Affinage

SEL1L

Protein sel-1 homolog 1 · UniProt Q9UBV2

Length
794 aa
Mass
88.8 kDa
Annotated
2026-04-28
100 papers in source corpus 39 papers cited in narrative 39 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SEL1L is the essential adaptor protein of the SEL1L-HRD1 endoplasmic reticulum-associated degradation (ERAD) complex, serving as the principal scaffold that recruits luminal substrate-recognition lectins (OS-9, XTP3-B, EDEM1) through its SLR motifs, engages the E3 ubiquitin ligase HRD1 via its SLR-C region to stabilize HRD1 protein levels, and recruits the E2 enzyme UBE2J1 and Derlin retrotranslocation factors to form a functional retrotranslocon (PMID:17043138, PMID:18264092, PMID:24453213, PMID:38365914). Structural studies reveal that SEL1L dimerizes through a domain-swapped central SLR region and, together with OS-9, forms a claw-like luminal assembly that captures misfolded substrates for ubiquitin-dependent retrotranslocation through the HRD1 channel (PMID:27064360, PMID:28682307, PMID:40661598). SEL1L additionally associates with cytosolic LC3-I to tune ERAD capacity by mediating vesicular removal of luminal ERAD regulators EDEM1 and OS-9 from the ER (PMID:22633958). Through substrate-specific degradation of diverse clients—including STING, pre-BCR, LepRb, CREBH, ceruloplasmin, TGF-β receptor 1, WNT5A, fibrinogen chains, and PIGK—the SEL1L-HRD1 complex governs innate and adaptive immunity, lipid and iron metabolism, neuroendocrine signaling, and proteostasis, and biallelic hypomorphic SEL1L variants cause neurodevelopmental disorders and agammaglobulinemia in humans (PMID:37142791, PMID:27568564, PMID:39343970, PMID:30389665, PMID:36595688, PMID:37943610, PMID:37943617).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 2006 High

    Establishing that mammalian SEL1L is a functional component of the ER dislocation machinery—analogous to yeast Hrd3p—resolved whether the ERAD retrotranslocation pathway is conserved in mammals.

    Evidence shRNA knockdown with pulse-chase degradation assays across multiple substrates (RI332, MHC class I) in mammalian cells

    PMID:17043138

    Open questions at the time
    • Identity of other mammalian ERAD complex components unknown
    • Whether SEL1L directly contacts substrates or acts indirectly was unresolved
  2. 2008 High

    Identification of SEL1L as the nucleating scaffold of a multiprotein ERAD complex containing OS-9, XTP3-B, GRP94, AUP1, UBXD8, and UBC6e defined the molecular architecture of the mammalian HRD1-SEL1L degradation machinery and how luminal lectins deliver substrates to the membrane complex.

    Evidence Reciprocal co-immunoprecipitation, mass spectrometry, domain mutagenesis mapping MRH domain requirements, sucrose gradient fractionation revealing 27S complex

    PMID:18264092 PMID:18502753 PMID:18711132

    Open questions at the time
    • Stoichiometry of the native complex was unknown
    • How SEL1L discriminates among substrates was unresolved
    • Whether EDEM family members also dock onto SEL1L was untested
  3. 2009 High

    Demonstrating that EDEM1 binds SEL1L through its mannosidase-like domain independently of substrate binding established EDEM1 as a third lectin targeting misfolded proteins to the SEL1L-containing ERAD machinery.

    Evidence Co-immunoprecipitation with mannosidase-like domain mutagenesis, kifunensine inhibition, pulse-chase assays

    PMID:19524542

    Open questions at the time
    • Relative contributions of OS-9, XTP3-B, and EDEM1 in substrate targeting were unresolved
    • Whether EDEM1-SEL1L interaction is regulated was unknown
  4. 2010 High

    Showing that soluble luminal ERAD substrates strictly require SEL1L while membrane-tethered luminal substrates do not revealed a mammalian pathway divergence that distinguishes ERAD-LS from ERAD-LM and defines SEL1L's functional boundary.

    Evidence siRNA knockdown with pulse-chase of paired soluble vs. membrane-tethered ERAD substrates

    PMID:20100910

    Open questions at the time
    • Mechanism by which membrane tethering bypasses SEL1L was unclear
    • Whether any transmembrane proteins use the SEL1L route was unresolved
  5. 2011 High

    Genetic knockout and domain complementation analysis identified the SLR motifs (but not the fibronectin II domain) as the essential functional unit of SEL1L and established that SEL1L stability depends on HRD1 association, with unassociated SEL1L undergoing rapid proteasomal degradation.

    Evidence DT40 cell gene targeting with deletion complementation; mammalian siRNA with pulse-chase defining Derlin-1/2, VIMP, and Herp as co-factors in the large native complex

    PMID:21454652 PMID:21857145

    Open questions at the time
    • Which SLR motifs bind HRD1 vs. substrates was not mapped
    • Structural basis of SEL1L-HRD1 interaction was unknown
  6. 2012 High

    Discovery that SEL1L forms a complex with cytosolic LC3-I to mediate COPII-independent vesicular removal of EDEM1 and OS-9 from the ER established a non-degradative 'ERAD tuning' function for SEL1L that adjusts ERAD capacity without activating the UPR.

    Evidence Co-immunoprecipitation of SEL1L-LC3-I, siRNA, live cell imaging, vesicle fractionation

    PMID:22633958

    Open questions at the time
    • Vesicle destination and machinery for LC3-I-coated vesicles were unclear
    • Whether this pathway operates in all cell types was untested
  7. 2013 High

    Identification of ATF6 as an ERAD-Lm substrate requiring SEL1L, and of ERdj5 as a direct SEL1L interactor linking disulfide reduction to retrotranslocation, expanded the spectrum of SEL1L clients to include UPR transducers and chaperone co-factors.

