase pathway is demonstrated by synthetic toxicity of a nonfunctional Ran-GFP allele in nup120 and nup133 deletion backgrounds.","method":"Deletion mutants, fluorescence microscopy, mRNA export assays, genetic epistasis/synthetic lethality","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with functional assays and epistasis, ortholog study in fission yeast","pmids":["15226438"],"is_preprint":false},{"year":2007,"finding":"Seh1 (yeast) directly interacts with importin Kap95 as detected by the Bead Halo equilibrium binding assay, suggesting a role for this interaction during nuclear pore complex biogenesis.","method":"Bead Halo in vitro binding assay (equilibrium-based)","journal":"Molecular & cellular proteomics","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single in vitro binding assay, functional consequence not directly demonstrated in this paper","pmids":["17897934"],"is_preprint":false},{"year":2018,"finding":"SEH1 contains a RV[S/T]F motif (PP1-binding motif) that is phosphorylated specifically during mitosis, predominantly by Aurora B kinase, abrogating PP1 binding to SEH1. This represents a mechanism by which Aurora B and PP1 coordinate to control mitotic progression via dissolution of PP1 holoenzymes.","method":"Phospho-specific antibody (RVpSF), mass spectrometry, kinase assays, immunoprecipitation","journal":"Science signaling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — phospho-specific antibody plus MS identification, Aurora B kinase assay, single study","pmids":["29764992"],"is_preprint":false},{"year":2026,"finding":"In yeast, cryo-EM structure of the SEAC (GATOR) bound to the EGOC (Ragulator-Rag GTPase complex) shows a single SEAC interacts with two EGOC molecules via SEACIT, binding exclusively to the 'active' EGOC conformation, without involvement of SEACAT (which contains Seh1/Sea2-4/Sec13). The Sea2 β-propeller domain of SEACAT is required for robust amino acid signaling to TORC1, suggesting it recruits a GAP inhibitor for fast signaling.","method":"Cryo-electron microscopy, genetic analysis (deletion mutants), TORC1 activity assays","journal":"Nature structural & molecular biology","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — cryo-EM structure with genetic validation, single study, yeast ortholog","pmids":["41680390"],"is_preprint":false},{"year":2024,"finding":"SEH1L silencing activates the ATF3/HMOX1/GPX4 axis, decreases mitochondrial membrane potential and GSH while increasing ROS and MDA, inducing ferroptosis and suppressing hepatocellular carcinoma progression. Knockdown of ATF3 reverses these effects. These findings were validated in vitro and in vivo (subcutaneous tumor model).","method":"siRNA knockdown, next-generation sequencing, RT-qPCR, western blotting, flow cytometry, xenograft model","journal":"Apoptosis","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, pathway placement via RNAseq + ATF3 rescue, no direct biochemical mechanism for how SEH1L regulates ATF3","pmids":["39095556"],"is_preprint":false},{"year":2023,"finding":"Nup133 and Seh1, two components of the Y-complex NPC subassembly, independently regulate a subset of genes including Lhx1 and Nup210l during neuroectodermal differentiation. Gene regulation by Seh1 in neural progenitors appears independent of nuclear pore basket integrity (Seh1 depletion causes only mild reduction in NPC density).","method":"Transcriptomic analysis, siRNA/genetic depletion, NPC density quantification, differentiation assays","journal":"Journal of cell science","confidence":"Low","confidence_rationale":"Tier 3 / Weak — transcriptomic correlation with depletion, limited direct mechanistic follow-up for Seh1 specifically","pmids":["37305998"],"is_preprint":false}],"current_model":"SEH1L (Seh1) is a dual-complex nucleoporin that functions as a structural subunit of both the Nup107-160 nuclear pore complex (NPC) and the GATOR2 complex: in the NPC it integrates via β-propeller blade donation to stabilize complex architecture and is required at kinetochores for Aurora B/CPC localization and chromosome segregation; in GATOR2 (together with WDR24, MIOS, WDR59, and SEC13) it forms part of a cage-like mTORC1 regulatory hub where its WDR24-Seh1L subcomplex directly binds the leucine sensor Sestrin2, enabling GATOR2 to antagonize GATOR1 GAP activity toward RagA/B GTPases and thereby promote amino acid-dependent mTORC1 activation; additionally, Seh1 has NPC-independent chromatin-associated functions including repression of p21 via the NuRD complex in neural stem cells and maintenance of genome stability through stabilizing SETDB1-KAP1 interaction in Schwann cells."