SEH1L

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).

1. 2004 High

   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

   PMID:15146057

   Open questions at the time

   • No structural detail on how Seh1 integrates into the Y-complex
   • Precise contribution of Seh1 versus other subunits at kinetochores was unclear
2. 2007 High

   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

   PMID:17363900

   Open questions at the time

   • Whether chromosome segregation defects arise from loss of a specific kinetochore effector or general Y-complex mislocalization was unresolved
3. 2009 High

   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)

   PMID:19641729 PMID:19864462

   Open questions at the time

   • 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
4. 2011 High

   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)

   PMID:21454883 PMID:21521741

   Open questions at the time

   • Mammalian equivalent of the SEA complex had not yet been defined
   • Whether Seh1's NPC and nutrient-sensing roles are functionally coupled was unknown
5. 2013 High

   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)

   PMID:23723238 PMID:23974112

   Open questions at the time

   • 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
6. 2014 High

   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

   PMID:25512509 PMID:27166823

   Open questions at the time

   • Molecular basis of the TORC1-independent lysosome function remained undefined
   • Whether Seh1 specifically contributes to the lysosome role versus other GATOR2 subunits was unclear
7. 2018 High

   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

   PMID:29618633 PMID:29764992

   Open questions at the time

   • 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
8. 2021 Medium

   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

   PMID:34037234

   Open questions at the time

   • Whether the proliferation defect is NPC-mediated or GATOR2-mediated was not dissected
   • Single study without independent replication
9. 2022 High

   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

   PMID:35831510

   Open questions at the time

   • Structure of GATOR2 bound to upstream sensors was not yet available
   • Conformational changes upon amino acid sensing were unresolved
10. 2023 High

    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

    PMID:37305998 PMID:37453065

    Open questions at the time

    • How Seh1 bridges SETDB1 and KAP1 structurally is unknown
    • Whether these chromatin roles are NPC-tethered or NPC-independent was not fully resolved
11. 2024 High

    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

    PMID:38272027

    Open questions at the time

    • 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
12. 2025 High

    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

    PMID:40742811

    Open questions at the time

    • 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

• 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.
• 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