    Evidence DT40 knockout with chimeric ATF6 constructs; Co-IP mapping ERdj5 to the N-terminal luminal domain of SEL1L with cholera toxin retrotranslocation assays

    PMID:23363602 PMID:24043630

    Open questions at the time
    • Whether SEL1L-dependent degradation of ATF6 feeds back on UPR signaling thresholds was unknown
    • Structural basis of ERdj5-SEL1L interaction was unresolved
  8. 2014 High

    Acute in vivo Sel1L knockout demonstrated that SEL1L is indispensable for organismal viability—causing HRD1 loss, ER stress, ribosomal aggregation, and pancreatic atrophy—while adipocyte-specific knockout revealed an ERAD-independent role in stabilizing the LPL maturation complex.

    Evidence Inducible global and adipocyte-specific Sel1L knockout mice with mass spectrometry, pulse-chase, and autophagy assays

    PMID:24453213 PMID:25066055

    Open questions at the time
    • Whether the LPL-chaperoning function is entirely HRD1-independent required further dissection
    • Cell types most vulnerable to SEL1L loss were not systematically mapped
  9. 2016 High

    Crystal structure of the SEL1L central domain revealed a head-to-tail homodimer mediated by domain-swapped SLR motif 9 and mapped SLR-C (motifs 10–11) as the HRD1 interaction surface, providing the first structural framework for SEL1L scaffold assembly.

    Evidence X-ray crystallography of SLR5–9, co-immunoprecipitation with domain truncations in mammalian cells

    PMID:27064360

    Open questions at the time
    • Full-length structure including transmembrane and cytoplasmic regions was missing
    • How dimerization relates to ERAD complex stoichiometry was unknown
  10. 2016 High

    Identification of pre-BCR as a BiP-dependent SEL1L-HRD1 substrate that controls the large-to-small pre-B cell transition demonstrated that ERAD substrate selectivity shapes immune cell development.

    Evidence B cell-specific Sel1L knockout mice with flow cytometry, Co-IP with BiP, adoptive transfer

    PMID:27568564

    Open questions at the time
    • Whether other immune receptors are similarly regulated was untested
    • Mechanism distinguishing pre-BCR from mature BCR recognition was unclear
  11. 2017 High

    Cryo-EM of the yeast Hrd1-Hrd3 complex revealed Hrd1 as a retrotranslocation channel with an aqueous cavity and lateral gate, and genetic epistasis defined Derlin2/3 and Herp1/2 as essential partners in the SEL1L-dependent route, completing the model of the retrotranslocon architecture.

    Evidence Cryo-EM structure; DT40 combinatorial knockouts with six ERAD-L substrates

    PMID:28552883 PMID:28682307

    Open questions at the time
    • Mammalian cryo-EM structure of the full SEL1L-HRD1 complex was not yet available
    • How Derlins and Herp proteins are recruited was mechanistically unresolved
  12. 2018 High

    Tissue-specific knockout studies expanded SEL1L-HRD1 substrates to include the ER-resident transcription factor CREBH (liver) and viral glycoprotein gO (HCMV infection), establishing that ERAD controls transcriptional programs and that viruses co-opt the SEL1L machinery.

    Evidence Liver-specific Sel1L KO with nuclear CREBH quantification and transcriptional reporters; MS-confirmed SEL1L-gO interaction with siRNA knockdown and pulse-chase

    PMID:29997207 PMID:30389665

    Open questions at the time
    • Whether SEL1L-mediated CREBH turnover is regulated by nutritional status was unclear
    • Mechanism by which viral UL148 modulates SEL1L function was incompletely defined
  13. 2020 High

    Demonstrating that SEL1L-HRD1 degrades TGF-β receptor 1 in pancreatic β cells, and that TGF-β inhibition rescues β cell identity in Sel1L-deficient islets, revealed ERAD as a determinant of cell fate through signaling receptor turnover.

    Evidence β cell-specific Sel1L KO mice with single-cell RNA-seq, TGF-β receptor turnover, and epistasis rescue

    PMID:32182217

    Open questions at the time
    • Whether TGF-β receptor 1 is directly recognized as misfolded or constitutively targeted was unresolved
    • Relevance to human diabetes was not established
  14. 2023 High

    Identification of STING and ceruloplasmin as SEL1L-HRD1 substrates showed that ERAD suppresses innate immune signaling and governs systemic iron homeostasis, broadening SEL1L's physiological reach beyond proteostasis.

    Evidence Macrophage- and hepatocyte-specific Sel1L KO mice with ubiquitination assays, viral/tumor models, and iron homeostasis measurements

    PMID:36595688 PMID:37142791

    Open questions at the time
    • Whether STING degradation is regulated by pathogen detection was unclear
    • Quantitative contribution of ERAD vs. other quality control to ceruloplasmin homeostasis was unresolved
  15. 2024 High

    Comprehensive identification of >100 ERAD substrates by proteomics, combined with tissue-specific knockouts targeting PIGK, WNT5A, LepRb, and fibrinogen, demonstrated that SEL1L-HRD1 enforces proteostasis of diverse secretory pathway clients with cell type-specific physiological consequences including hepatocellular inclusion body disease and metabolic obesity.

    Evidence Proteomics with ML filtering, hepatocyte/POMC neuron-specific Sel1L KO mice, pulse-chase, tumor assays, metabolic phenotyping

    PMID:36238898 PMID:38253565 PMID:39343970 PMID:39455574

    Open questions at the time
    • Rules governing substrate prioritization among >100 clients remain unknown
    • Whether all identified substrates are direct SEL1L-binding clients or indirect HRD1 substrates is unresolved
  16. 2024 High

    Functional characterization of human biallelic SEL1L variants established that distinct mutations impair substrate recruitment (Gly585Asp), SEL1L-HRD1 complex formation (Met528Arg, Ser658Pro), or SEL1L stability (Cys141Tyr), causing neurodevelopmental disorders and ENDI-agammaglobulinemia with severity correlating inversely with residual ERAD activity.

    Evidence Patient-derived cell lines, knock-in mouse models, ERAD functional assays, B cell development analysis, Co-IP with mutagenesis

    PMID:37943610 PMID:37943617 PMID:38365914 PMID:39352758

    Open questions at the time
    • Genotype-phenotype relationships for milder hypomorphic alleles are incomplete
    • Whether therapeutic enhancement of residual ERAD can ameliorate disease is untested
  17. 2025 High

    Cryo-EM of the mammalian OS9-SEL1L-HRD1 complex revealed the dimeric claw-like luminal architecture of SEL1L-OS9 for substrate engagement and HRD1 dimerization within the membrane, placing pathogenic mutations at structurally defined interfaces.