},"narrative":{"mechanistic_narrative":"SEH1L (Seh1) is a WD40 β-propeller protein that functions as a shared structural subunit of two distinct β-propeller-based assemblies — the Nup107-160 nuclear pore subcomplex and the GATOR2 complex — and additionally carries out NPC-independent chromatin functions [PMID:15146057, PMID:23723238, PMID:38272027]. In GATOR2, Seh1L assembles with Mios, WDR24, WDR59, and Sec13 to positively regulate mTORC1 signaling, acting upstream of and antagonizing the GATOR1 GAP toward Rag GTPases in the amino acid-sensing pathway [PMID:23723238, PMID:25512509]. Cryo-EM defines GATOR2 as a 1.1 MDa two-fold-symmetric cage in which SEH1L and SEC13 integrate via β-propeller blade donation to stabilize the scaffold, and the WDR24-Seh1L subcomplex serves as the direct docking site for the leucine sensor Sestrin2, which induces conformational changes that gate signaling [PMID:35831510, PMID:40742811]. In the nuclear pore, Seh1 forms the short arm of the Y-shaped Nup84/Nup107-160 complex through an ancestral coatomer element (ACE1) interface with Nup85, and is required to target this complex to kinetochores during mitosis [PMID:19641729, PMID:15146057, PMID:17363900]. Loss of Seh1 strips the Nup107-160 complex from kinetochores and impairs centromeric recruitment of Aurora B/the chromosomal passenger complex, causing biorientation defects, reduced kinetochore tension, and chromosome missegregation [PMID:17363900, PMID:19864462, PMID:29618633]. Beyond the pore, Seh1 cooperates with the NuRD complex at the nuclear periphery to repress p21 in neural stem cells, and stabilizes the SETDB1-KAP1 interaction to maintain genome stability in Schwann cells — chromatin-associated roles independent of nucleocytoplasmic transport [PMID:38272027, PMID:37453065].","teleology":[{"year":2004,"claim":"Established Seh1 as a constituent of the vertebrate Nup107-160 nuclear pore subcomplex and showed it shares the loss-of-function phenotypes of its partners, defining its baseline structural role at the NPC.","evidence":"Co-IP, RNAi knockdown, and live-cell imaging in vertebrate cells; deletion/genetic analysis of the conserved Nup107-120 complex in S. pombe","pmids":["15146057","15226438"],"confidence":"High","gaps":["Did not resolve the structural interface tethering Seh1 within the complex","Mitotic kinetochore function not yet mechanistically dissected"]},{"year":2007,"claim":"Demonstrated that Seh1 specifically anchors the Nup107-160 complex at kinetochores and that this is required to recruit downstream Crm1 and RanGAP1-RanBP2, linking the nucleoporin to mitotic fidelity.","evidence":"siRNA depletion with immunofluorescence, live-cell imaging, and mitotic phenotype analysis","pmids":["17363900"],"confidence":"High","gaps":["How Seh1 loss selectively removes the complex from kinetochores not defined","Did not yet connect to Aurora B/CPC"]},{"year":2009,"claim":"Identified the mechanistic consequence of Seh1 loss as failure to load Aurora B/the CPC at centromeres, explaining biorientation and segregation defects independent of microtubule attachment integrity.","evidence":"siRNA knockdown with immunofluorescence, electron microscopy, and live-cell imaging; crystal structure of the Nup85-Seh1 ACE1 interface with mutagenesis","pmids":["19864462","19641729"],"confidence":"High","gaps":["Molecular link between Nup107-160 presence and CPC recruitment unresolved","ACE1 functional sites verified by analogy rather than full reconstitution"]},{"year":2013,"claim":"Placed Seh1L within the GATOR2 complex as a positive regulator of mTORC1 acting upstream of GATOR1, defining a second, transport-independent macromolecular role.","evidence":"siRNA knockdown, reciprocal co-IP, epistasis, and phospho-S6K mTORC1 activity assays in human cells; genetic epistasis and TORC1 assays in yeast SEACAT/SEACIT","pmids":["23723238","23974112"],"confidence":"High","gaps":["Structural basis of GATOR2 assembly not yet known","How GATOR2 antagonizes GATOR1 GAP activity mechanistically unclear"]},{"year":2011,"claim":"Showed across yeast and Drosophila that Seh1 stabilizes its GATOR2/SEA partners (e.g. Mio) and that the complex resembles membrane-coating assemblies, tying its β-propeller architecture to nutrient and trafficking functions.","evidence":"Affinity purification/MS, computational structure prediction, and live imaging of the yeast SEA complex; Drosophila null allele with Co-IP and protein stability assays","pmids":["21454883","21521741"],"confidence":"High","gaps":["Direct structural demonstration of coat-like architecture not yet achieved","Stoichiometry of the assembled complex undefined"]},{"year":2014,"claim":"Confirmed in a whole-organism context that Seh1/GATOR2 opposes GATOR1 to permit TORC1 activity, with developmental consequences for oocyte growth.","evidence":"Drosophila null alleles, epistasis, rapamycin treatment, and TORC1 activity assays","pmids":["25512509"],"confidence":"High","gaps":["Mammalian developmental relevance not addressed in this work"]},{"year":2016,"claim":"Revealed a TORC1-independent function of Seh1/GATOR2 in lysosome function and autophagic flux, expanding its role beyond the canonical Rag GTPase axis.","evidence":"Drosophila null alleles, epistasis with GATOR1, lysosome acidification and autophagy flux assays","pmids":["27166823"],"confidence":"Medium","gaps":["Molecular mechanism of the lysosomal role undefined","Single-organism study"]},{"year":2018,"claim":"Distinguished Seh1's two roles on mitotic chromosomes — dispensable for Nup107 complex but essential for GATOR2 and Nup153 association and CPC loading — and uncovered Aurora B phosphorylation of a SEH1 PP1-binding motif as a regulatory switch.","evidence":"Auxin-inducible degron with quantitative chromosome proteomics and immunofluorescence; phospho-specific