    Evidence Cryo-EM with mutagenesis, crosslinking, and ERAD functional assays (preprint)

    PMID:40661598

    Open questions at the time
    • Structure of the full complex with Derlins, Herp, and UBE2J1 is missing
    • Mechanism of substrate handoff from the luminal claw to the HRD1 channel remains unresolved
    • Conformational dynamics during retrotranslocation are unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • The mechanistic basis of substrate selectivity among the >100 identified ERAD clients, the conformational dynamics of substrate translocation through the HRD1 channel, and therapeutic strategies for SEL1L-deficient diseases remain unresolved.
  • No structural snapshots of substrate engaged within the retrotranslocation channel
  • Rules distinguishing constitutive vs. conditional ERAD substrates are unknown
  • Whether the LC3-I-mediated ERAD tuning pathway is targetable pharmacologically is untested

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 7 GO:0044183 protein folding chaperone 1
Localization
GO:0005783 endoplasmic reticulum 7
Pathway
R-HSA-392499 Metabolism of proteins 12 R-HSA-1643685 Disease 3 R-HSA-168256 Immune System 3 R-HSA-8953897 Cellular responses to stimuli 3
Partners
DERL2EDEM1ERDJ5HRD1LC3OS9UBE2J1XTP3B
Complex memberships
OS9-SEL1L-HRD1 retrotransloconSEL1L-HRD1 ERAD complexSEL1L-LC3-I ERAD tuning complex

Evidence

Reading pass · 39 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2006 SEL1L (mammalian homolog of yeast Hrd3p) is required for dislocation of misfolded proteins from the ER; perturbation of SEL1L discriminates between the US11 and US2 dislocation pathways for MHC class I heavy chains, and SEL1L knockdown inhibits degradation of misfolded ribophorin fragment (RI332) independently of viral accessories, placing SEL1L in the mammalian dislocation machinery. shRNA knockdown, pulse-chase degradation assays, dominant-negative approaches in mammalian cells The Journal of cell biology High 17043138
2008 SEL1L nucleates a protein complex required for dislocation of misfolded glycoproteins; biochemical search identified AUP1, UBXD8, UBC6e, and OS9 as components of the SEL1L-containing degradation complex, confirmed by mutagenesis and dominant-negative versions. Co-immunoprecipitation/biochemical pulldown, mass spectrometry, mutagenesis, dominant-negative approaches Proceedings of the National Academy of Sciences of the United States of America High 18711132
2008 OS-9 and GRP94 deliver mutant alpha1-antitrypsin to the HRD1-SEL1L ubiquitin ligase complex for ERAD; OS-9 and XTP3-B bind ERAD substrates and interact with SEL1L through their MRH domains, which are required for SEL1L interaction but not substrate binding. OS-9 associates with GRP94, and both HRD1 and SEL1L are required for degradation of misfolded alpha1-antitrypsin. Co-immunoprecipitation, siRNA knockdown, pulse-chase degradation assays, domain mutagenesis Nature cell biology High 18264092
2008 XTP3-B long isoform associates with the HRD1-SEL1L membrane-anchored ubiquitin ligase complex and BiP, forming a 27S ER quality control scaffold complex; XTP3-B short isoform is excluded from scaffold formation. OS-9 is also incorporated into this large complex but gp78 is not. Immunoprecipitation, sucrose density gradient centrifugation fractionation The Journal of biological chemistry High 18502753
2009 EDEM1 binds nonnative proteins in a glycan-independent manner, and its mannosidase-like domain (but not its substrate binding activity) is required for association with the ER membrane adaptor SEL1L, supporting a model where EDEM1 targets aberrant proteins to the SEL1L-containing dislocation/ubiquitination complex. Co-immunoprecipitation, mutagenesis of mannosidase-like domain, kifunensine inhibition, pulse-chase assays Molecular cell High 19524542
2010 Disposal of soluble ERAD-L substrates (ERAD-LS) strictly requires HRD1, SEL1L, and the lectins OS-9 and XTP3-B; these factors become dispensable when the same substrates are membrane-tethered (ERAD-LM), revealing pathway divergence not seen in yeast. siRNA knockdown, pulse-chase degradation assays with multiple ERAD substrates The Journal of cell biology High 20100910
2011 Mammalian SEL1L stability depends on HRD1: SEL1L unassociated with HRD1 is rapidly degraded by the ubiquitin-proteasome pathway. Endogenous HRD1-SEL1L forms a large ERAD complex (Complex I) with Derlin-1/2, VIMP, and Herp, whereas transiently expressed HRD1-SEL1L forms a smaller Complex II lacking these components but still supporting substrate retrotranslocation. siRNA knockdown, co-immunoprecipitation, pulse-chase, transient and stable transfection The Journal of biological chemistry High 21454652
2011 SEL1L is required for ERAD of misfolded luminal proteins (glycosylated NHK and unglycosylated NHK-QQQ) but dispensable for misfolded transmembrane proteins (NHK-BACE and CD3-δ) in chicken DT40 cells. The SEL1-like tetratricopeptide repeats (SLR motifs), but not the fibronectin II domain, are required for SEL1L function. Gene targeting/knockout in DT40 cells, pulse-chase degradation assays, deletion mutant complementation Cell structure and function High 21857145
2012 SEL1L forms a complex with cytosolic LC3-I that acts as an ERAD tuning receptor, mediating COPII-independent, vesicle-mediated removal of lumenal ERAD regulators EDEM1 and OS-9 from the ER. Expression of folding-defective polypeptides enhances lumenal EDEM1 and OS-9 by inhibiting SEL1L:LC3-I-mediated segregation, raising ERAD activity without UPR induction. Co-immunoprecipitation, siRNA knockdown, live cell imaging, vesicle fractionation Molecular cell High 22633958
2013 ATF6, a transmembrane UPR sensor/transducer, is an ERAD-L substrate requiring SEL1L for degradation despite its transmembrane nature; its luminal domain is the determinant for SEL1L-dependent degradation, and mannose trimming is also required. This defines a novel ERAD-Lm subclass. Gene targeting in DT40 cells, pulse-chase degradation assays, chimeric/deletion constructs, kifunensine inhibition The Journal of biological chemistry High 24043630
2013 ERdj5 interacts directly with SEL1L's N-terminal luminal domain, linking ERdj5 to the HRD1 complex; both ERdj5 and SEL1L bind CTA (cholera toxin A subunit) and facilitate CTA1 retrotranslocation. ERdj5 regulates BiP-CTA interaction proximal to the Hrd1 complex, enabling efficient toxin capture for retrotranslocation. Co-immunoprecipitation, loss-of-function/gain-of-function assays, domain mapping, siRNA knockdown Molecular biology of the cell High 23363602
2014 Sel1L is indispensable for HRD1 stability in mammals; acute Sel1L knockout in mice and cells causes loss of Hrd1 protein, impaired ERAD function, ER stress, attenuated translation, ribosomal subunit aggregation, profound pancreatic atrophy, and death within 3 weeks. Inducible Sel1L knockout mouse model, biochemical fractionation, mass spectrometry, in vitro and in vivo ERAD assays Proceedings of the National Academy of Sciences of the United States of America High 24453213
2014 Sel1L physically interacts with and stabilizes the LPL maturation complex (LPL + LMF1), independently of its role in Hrd1-mediated ERAD; in Sel1L-deficient adipocytes, LPL is retained in the ER, forms aggregates, and is degraded by autophagy rather than the proteasome. Adipocyte-specific Sel1L knockout mice, co-immunoprecipitation, pulse-chase, autophagy inhibition assays Cell metabolism High 25066055