antibody, MS, and Aurora B kinase assays","pmids":["29618633","29764992"],"confidence":"High","gaps":["Functional consequence of PP1-motif phosphorylation on segregation not fully resolved","How GATOR2 is recruited to chromosomes unclear"]},{"year":2022,"claim":"Provided the structural basis of GATOR2, showing SEH1L integrates via β-propeller blade donation to stabilize a cage-like scaffold that positions WD40 dimers for sensor and GATOR1 contacts.","evidence":"Cryo-EM structure of the human 1.1 MDa GATOR2 complex with functional validation of subunit integration","pmids":["35831510"],"confidence":"High","gaps":["How sensor binding propagates to GATOR1 inhibition not resolved in this state","Dynamics of the apo vs sensor-bound states not captured"]},{"year":2023,"claim":"Uncovered NPC-independent chromatin functions of Seh1, including stabilizing the SETDB1-KAP1 silencing axis to maintain genome stability and prevent necroptosis in Schwann cells.","evidence":"Conditional knockout, Co-IP of SETDB1/KAP1, transcriptome analysis, and necroptosis assays; transcriptomic gene-regulation analysis during neuroectodermal differentiation","pmids":["37453065","37305998"],"confidence":"Medium","gaps":["Direct biochemical role of Seh1 in bridging SETDB1-KAP1 not structurally defined","Gene-regulation findings are largely correlative"]},{"year":2024,"claim":"Defined a NuRD-dependent transcriptional repression role for Seh1 at the nuclear periphery controlling p21 and neurogenesis, separating this chromatin function from nucleocytoplasmic transport.","evidence":"Conditional knockout, transcriptome analysis, and p21 knockdown rescue in neural progenitors","pmids":["38272027"],"confidence":"Medium","gaps":["How Seh1 recruits or stabilizes NuRD at target loci unknown","Single-lab study"]},{"year":2025,"claim":"Resolved inhibitory GATOR2 states showing the WDR24-Seh1L subcomplex as the direct Sestrin2 docking site and capturing the conformational dynamics underlying amino acid sensing.","evidence":"Cryo-EM structures of CASTOR1-, Sestrin2-, and dual-bound GATOR2 with HDX-MS","pmids":["40742811"],"confidence":"High","gaps":["Direct link from sensor-induced conformation to RagA/B GAP modulation still incomplete"]},{"year":2026,"claim":"Mapped how the SEAC/GATOR engages the Rag-Ragulator complex, finding the GATOR1-equivalent does the direct binding while the Seh1-containing SEACAT contributes via a β-propeller required for robust signaling.","evidence":"Cryo-EM of yeast SEAC-EGOC complex with deletion mutants and TORC1 activity assays","pmids":["41680390"],"confidence":"Medium","gaps":["Whether the SEACAT β-propeller recruits a GAP inhibitor not directly demonstrated","Yeast ortholog; human GATOR-Rag engagement geometry not confirmed"]},{"year":null,"claim":"How a single small β-propeller protein is partitioned between the NPC, GATOR2, and chromatin-silencing complexes, and what governs that partitioning, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No mechanism described for how Seh1 is allocated among its distinct complexes","Mendelian disease association absent from the corpus despite microcephaly phenotypes in models"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[1,3,12]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[2,14]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,8]}],"localization":[{"term_id":"GO:0005635","term_label":"nuclear envelope","supporting_discovery_ids":[3,16]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[14,13]},{"term_id":"GO:0005694","term_label":"chromosome","supporting_discovery_ids":[4,5,6]}],"pathway":[{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[4,5,6]},{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[3,4]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[14,13]}],"complexes":["GATOR2","Nup107-160 (Nup84/Y-complex)","SEA complex (yeast SEACAT)"],"partners":["WDR24","MIOS","WDR59","SEC13","NUP85","SESN2","SETDB1","KAP1"],"other_free_text":[]}},"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 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subunit of the GATOR2 complex (together with Mios, WDR24, WDR59, and Sec13), which positively regulates mTORC1 signaling. Inhibition of GATOR2 subunits including Seh1L suppresses mTORC1 signaling; epistasis analysis shows GATOR2 negatively regulates DEPDC5 (a GATOR1 subunit), placing GATOR2 upstream of GATOR1 in the amino acid-sensing pathway to mTORC1.\",\n      \"method\": \"siRNA knockdown, epistasis analysis, co-immunoprecipitation, mTORC1 activity assays (phospho-S6K)\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, epistasis, multiple orthogonal methods, replicated across multiple subsequent 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. SEH1L and SEC13 are integrated into the octagonal scaffold through β-propeller blade donation (blade insertion), which stabilizes the GATOR2 complex and reveals an evolutionary relationship to the nuclear pore and membrane-coating complexes. The scaffold orients WD40 β-propeller dimers that mediate interactions with SESN2, CASTOR1, and GATOR1.\",\n      \"method\": \"Cryo-electron microscopy (cryo-EM) structure determination\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cryo-EM structure at near-atomic resolution with functional validation of subunit integration mechanism\",\n      \"pmids\": [\"35831510\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Cryo-EM structures of GATOR2 in inhibitory states (CASTOR1-bound, Sestrin2-bound, and dual-bound) show that Sestrin2 (leucine sensor) interacts specifically with the WDR24-Seh1L subcomplex of GATOR2, inducing conformational movements. HDX-MS confirmed dynamic motions in apo-GATOR2 and its complexes with amino acid sensors.\",\n      \"method\": \"Cryo-electron microscopy (cryo-EM), hydrogen-deuterium exchange mass spectrometry (HDX-MS)\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — cryo-EM structure with HDX-MS validation, single study with multiple orthogonal methods\",\n      \"pmids\": [\"40742811\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Seh1 is identified as a member of the Nup107-160 nuclear pore subcomplex in vertebrates. RNAi-mediated depletion of Seh1 leads to phenotypes similar to knockdown of other Nup107-160 constituents. Seh1, along with all other Nup107-160 complex members, is targeted to kinetochores from prophase to anaphase of mitosis.\",\n      \"method\": \"Co-immunoprecipitation, RNAi knockdown, GFP live-cell imaging, immunofluorescence\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, RNAi phenotype, live imaging, replicated in multiple subsequent studies\",\n      \"pmids\": [\"15146057\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Depletion of Seh1 alone is sufficient to efficiently remove the Nup107-160 complex from kinetochores, causing mitotic delay, impaired chromosome congression, reduced kinetochore tension, and kinetochore-microtubule attachment defects. The presence of the Nup107-160 complex at kinetochores (dependent on Seh1) is required for the recruitment of Crm1 and RanGAP1-RanBP2 to kinetochores.\",\n      \"method\": \"siRNA knockdown, immunofluorescence, live-cell imaging, mitotic phenotype analysis\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean siRNA depletion with multiple specific phenotypic readouts and downstream pathway placement, replicated across labs\",\n      \"pmids\": [\"17363900\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Seh1 depletion impairs Aurora B localization to centromeres (the chromosomal passenger complex, CPC), resulting in defects in biorientation and organization of the spindle midzone and midbody. Seh1 regulates chromosome alignment and segregation by controlling centromeric localization of Aurora B; microtubule-kinetochore attachments (assessed by EM) are intact in Seh1-depleted cells.\",\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 / Strong — clean KD with specific mechanistic readout (Aurora B mislocalization), electron microscopy structural validation, multiple methods\",\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 is shown to be dispensable for association of the Nup107 complex with mitotic chromosomes, but essential for the association of the GATOR2 complex and nucleoporin Nup153 with mitotic chromosomes. Seh1 is also required at human centromeres for efficient localization of the chromosomal passenger complex (CPC).\",\n      \"method\": \"Auxin-inducible degron (chemical genetics), quantitative mass spectrometry-based chromosome proteomics, immunofluorescence\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — rapid inducible depletion with quantitative proteomics, multiple orthogonal methods, clean mechanistic distinction from Nup107 complex function\",\n      \"pmids\": [\"29618633\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"In Drosophila, Seh1 (SEH1L ortholog) associates with the product of the missing oocyte (mio) gene (a GATOR2 component). Loss of seh1 in the female germline causes failure of oocytes to maintain the meiotic cycle (pseudo-nurse cell development), phenocopying mio mutants. Mio protein accumulation is greatly diminished in seh1 mutant background, indicating Seh1 stabilizes Mio. Seh1 is dispensable for development of somatic tissues.\",\n      \"method\": \"Genetic null allele, co-immunoprecipitation, immunofluorescence, genetic interaction analysis\",\n      \"journal\": \"Development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — null allele with specific germline phenotype, Co-IP demonstrating physical interaction, protein stability assay\",\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 Iml1/GATOR1 activity to prevent constitutive inhibition of TORC1, and their loss causes a block to oocyte growth and development. Epistasis analysis places GATOR2 (including Seh1) as an antagonist of GATOR1 in the TORC1 pathway during oogenesis.\",\n      \"method\": \"Genetic null alleles, epistasis analysis, rapamycin treatment, TORC1 activity assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis with null alleles, pharmacological validation with rapamycin, replicated across organisms\",\n      \"pmids\": [\"25512509\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"The SEA (Seh1-associated) complex in yeast contains Seh1 and Sec13 (along with Npr2, Npr3, and Sea1-Sea4). Combined computational and biochemical analysis indicates SEA complex proteins possess structural characteristics similar to membrane coating complexes (COPI, COPII, NPC). The SEA complex dynamically associates with the vacuole in vivo and functions in intracellular trafficking, amino acid biogenesis, and response to nitrogen starvation.