2015 PDI reduces disulfide bonds of Akita proinsulin, priming it for ERAD; the Hrd1-Sel1L membrane complex then conducts Akita proinsulin from the ER lumen to the cytosol, and p97 ATPase couples cytosolic arrival with proteasomal degradation. PDI engagement appears linked to Hrd1 availability, suggesting coordinated retrotranslocation. siRNA knockdown of ERAD components, pulse-chase, co-immunoprecipitation, proteasome inhibition Molecular biology of the cell High 26269577
2015 The inherent instability of human SEL1L lies in its transmembrane domain; HRD1 association with the SEL1L transmembrane domain restores SEL1L stability. The SEL1L luminal domain, when expressed alone, retains misfolded cargo in the ER and inhibits degradation of alpha1-antitrypsin null Hong Kong variant. siRNA knockdown, domain deletion/chimera constructs, pulse-chase, co-immunoprecipitation The FEBS journal High 26471130
2016 SEL1L-HRD1 ERAD selectively recognizes and targets the pre-B cell receptor (pre-BCR) for proteasomal degradation in a BiP-dependent manner; Sel1L deficiency causes pre-BCR accumulation intracellularly and at the cell surface, leading to persistent pre-BCR signaling and a developmental block at the large-to-small pre-B cell transition. B cell-specific Sel1L knockout mice, flow cytometry, co-immunoprecipitation with BiP, cell surface staining, adoptive transfer Cell reports High 27568564
2016 Crystal structure of the mouse SEL1L central domain (SLR motifs 5–9) reveals a homodimer with two-fold symmetry in a head-to-tail manner, with SLR motif 9 forming a domain-swapped dimeric interface; full-length SEL1L self-oligomerizes through this central domain in mammalian cells, and SLR-C (motifs 10–11) directly interacts with N-terminal luminal loops of HRD1. X-ray crystallography, co-immunoprecipitation in mammalian cells, domain mapping Scientific reports High 27064360
2017 Cryo-EM structure of yeast Hrd1 (SEL1L homolog Hrd3 partner) in complex with Hrd3 reveals that Hrd1 forms a dimer with an aqueous cavity extending from the cytosol to near the ER lumen and a lateral gate, suggesting Hrd1 functions as a retrotranslocation channel for misfolded polypeptides. Cryo-electron microscopy, structural analysis Nature High 28682307
2017 SEL1L-dependent ERAD substrates require Derlin2 or Derlin3 (redundantly) and Herp1 or Herp2 (redundantly) for degradation, defining a retrotranslocon route (HRD1-SEL1L-Derlin2/3-Herp1/2) distinct from an alternative SEL1L-independent HRD1 route. Gene targeting in DT40 cells to create single and combined knockouts, pulse-chase degradation assays of six ERAD-L substrates Cell structure and function High 28552883
2018 Hepatic Sel1L-Hrd1 ERAD controls Fgf21 transcription by regulating ubiquitination and turnover of the ER-resident transcription factor Crebh; liver-specific Sel1L deletion elevates nuclear Crebh abundance without affecting Pparα, revealing a hepatic 'ERAD-Crebh-Fgf21' axis linking ER protein turnover to systemic metabolic regulation. Liver-specific Sel1L knockout mice, ubiquitination assays, nuclear fractionation, transcriptional reporter assays The EMBO journal High 30389665
2018 HCMV UL148 interacts with SEL1L and slows gO (glycoprotein O) degradation; gO is a constitutive ERAD substrate during infection, and siRNA knockdown of SEL1L or HRD1 strongly stabilizes gO. gO also associates with OS-9 in a SEL1L-dependent manner. Mass spectrometry co-immunoprecipitation, siRNA knockdown, pulse-chase assays, ERAD pharmacological inhibition Journal of virology High 29997207
2020 Sel1L-Hrd1 ERAD maintains β cell identity by mediating proteasomal degradation of TGF-β receptor 1; Sel1L deficiency in β cells causes loss of β cell identity (not apoptosis), and inhibition of TGF-β signaling in Sel1L-deficient β cells restores β cell maturation markers and insulin content. β cell-specific Sel1L knockout mice, single-cell RNA-seq, TGF-β receptor turnover assays, TGF-β pathway inhibition rescue experiments The Journal of clinical investigation High 32182217
2021 Murine cytomegalovirus M50 protein mediates IRE1 degradation by tethering IRE1 to SEL1L; M50 binds both IRE1 and SEL1L simultaneously, and SEL1L ablation blocks M50-dependent IRE1 proteasomal degradation. p97/VCP inhibition also blocks this process, defining the ERAD pathway used. Co-immunoprecipitation, genetic ablation of SEL1L, pharmacological inhibition of p97/VCP, proteasome assays Journal of virology High 33472927
2022 SEL1L-HRD1 ERAD suppresses hepatocyte proliferation and liver cancer; nascent WNT5A is a misfolding-prone ERAD substrate targeted by SEL1L-HRD1; in ERAD-deficient liver, WNT5A misfolds, is retained in the ER, and forms aggregates, causing loss-of-function and attenuated suppression of hepatocyte proliferation. Hepatocyte-specific Sel1L or Hrd1 knockout mice, proteomics screen, co-immunoprecipitation, high-molecular weight complex analysis, tumor induction assays iScience High 36238898
2023 SEL1L-HRD1 ERAD ubiquitinates and targets nascent STING for proteasomal degradation in the basal state, uncoupled from ER stress or IRE1α; SEL1L or HRD1 deficiency in macrophages amplifies STING signaling and enhances immunity against viral infection and tumor growth. Macrophage-specific Sel1L/Hrd1 knockout mice, ubiquitination assays, viral infection models, tumor co-culture assays, pulse-chase Nature cell biology High 37142791
2023 Hepatic SEL1L-HRD1 ERAD controls systemic iron homeostasis via ceruloplasmin (CP), a ferroxidase that is a bona fide ERAD substrate; in ERAD-deficient liver, CP accumulates in the ER and is shunted to refolding, leading to elevated secretion and altered systemic iron distribution. Disease-causing CP mutants are also degraded by SEL1L-HRD1 ERAD. Hepatocyte-specific Sel1L knockout mice, proteomics, co-immunoprecipitation, pulse-chase, iron homeostasis assays Proceedings of the National Academy of Sciences of the United States of America High 36595688
2024 SEL1L-HRD1 interaction is required for formation of a functional HRD1 ERAD complex; SEL1L recruits E2 enzyme UBE2J1 and DERLIN to HRD1. The pathogenic SEL1L S658P variant attenuates SEL1L-HRD1 interaction via electrostatic repulsion between SEL1L F668 and HRD1 Y30, reduces SEL1L protein stability, and causes cerebellar ataxia in homozygous mice. Knock-in mouse model, proteomic screens of SEL1L and HRD1 interactomes, biochemical interaction assays, mutagenesis Nature communications High 38365914
2024 Biallelic hypomorphic SEL1L variants (p.Gly585Asp and p.Met528Arg) in humans impair ERAD function at distinct steps: Gly585Asp disrupts substrate recruitment, and Met528Arg disrupts SEL1L-HRD1 complex formation. These variants cause neurodevelopmental disorders, establishing a structure-function relationship of SEL1L-HRD1 ERAD in humans. Patient-derived cell lines, in vitro ERAD functional assays, co-immunoprecipitation, pulse-chase The Journal of clinical investigation High 37943610
2024 Biallelic SEL1L p.Cys141Tyr variant disrupts a disulfide bond in the luminal fibronectin II domain, largely abolishing SEL1L-HRD1 ERAD complex function partly via proteasomal self-destruction by HRD1; patients exhibit ENDI-agammaglobulinemia syndrome with absent mature B cells, establishing inverse correlation between ERAD functionality and disease severity. Patient cell line analysis, disulfide bond disruption characterization, ERAD functional assays, B cell development analysis The Journal of clinical investigation High 37943617
2024 Proteomics strategy identified over 100 high-confidence SEL1L-HRD1 ERAD substrates; PIGK (catalytic subunit of GPI-transamidase) is a top shared substrate—SEL1L-HRD1 ERAD attenuates GPI-anchored protein biogenesis by targeting PIGK for proteasomal degradation. Several PIGK disease variants in inherited GPI deficiency are also ERAD substrates. Proteomics with machine learning filtering, in vitro and in vivo substrate identification, pulse-chase, co-immunoprecipitation Nature communications High 38253565
2024 SEL1L-HRD1 ERAD in POMC-expressing neurons regulates leptin signaling and diet-induced obesity partly by controlling turnover of the long isoform of Leptin receptor (LepRb); nascent LepRb (including disease-associated Cys604Ser variant) is misfolding-prone and a bona fide SEL1L-HRD1 substrate retained in the ER in ERAD-deficient neurons. POMC neuron-specific Sel1L knockout mice, pulse-chase, co-immunoprecipitation, leptin signaling assays, metabolic phenotyping Nature communications High 39343970
2024 SEL1L-HRD1 ERAD mediates degradation of misfolded fibrinogen Aα, Bβ, and γ chains, which is indispensable for functional fibrinogen complex assembly in the ER; ERAD deficiency leads to hepatocellular inclusion body formation. Disease-causing fibrinogen γ mutants are also SEL1L-HRD1 ERAD substrates. Hepatocyte-specific Sel1L knockout mice, proteomics, co-immunoprecipitation, pulse-chase, electron microscopy Nature communications High 39455574
2024 Genome-wide screens identified SEL1L as a regulator of intracellular collagen clearance via a noncanonical function; SEL1L senses collagen biosynthesis internally and regulates extracellular collagen clearance as a homeostatic negative feedback loop. This pathway is impaired in human fibrotic lung disease. Genome-wide CRISPR screens, SEL1L loss-of-function, collagen uptake/degradation assays, human tissue analysis Nature communications Medium 38378719
2024 Purkinje cell-specific SEL1L deficiency causes early-onset progressive cerebellar ataxia with progressive Purkinje cell loss, dilated ER, and fragmented nuclei, demonstrating the pathophysiological importance of SEL1L-HRD1 ERAD in Purkinje cells. Purkinje cell-specific Sel1L conditional knockout mice (Sel1LPcp2Cre), motor behavior testing, transmission electron microscopy, histology JCI insight High 39352758
2025 Cryo-EM structure of the mammalian OS9-SEL1L-HRD1 core ERAD complex reveals a dimeric assembly where SEL1L and OS9 form a claw-like configuration in the ER lumen mediating substrate engagement, and HRD1 dimerizes within the membrane to facilitate substrate translocation. Pathogenic SEL1L mutations at SEL1L-OS9 (Gly585Asp) and SEL1L-HRD1 (Ser658Pro) interfaces disrupt complex formation. A new HRD1 variant (Ala91Asp) impairs HRD1 dimerization and substrate processing. Cryo-EM, mutagenesis, crosslinking assays, ERAD functional assays bioRxivpreprint High 40661598
2021 SEL1L degradation intermediates appear in the cytosol when proteasome activity is inhibited; OS-9 and XTP3-B inhibit SEL1L degradation. The C-terminal Pro-rich region of SEL1L generates a ladder of degradation products, and these cytosolic intermediates stimulate aggregation of polyglutamine-expanded Huntingtin by interacting with aggregation-prone proteins. Proteasome inhibition, co-immunoprecipitation, identification of OS-9 and XTP3-B as SEL1L degradation regulators, aggregation assays The FEBS journal Medium 33576152
2023 SIRT4 deacetylates lysine 547 of SEL1L, increasing HRD1 protein levels; the elevated SEL1L-HRD1 complex reduces stability of mitochondrial protein ALKBH1, which blocks transcription of mitochondrial DNA-coded genes and causes mitochondrial damage in pancreatic cancer cells. Co-immunoprecipitation, deacetylation assays, ALKBH1 stability assays, mitochondrial function analysis Biochimica et biophysica acta. Gene regulatory mechanisms Medium 37146713
2008 SEL1L and HRD1 are involved in the degradation of unassembled secretory Ig-μ chains; co-immunoprecipitation, silencing, and overexpression assays demonstrated SEL1L and HRD1 involvement in Ig-μs ERAD but minor effects on TCR-α degradation. SEL1L and HRD1 localize in the early secretory apparatus and are induced by ER stress and during B cell differentiation. Co-immunoprecipitation, siRNA silencing, overexpression assays, pulse-chase Journal of cellular physiology Medium 18314878
2013 SEL1L co-immunoprecipitates with β1-integrin in pancreatic β-cells; SEL1L downmodulation negatively influences cell adhesion, proliferation (via altered ERK signaling), and glucose-stimulated insulin secretion in isolated mouse islets. The β1-integrin phenotype is rescued by ectopic β1-integrin expression. Co-immunoprecipitation, siRNA knockdown, glucose-stimulated insulin secretion assay, ectopic expression rescue PloS one Medium 24324549