\",\n      \"method\": \"Affinity purification/mass spectrometry, computational structural prediction, live-cell fluorescence microscopy, genetic assays\",\n      \"journal\": \"Molecular & cellular proteomics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — biochemical complex purification, MS identification, live imaging, genetic validation, multiple orthogonal methods\",\n      \"pmids\": [\"21454883\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"In yeast, SEACAT (the GATOR2 equivalent subcomplex containing Seh1, Sea2-4, and Sec13) antagonizes the GAP function of SEACIT (GATOR1 equivalent) toward Gtr1 (RagA ortholog), as demonstrated by genetic epistasis. Loss of SEACAT subunits suppresses TORC1 activity downstream of amino acid signaling.\",\n      \"method\": \"Genetic epistasis analysis, TORC1 activity assays\",\n      \"journal\": \"Cell cycle\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis analysis in yeast, single lab, consistent with mammalian findings\",\n      \"pmids\": [\"23974112\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"In Drosophila, Seh1 (GATOR2 component) has a TORC1-independent role in the regulation of lysosome function and autophagic flux, in addition to its role in TORC1 activation. This TORC1-independent lysosome function is shared with other GATOR2 members Mio and Wdr24.\",\n      \"method\": \"Genetic null alleles, epistasis analysis with GATOR1 components, lysosome acidification assays, autophagy flux assays\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis with null alleles, cell biological assays, single study\",\n      \"pmids\": [\"27166823\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"The crystal structure of Nup85 in complex with Seh1 defines a new tripartite protein element (ancestral coatomer element ACE1) shared with other nucleoporins and vesicle coat proteins. Seh1 forms the short arm of the Y-shaped Nup84 complex together with Nup85. Functional sites predicted by analogy to COPII coat interactions were verified experimentally.\",\n      \"method\": \"Crystal structure determination, mutagenesis, functional interaction assays\",\n      \"journal\": \"Communicative & integrative biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure with functional mutagenesis, single study\",\n      \"pmids\": [\"19641729\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Seh1 (SEH1L) maintains Schwann cell homeostasis by safeguarding genome stability through mediating the interaction between SETDB1 and KAP1. Loss of Seh1 disrupts this interaction, derepresses endogenous retroviruses, and triggers ZBP1-dependent necroptosis in Schwann cells, leading to progressive reduction of non-myelinating Schwann cells and neural fiber degeneration.\",\n      \"method\": \"Conditional knockout, co-immunoprecipitation, transcriptome analysis, immunofluorescence, necroptosis assays\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with specific mechanistic follow-up (Co-IP of SETDB1/KAP1 interaction), single lab study\",\n      \"pmids\": [\"37453065\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Seh1 cooperates with the NuRD transcription repressor complex at the nuclear periphery to repress p21 expression in neural stem cells. Depletion of Seh1 in radial glial progenitors derepresses p21, leading to defective neural progenitor proliferation and differentiation, impaired neurogenesis, and microcephaly. This function is independent of nucleocytoplasmic transport defects.\",\n      \"method\": \"Conditional knockout, transcriptome analysis, p21 knockdown rescue experiment, co-localization/nuclear periphery association assays\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with transcriptomic and functional rescue (p21 knockdown), mechanistic pathway placement, single lab\",\n      \"pmids\": [\"38272027\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Seh1 and Nup43 are dispensable in pluripotent mouse embryonic stem cells but required for normal cell growth rates and viability upon neuroectodermal differentiation, as well as maintenance of proper nuclear pore complex density. An N-terminally truncated Nup85 mutation that greatly impairs interaction with Seh1 reduces NPC density but does not affect proliferation or differentiation, indicating Y-complex integrity (not NPC number per se) is critical.\",\n      \"method\": \"CRISPR/Cas9 genome editing, cell viability assays, NPC density quantification by electron microscopy/immunofluorescence, differentiation assays\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean genetic KO with specific functional readouts and mechanistic distinction, single lab\",\n      \"pmids\": [\"34037234\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"In S. pombe, Seh1 (ortholog) is localized at the nuclear envelope as part of the conserved Nup107-120 complex. Deletion of Nup107-120 complex members causes mRNA export defects and cell division defects (abnormal septa, mitotic spindles, chromosome missegregation) at restrictive temperature; genetic interaction with the Ran GTPase pathway is demonstrated by synthetic toxicity of a nonfunctional Ran-GFP allele in nup120 and nup133 deletion backgrounds.