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2008 OS-9 and GRP94 deliver mutant alpha1-antitrypsin to the Hrd1-SEL1L ubiquitin ligase complex for ERAD. Nature cell biology 419 18264092
2008 SEL1L nucleates a protein complex required for dislocation of misfolded glycoproteins. Proceedings of the National Academy of Sciences of the United States of America 229 18711132
2014 Sel1L is indispensable for mammalian endoplasmic reticulum-associated degradation, endoplasmic reticulum homeostasis, and survival. Proceedings of the National Academy of Sciences of the United States of America 188 24453213
2006 SEL1L, the homologue of yeast Hrd3p, is involved in protein dislocation from the mammalian ER. The Journal of cell biology 185 17043138
2008 Human XTP3-B forms an endoplasmic reticulum quality control scaffold with the HRD1-SEL1L ubiquitin ligase complex and BiP. The Journal of biological chemistry 161 18502753
2017 Cryo-EM structure of the protein-conducting ERAD channel Hrd1 in complex with Hrd3. Nature 160 28682307
2010 Stringent requirement for HRD1, SEL1L, and OS-9/XTP3-B for disposal of ERAD-LS substrates. The Journal of cell biology 147 20100910
2009 EDEM1 recognition and delivery of misfolded proteins to the SEL1L-containing ERAD complex. Molecular cell 112 19524542
2014 The ER-associated degradation adaptor protein Sel1L regulates LPL secretion and lipid metabolism. Cell metabolism 109 25066055
2011 SEL1L protein critically determines the stability of the HRD1-SEL1L endoplasmic reticulum-associated degradation (ERAD) complex to optimize the degradation kinetics of ERAD substrates. The Journal of biological chemistry 95 21454652
2010 Deficiency of suppressor enhancer Lin12 1 like (SEL1L) in mice leads to systemic endoplasmic reticulum stress and embryonic lethality. The Journal of biological chemistry 86 20197277
2023 SEL1L-HRD1 endoplasmic reticulum-associated degradation controls STING-mediated innate immunity by limiting the size of the activable STING pool. Nature cell biology 80 37142791
2018 Hepatic Sel1L-Hrd1 ER-associated degradation (ERAD) manages FGF21 levels and systemic metabolism via CREBH. The EMBO journal 80 30389665
2020 Sel1L-Hrd1 ER-associated degradation maintains β cell identity via TGF-β signaling. The Journal of clinical investigation 79 32182217
2013 The unfolded protein response transducer ATF6 represents a novel transmembrane-type endoplasmic reticulum-associated degradation substrate requiring both mannose trimming and SEL1L protein. The Journal of biological chemistry 74 24043630
2000 The IBD2 locus shows linkage heterogeneity between ulcerative colitis and Crohn disease. American journal of human genetics 73 11078482
2016 The Sel1L-Hrd1 Endoplasmic Reticulum-Associated Degradation Complex Manages a Key Checkpoint in B Cell Development. Cell reports 65 27568564
2016 Direct and essential function for Hrd3 in ER-associated degradation. Proceedings of the National Academy of Sciences of the United States of America 60 27170191
2012 A SEL1L mutation links a canine progressive early-onset cerebellar ataxia to the endoplasmic reticulum-associated protein degradation (ERAD) machinery. PLoS genetics 59 22719266
2015 Epithelial Sel1L is required for the maintenance of intestinal homeostasis. Molecular biology of the cell 50 26631554
1998 Cloning and characterization of Sel-1l, a murine homolog of the C. elegans sel-1 gene. Mechanisms of development 46 9858735
2015 PDI reductase acts on Akita mutant proinsulin to initiate retrotranslocation along the Hrd1/Sel1L-p97 axis. Molecular biology of the cell 45 26269577
2002 SEL1L expression decreases breast tumor cell aggressiveness in vivo and in vitro. Cancer research 43 11809711
2018 Human Cytomegalovirus Tropism Modulator UL148 Interacts with SEL1L, a Cellular Factor That Governs Endoplasmic Reticulum-Associated Degradation of the Viral Envelope Glycoprotein gO. Journal of virology 41 29997207
2006 SEL1L a multifaceted protein playing a role in tumor progression. Journal of cellular physiology 41 16331677
2008 SEL1L and HRD1 are involved in the degradation of unassembled secretory Ig-mu chains. Journal of cellular physiology 39 18314878
2013 Putative tumor suppressor gene SEL1L was downregulated by aberrantly upregulated hsa-mir-155 in human pancreatic ductal adenocarcinoma. Molecular carcinogenesis 37 23661430
2003 SEL1L expression in pancreatic adenocarcinoma parallels SMAD4 expression and delays tumor growth in vitro and in vivo. Oncogene 37 14508516
2013 The ERdj5-Sel1L complex facilitates cholera toxin retrotranslocation. Molecular biology of the cell 36 23363602
2012 Role of the SEL1L:LC3-I complex as an ERAD tuning receptor in the mammalian ER. Molecular cell 34 22633958
2005 SEL1L affects human pancreatic cancer cell cycle and invasiveness through modulation of PTEN and genes related to cell-matrix interactions. Neoplasia (New York, N.Y.) 34 16331889
2024 SEL1L-HRD1 interaction is required to form a functional HRD1 ERAD complex. Nature communications 32 38365914
2024 Hypomorphic variants of SEL1L-HRD1 ER-associated degradation are associated with neurodevelopmental disorders. The Journal of clinical investigation 29 37943610
2014 The interplay of Hrd3 and the molecular chaperone system ensures efficient degradation of malfolded secretory proteins. Molecular biology of the cell 29 25428985
2013 Down-modulation of SEL1L, an unfolded protein response and endoplasmic reticulum-associated degradation protein, sensitizes glioma stem cells to the cytotoxic effect of valproic acid. The Journal of biological chemistry 27 24311781
2024 Biallelic Cys141Tyr variant of SEL1L is associated with neurodevelopmental disorders, agammaglobulinemia, and premature death. The Journal of clinical investigation 26 37943617
2000 SEL1L, the human homolog of C. elegans sel-1: refined physical mapping, gene structure and identification of polymorphic markers. Human genetics 25 10746565
2005 Protein profile changes in the human breast cancer cell line MCF-7 in response to SEL1L gene induction. Proteomics 24 15880780
2006 A novel polymorphism in SEL1L confers susceptibility to Alzheimer's disease. Neuroscience letters 23 16412574
2012 SEL1L, an UPR response protein, a potential marker of colonic cell transformation. Digestive diseases and sciences 22 22350780
2011 SEL1L is required for endoplasmic reticulum-associated degradation of misfolded luminal proteins but not transmembrane proteins in chicken DT40 cell line. Cell structure and function 22 21857145
1999 Identification of SEC12, SED4, truncated SEC16, and EKS1/HRD3 as multicopy suppressors of ts mutants of Sar1 GTPase. Journal of biochemistry 22 9880808
2023 Hepatic SEL1L-HRD1 ER-associated degradation regulates systemic iron homeostasis via ceruloplasmin. Proceedings of the National Academy of Sciences of the United States of America 21 36595688
2022 SEL1L-HRD1 ER-associated degradation suppresses hepatocyte hyperproliferation and liver cancer. iScience 21 36238898
2016 Crystal structure of SEL1L: Insight into the roles of SLR motifs in ERAD pathway. Scientific reports 21 27064360
2010 SEL1L deficiency impairs growth and differentiation of pancreatic epithelial cells. BMC developmental biology 21 20170518
2006 Phenotype-stratified genetic linkage study demonstrates that IBD2 is an extensive ulcerative colitis locus. The American journal of gastroenterology 21 16542294
2002 Production of a monoclonal antibody directed against the recombinant SEL1L protein. The International journal of biological markers 21 12113576
2015 Association of the SEL1L protein transmembrane domain with HRD1 ubiquitin ligase regulates ERAD-L. The FEBS journal 20 26471130
2004 Identification of a region within SEL1L protein required for tumour growth inhibition. Gene 20 14729273