\",\n      \"method\": \"Deletion mutants, fluorescence microscopy, mRNA export assays, genetic epistasis/synthetic lethality\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with functional assays and epistasis, ortholog study in fission yeast\",\n      \"pmids\": [\"15226438\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Seh1 (yeast) directly interacts with importin Kap95 as detected by the Bead Halo equilibrium binding assay, suggesting a role for this interaction during nuclear pore complex biogenesis.\",\n      \"method\": \"Bead Halo in vitro binding assay (equilibrium-based)\",\n      \"journal\": \"Molecular & cellular proteomics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single in vitro binding assay, functional consequence not directly demonstrated in this paper\",\n      \"pmids\": [\"17897934\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"SEH1 contains a RV[S/T]F motif (PP1-binding motif) that is phosphorylated specifically during mitosis, predominantly by Aurora B kinase, abrogating PP1 binding to SEH1. This represents a mechanism by which Aurora B and PP1 coordinate to control mitotic progression via dissolution of PP1 holoenzymes.\",\n      \"method\": \"Phospho-specific antibody (RVpSF), mass spectrometry, kinase assays, immunoprecipitation\",\n      \"journal\": \"Science signaling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — phospho-specific antibody plus MS identification, Aurora B kinase assay, single study\",\n      \"pmids\": [\"29764992\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"In yeast, cryo-EM structure of the SEAC (GATOR) bound to the EGOC (Ragulator-Rag GTPase complex) shows a single SEAC interacts with two EGOC molecules via SEACIT, binding exclusively to the 'active' EGOC conformation, without involvement of SEACAT (which contains Seh1/Sea2-4/Sec13). The Sea2 β-propeller domain of SEACAT is required for robust amino acid signaling to TORC1, suggesting it recruits a GAP inhibitor for fast signaling.\",\n      \"method\": \"Cryo-electron microscopy, genetic analysis (deletion mutants), TORC1 activity assays\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — cryo-EM structure with genetic validation, single study, yeast ortholog\",\n      \"pmids\": [\"41680390\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SEH1L silencing activates the ATF3/HMOX1/GPX4 axis, decreases mitochondrial membrane potential and GSH while increasing ROS and MDA, inducing ferroptosis and suppressing hepatocellular carcinoma progression. Knockdown of ATF3 reverses these effects. These findings were validated in vitro and in vivo (subcutaneous tumor model).\",\n      \"method\": \"siRNA knockdown, next-generation sequencing, RT-qPCR, western blotting, flow cytometry, xenograft model\",\n      \"journal\": \"Apoptosis\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, pathway placement via RNAseq + ATF3 rescue, no direct biochemical mechanism for how SEH1L regulates ATF3\",\n      \"pmids\": [\"39095556\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Nup133 and Seh1, two components of the Y-complex NPC subassembly, independently regulate a subset of genes including Lhx1 and Nup210l during neuroectodermal differentiation. Gene regulation by Seh1 in neural progenitors appears independent of nuclear pore basket integrity (Seh1 depletion causes only mild reduction in NPC density).\",\n      \"method\": \"Transcriptomic analysis, siRNA/genetic depletion, NPC density quantification, differentiation assays\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — transcriptomic correlation with depletion, limited direct mechanistic follow-up for Seh1 specifically\",\n      \"pmids\": [\"37305998\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SEH1L (Seh1) is a dual-complex nucleoporin that functions as a structural subunit of both the Nup107-160 nuclear pore complex (NPC) and the GATOR2 complex: in the NPC it integrates via β-propeller blade donation to stabilize complex architecture and is required at kinetochores for Aurora B/CPC localization and chromosome segregation; in GATOR2 (together with WDR24, MIOS, WDR59, and SEC13) it forms part of a cage-like mTORC1 regulatory hub where its WDR24-Seh1L subcomplex directly binds the leucine sensor Sestrin2, enabling GATOR2 to antagonize GATOR1 GAP activity toward RagA/B GTPases and thereby promote amino acid-dependent mTORC1 activation; additionally, Seh1 has NPC-independent chromatin-associated functions including repression of p21 via the NuRD complex in neural stem cells and maintenance of genome stability through stabilizing SETDB1-KAP1 interaction in Schwann cells.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SEH1L (Seh1) is a WD40 β-propeller protein that functions as a shared structural subunit of two distinct β-propeller-based assemblies — the Nup107-160 nuclear pore subcomplex and the GATOR2 complex — and additionally carries out NPC-independent chromatin functions [#3, #0, #14]. In GATOR2, Seh1L assembles with Mios, WDR24, WDR59, and Sec13 to positively regulate mTORC1 signaling, acting upstream of and antagonizing the GATOR1 GAP toward Rag GTPases in the amino acid-sensing pathway [#0, #8]. Cryo-EM defines GATOR2 as a 1.1 MDa two-fold-symmetric cage in which SEH1L and SEC13 integrate via β-propeller blade donation to stabilize the scaffold, and the WDR24-Seh1L subcomplex serves as the direct docking site for the leucine sensor Sestrin2, which induces conformational changes that gate signaling [#1, #2]. In the nuclear pore, Seh1 forms the short arm of the Y-shaped Nup84/Nup107-160 complex through an ancestral coatomer element (ACE1) interface with Nup85, and is required to target this complex to kinetochores during mitosis [#12, #3, #4]. Loss of Seh1 strips the Nup107-160 complex from kinetochores and impairs centromeric recruitment of Aurora B/the chromosomal passenger complex, causing biorientation defects, reduced kinetochore tension, and chromosome missegregation [#4, #5, #6]. Beyond the pore, Seh1 cooperates with the NuRD complex at the nuclear periphery to repress p21 in neural stem cells, and stabilizes the SETDB1-KAP1 interaction to maintain genome stability in Schwann cells — chromatin-associated roles independent of nucleocytoplasmic transport [#14, #13].\",\n  \"teleology\": [\n    {\n      \"year\": 2004,\n      \"claim\": \"Established Seh1 as a constituent of the vertebrate Nup107-160 nuclear pore subcomplex and showed it shares the loss-of-function phenotypes of its partners, defining its baseline structural role at the NPC.\",\n      \"evidence\": \"Co-IP, RNAi knockdown, and live-cell imaging in vertebrate cells; deletion/genetic analysis of the conserved Nup107-120 complex in S. pombe\",\n      \"pmids\": [\"15146057\", \"15226438\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve the structural interface tethering Seh1 within the complex\", \"Mitotic kinetochore function not yet mechanistically dissected\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Demonstrated that Seh1 specifically anchors the Nup107-160 complex at kinetochores and that this is required to recruit downstream Crm1 and RanGAP1-RanBP2, linking the nucleoporin to mitotic fidelity.\",\n      \"evidence\": \"siRNA depletion with immunofluorescence, live-cell imaging, and mitotic phenotype analysis\",\n      \"pmids\": [\"17363900\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How Seh1 loss selectively removes the complex from kinetochores not defined\", \"Did not yet connect to Aurora B/CPC\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Identified the mechanistic consequence of Seh1 loss as failure to load Aurora B/the CPC at centromeres, explaining biorientation and segregation defects independent of microtubule attachment integrity.\",\n      \"evidence\": \"siRNA knockdown with immunofluorescence, electron microscopy, and live-cell imaging; crystal structure of the Nup85-Seh1 ACE1 interface with mutagenesis\",\n      \"pmids\": [\"19864462\", \"19641729\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular link between Nup107-160 presence and CPC recruitment unresolved\", \"ACE1 functional sites verified by analogy rather than full reconstitution\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Placed Seh1L within the GATOR2 complex as a positive regulator of mTORC1 acting upstream of GATOR1, defining a second, transport-independent macromolecular role.\",\n      \"evidence\": \"siRNA knockdown, reciprocal co-IP, epistasis, and phospho-S6K mTORC1 activity assays in human cells; genetic epistasis and TORC1 assays in yeast SEACAT/SEACIT\",\n      \"pmids\": [\"23723238\", \"23974112\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of GATOR2 assembly not yet known\", \"How GATOR2 antagonizes GATOR1 GAP activity mechanistically unclear\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Showed across yeast and Drosophila that Seh1 stabilizes its GATOR2/SEA partners (e.g. Mio) and that the complex resembles membrane-coating assemblies, tying its β-propeller architecture to nutrient and trafficking functions.\",\n      \"evidence\": \"Affinity purification/MS, computational structure prediction, and live imaging of the yeast SEA complex; Drosophila null allele with Co-IP and protein stability assays\",\n      \"pmids\": [\"21454883\", \"21521741\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct structural demonstration of coat-like architecture not yet achieved\", \"Stoichiometry of the assembled complex undefined\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Confirmed in a whole-organism context that Seh1/GATOR2 opposes GATOR1 to permit TORC1 activity, with developmental consequences for oocyte growth.\",\n      \"evidence\": \"Drosophila null alleles, epistasis, rapamycin treatment, and TORC1 activity assays\",\n      \"pmids\": [\"25512509\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mammalian developmental relevance not addressed in this work\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Revealed a TORC1-independent function of Seh1/GATOR2 in lysosome function and autophagic flux, expanding its role beyond the canonical Rag GTPase axis.