2024 Proteomic screens of SEL1L-HRD1 ER-associated degradation substrates reveal its role in glycosylphosphatidylinositol-anchored protein biogenesis. Nature communications 19 38253565
2004 SEL1L and squamous cell carcinoma of the esophagus. Clinical cancer research : an official journal of the American Association for Cancer Research 19 15355917
2000 The expression of SEL1L and TAN-1 in normal and neoplastic cells. The International journal of biological markers 19 10763137
2011 Secretion of novel SEL1L endogenous variants is promoted by ER stress/UPR via endosomes and shed vesicles in human cancer cells. PloS one 17 21359144
2009 Functional characterization of two secreted SEL1L isoforms capable of exporting unassembled substrate. The Journal of biological chemistry 16 19204006
2025 SEL1L-HRD1-mediated ERAD in mammals. Nature cell biology 14 40562846
2024 Genome-wide screens identify SEL1L as an intracellular rheostat controlling collagen turnover. Nature communications 14 38378719
2023 Sirtuin4 impacts mitochondrial homeostasis in pancreatic cancer cells by reducing the stability of AlkB homolog 1 via deacetylation of the HRD1-SEL1L complex. Biochimica et biophysica acta. Gene regulatory mechanisms 14 37146713
2017 SEL1L-dependent Substrates Require Derlin2/3 and Herp1/2 for Endoplasmic Reticulum-associated Degradation. Cell structure and function 14 28552883
2015 SEL1L SNP rs12435998, a predictor of glioblastoma survival and response to radio-chemotherapy. Oncotarget 14 25948789
2002 Genomic structure, chromosome mapping and expression analysis of the human AVIL gene, and its exclusion as a candidate for locus for inflammatory bowel disease at 12q13-14 (IBD2). Gene 14 12034507
2002 Cross-species conservation of SEL1L, a human pancreas-specific expressing gene. Omics : a journal of integrative biology 14 12143964
2001 Cloning and functional analysis of SEL1L promoter region, a pancreas-specific gene. DNA and cell biology 14 11242538
2001 Activin A induces expression of rat Sel-1l mRNA, a negative regulator of notch signaling, in rat salivary gland-derived epithelial cells. Biochemical and biophysical research communications 14 11401526
2006 SEL1L expression in non-small cell lung cancer. Human pathology 13 16647946
2003 No evidence for involvement of IL-4R and CD11B from the IBD1 region and STAT6 in the IBD2 region in Crohn's disease. European journal of human genetics : EJHG 13 14571275
2024 Regulation of leptin signaling and diet-induced obesity by SEL1L-HRD1 ER-associated degradation in POMC expressing neurons. Nature communications 12 39343970
2023 SEL1L preserves CD8+ T-cell survival and homeostasis by fine-tuning PERK signaling and the IL-15 receptor-mediated mTORC1 axis. Cellular & molecular immunology 12 37644166
2001 No evidence for SEL1L as a candidate gene for IDDM11-conferred susceptibility. Diabetes/metabolism research and reviews 12 11544613
2024 Regulation of hepatic inclusions and fibrinogen biogenesis by SEL1L-HRD1 ERAD. Nature communications 11 39455574
2023 METTL3 activates PERK-eIF2α dependent coelomocyte apoptosis by targeting the endoplasmic reticulum degradation-related protein SEL1L in echinoderms. Biochimica et biophysica acta. Gene regulatory mechanisms 11 36933883
2022 Suppression of RNF213, a susceptibility gene for moyamoya disease, inhibits endoplasmic reticulum stress through SEL1L upregulation. Biochemical and biophysical research communications 11 35413541
2011 Haploid insufficiency of suppressor enhancer Lin12 1-like (SEL1L) protein predisposes mice to high fat diet-induced hyperglycemia. The Journal of biological chemistry 11 21536682
2001 SEL1L microsatellite polymorphism in Japanese patients with autoimmune thyroid diseases. Thyroid : official journal of the American Thyroid Association 11 11349831
2023 Luteolin Protects Against 6-Hydoroxydopamine-Induced Cell Death via an Upregulation of HRD1 and SEL1L. Neurochemical research 10 37632637
2019 SEL1L plays a major role in human malignant gliomas. The journal of pathology. Clinical research 10 31111685
2013 SEL1L regulates adhesion, proliferation and secretion of insulin by affecting integrin signaling. PloS one 10 24324549
2024 ER-associated degradation adapter Sel1L is required for CD8+ T cell function and memory formation following acute viral infection. Cell reports 9 38687642
2019 Host Gene SEL1L Involved in Endoplasmic Reticulum-Associated Degradation Pathway Could Inhibit Hepatitis B Virus at RNA, DNA, and Protein Levels. Frontiers in microbiology 9 31921048
2017 Quantitative proteomics in A30P*A53T α-synuclein transgenic mice reveals upregulation of Sel1l. PloS one 9 28771510
2024 Purkinje cell-specific deficiency in SEL1L-hrd1 endoplasmic reticulum-associated degradation causes progressive cerebellar ataxia in mice. JCI insight 8 39352758
2022 T-cell-specific Sel1L deletion exacerbates EAE by promoting Th1/Th17-cell differentiation. Molecular immunology 8 35696849
2021 Viral mediated tethering to SEL1L facilitates ER-associated degradation of IRE1. Journal of virology 8 33472927
2004 RNA-mediated interference indicates that SEL1L plays a role in pancreatic beta-cell growth. DNA and cell biology 7 15307954
2002 Association of ulcerative colitis with the inflammatory bowel disease susceptibility locus IBD2 in non-Jewish Caucasians and evidence of genetic heterogeneity among racial and ethnic populations with Crohn disease. American journal of medical genetics 7 12439891
2012 Single nucleotide polymorphisms in C-type lectin genes, clustered in the IBD2 and IBD6 susceptibility loci, may play a role in the pathogenesis of inflammatory bowel diseases. European journal of gastroenterology & hepatology 6 22664939
2001 Allelic polymorphisms in the transcriptional regulatory region of human SEL1L. Mutation research 6 11691638
2002 Notch signal transduction is not regulated by SEL1L in leukaemia and lymphoma cells in culture. Anticancer research 5 12553058
2024 The HRD1-SEL1L ubiquitin ligase regulates stress granule homeostasis in couple with distinctive signaling branches of ER stress. iScience 4 38979013
2022 Sel1l May Contributes to the Determinants of Neuronal Lineage and Neuronal Maturation Regardless of Hrd1 via Atf6-Sel1l Signaling. Neurochemical research 4 36074198
2021 SEL1L degradation intermediates stimulate cytosolic aggregation of polyglutamine-expanded protein. The FEBS journal 4 33576152
2018 Sel1l knockdown negatively influences zebrafish embryos endothelium. Journal of cellular physiology 4 29215726
2002 IBD2 encodes a novel component of the Bub2p-dependent spindle checkpoint in the budding yeast Saccharomyces cerevisiae. Genetics 4 12072457
2025 Structural basis and pathological implications of the dimeric OS9-SEL1L-HRD1 ERAD Core Complex. bioRxiv : the preprint server for biology 3 40661598
2024 Hypomorphic human SEL1L and HRD1 variants uncouple multilayered ER-associated degradation machinery. The Journal of clinical investigation 3 38226624
2024 Role of SEL1L in the progression of solid tumors, with a special focus on its recent therapeutic potential. Cell biology international 3 39364680
2022 Characterization of dietary and herbal sourced natural compounds that modulate SEL1L-HRD1 ERAD activity and alleviate protein misfolding in the ER. The Journal of nutritional biochemistry 3 36228974
2004 Identification of a novel polymorphism in the fibronectin type II domain of the SEL1L gene and possible relation to the persistent hyperinsulinemic hypoglycemia of infancy. Mutation research 3 15450414
2025 Modulation of Sel1L can alleviate altered ER homeostasis towards white matter damage in CKD-stroke complex. Communications biology 2 40301526
2025 Bromodomain proteins IBD1 and IBD2 link histone acetylation to SWR1- and INO80-mediated H2A.Z regulation in Tetrahymena. Epigenetics & chromatin 2 40764940