\",\n      \"evidence\": \"Drosophila null alleles, epistasis with GATOR1, lysosome acidification and autophagy flux assays\",\n      \"pmids\": [\"27166823\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular mechanism of the lysosomal role undefined\", \"Single-organism study\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Distinguished Seh1's two roles on mitotic chromosomes — dispensable for Nup107 complex but essential for GATOR2 and Nup153 association and CPC loading — and uncovered Aurora B phosphorylation of a SEH1 PP1-binding motif as a regulatory switch.\",\n      \"evidence\": \"Auxin-inducible degron with quantitative chromosome proteomics and immunofluorescence; phospho-specific antibody, MS, and Aurora B kinase assays\",\n      \"pmids\": [\"29618633\", \"29764992\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of PP1-motif phosphorylation on segregation not fully resolved\", \"How GATOR2 is recruited to chromosomes unclear\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Provided the structural basis of GATOR2, showing SEH1L integrates via β-propeller blade donation to stabilize a cage-like scaffold that positions WD40 dimers for sensor and GATOR1 contacts.\",\n      \"evidence\": \"Cryo-EM structure of the human 1.1 MDa GATOR2 complex with functional validation of subunit integration\",\n      \"pmids\": [\"35831510\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How sensor binding propagates to GATOR1 inhibition not resolved in this state\", \"Dynamics of the apo vs sensor-bound states not captured\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Uncovered NPC-independent chromatin functions of Seh1, including stabilizing the SETDB1-KAP1 silencing axis to maintain genome stability and prevent necroptosis in Schwann cells.\",\n      \"evidence\": \"Conditional knockout, Co-IP of SETDB1/KAP1, transcriptome analysis, and necroptosis assays; transcriptomic gene-regulation analysis during neuroectodermal differentiation\",\n      \"pmids\": [\"37453065\", \"37305998\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct biochemical role of Seh1 in bridging SETDB1-KAP1 not structurally defined\", \"Gene-regulation findings are largely correlative\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defined a NuRD-dependent transcriptional repression role for Seh1 at the nuclear periphery controlling p21 and neurogenesis, separating this chromatin function from nucleocytoplasmic transport.\",\n      \"evidence\": \"Conditional knockout, transcriptome analysis, and p21 knockdown rescue in neural progenitors\",\n      \"pmids\": [\"38272027\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How Seh1 recruits or stabilizes NuRD at target loci unknown\", \"Single-lab study\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Resolved inhibitory GATOR2 states showing the WDR24-Seh1L subcomplex as the direct Sestrin2 docking site and capturing the conformational dynamics underlying amino acid sensing.\",\n      \"evidence\": \"Cryo-EM structures of CASTOR1-, Sestrin2-, and dual-bound GATOR2 with HDX-MS\",\n      \"pmids\": [\"40742811\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct link from sensor-induced conformation to RagA/B GAP modulation still incomplete\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Mapped how the SEAC/GATOR engages the Rag-Ragulator complex, finding the GATOR1-equivalent does the direct binding while the Seh1-containing SEACAT contributes via a β-propeller required for robust signaling.\",\n      \"evidence\": \"Cryo-EM of yeast SEAC-EGOC complex with deletion mutants and TORC1 activity assays\",\n      \"pmids\": [\"41680390\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether the SEACAT β-propeller recruits a GAP inhibitor not directly demonstrated\", \"Yeast ortholog; human GATOR-Rag engagement geometry not confirmed\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How a single small β-propeller protein is partitioned between the NPC, GATOR2, and chromatin-silencing complexes, and what governs that partitioning, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No mechanism described for how Seh1 is allocated among its distinct complexes\", \"Mendelian disease association absent from the corpus despite microcephaly phenotypes in models\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [1, 3, 12]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [2, 14]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 8]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005635\", \"supporting_discovery_ids\": [3, 16]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [14, 13]},\n      {\"term_id\": \"GO:0005694\", \"supporting_discovery_ids\": [4, 5, 6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-165159\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [4, 5, 6]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [3, 4]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [14, 13]}\n    ],\n    \"complexes\": [\n      \"GATOR2\",\n      \"Nup107-160 (Nup84/Y-complex)\",\n      \"SEA complex (yeast SEACAT)\"\n    ],\n    \"partners\": [\n      \"WDR24\",\n      \"MIOS\",\n      \"WDR59\",\n      \"SEC13\",\n      \"NUP85\",\n      \"SESN2\",\n      \"SETDB1\",\n      \"KAP1\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}