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Showing SEL1L — HRD3 is a alias.

SEL1L

Protein sel-1 homolog 1 · UniProt Q9UBV2

Length
794 aa
Mass
88.8 kDa
Annotated
2026-06-10
100 papers in source corpus 40 papers cited in narrative 40 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SEL1L is an ER-resident single-pass transmembrane adaptor that forms the core of the mammalian SEL1L-HRD1 ER-associated degradation (ERAD) machinery, where it nucleates the dislocation complex required to extract and degrade misfolded ER proteins (PMID:17043138, PMID:18711132). Through its luminal SEL1L-repeat (SLR) domains, SEL1L bridges substrate-recognition lectins and chaperones — OS-9, XTP3-B, EDEM1, and ERdj5 — to the membrane-embedded E3 ligase HRD1, assembling a large ER quality-control scaffold that channels glycoprotein and other substrates toward ubiquitination (PMID:18711132, PMID:18264092, PMID:18502753, PMID:19524542, PMID:23363602). This handoff is pathway-selective: degradation of soluble luminal substrates strictly depends on SEL1L, OS-9, and XTP3-B, whereas membrane-tethered substrates can bypass these factors, and a distinct HRD1 route requires Derlins and Herp downstream of SEL1L (PMID:20100910, PMID:28552883). SEL1L is essential for assembly and activity of the complex — it stabilizes HRD1 and is itself a prerequisite for recruiting the E2 enzyme UBE2J1 and Derlin to HRD1, with the two proteins reciprocally stabilizing each other through their transmembrane and luminal interfaces (PMID:24453213, PMID:38365914, PMID:21454652). Structurally, SEL1L homodimerizes via its central SLR domain and contacts the HRD1 luminal loops, and the core OS9-SEL1L-HRD1 assembly forms a luminal claw-like substrate-engagement platform above a dimeric HRD1 membrane channel (PMID:27064360, PMID:40661598). Beyond bulk quality control, SEL1L-HRD1 ERAD degrades a broad and physiologically defined substrate set — STING, TGF-β receptor 1, CREBH, ceruloplasmin, LepRb, pre-BCR, PIGK, WNT5A, and fibrinogen chains — thereby tuning innate immune signaling, β-cell identity, iron and lipid homeostasis, leptin signaling, B-cell development, and GPI-anchored protein biogenesis (PMID:27568564, PMID:30389665, PMID:32182217, PMID:37142791, PMID:36595688, PMID:38253565, PMID:39343970, PMID:39455574). SEL1L also performs ERAD-independent functions, stabilizing the LPL-LMF1 maturation complex to promote lipase secretion (PMID:25066055). In humans, biallelic hypomorphic SEL1L variants that disrupt the SEL1L-OS9 or SEL1L-HRD1 interfaces or destabilize the protein cause neurodevelopmental disorders and agammaglobulinemia (PMID:38365914, PMID:37943610, PMID:37943617).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 2006 High

    Established that the mammalian Hrd3p homolog SEL1L is a required component of the ER dislocation machinery, placing it in the pathway that extracts misfolded proteins from the ER.

    Evidence shRNA knockdown with pulse-chase degradation of misfolded RI332 and discrimination of viral US11/US2 dislocation routes

    PMID:17043138

    Open questions at the time
    • Molecular interactions and complex composition not yet defined
    • Did not identify the E3 ligase partner
  2. 2008 High

    Defined SEL1L as the adaptor that nucleates a dislocation complex, physically linking substrate-recognition lectins OS-9 and XTP3-B to the HRD1 E3 ligase and forming a large ~27S quality-control scaffold.

    Evidence Reciprocal co-IP, mass-spec interactome, sucrose-gradient fractionation, domain mapping, and substrate degradation assays across three studies

    PMID:18264092 PMID:18502753 PMID:18711132

    Open questions at the time
    • Stoichiometry and architecture of the scaffold unresolved at atomic level
    • How substrates are passed from lectins to HRD1 unknown
  3. 2009 Medium

    Showed substrate-recognition chaperones EDEM1 and ERdj5 deliver nonnative proteins to the SEL1L complex via direct binding to SEL1L domains, connecting recognition to dislocation.

    Evidence Co-IP with domain mutagenesis, kifunensine treatment, and degradation assays (EDEM1, 2009; ERdj5/CTA, 2013)

    PMID:19524542 PMID:23363602

    Open questions at the time
    • ERdj5 finding from a single lab
    • Order of chaperone engagement relative to lectins not established
  4. 2010 High

    Resolved that SEL1L's requirement is substrate-topology-selective — strictly needed for soluble luminal ERAD substrates but dispensable when substrates are membrane-tethered.

    Evidence siRNA knockdown with defined ERAD-LS vs ERAD-LM substrate pulse-chase

    PMID:20100910

    Open questions at the time
    • Mechanistic basis for topology selectivity not defined
    • Did not enumerate the full substrate repertoire
  5. 2014 High

    Established the mammalian-specific reciprocal stability relationship: SEL1L stabilizes HRD1 (opposite to yeast), with in vivo loss causing ERAD collapse, ER stress, and lethal pancreatic atrophy.

    Evidence Inducible knockout mice, biochemical fractionation, proteomics, and pulse-chase ERAD assay; complemented by reciprocal stabilization studies via the TM domain

    PMID:21454652 PMID:24453213 PMID:26471130

    Open questions at the time
    • E3 ligase degrading free SEL1L not identified
    • Tissue-specific essentiality determinants unclear
  6. 2014 High

    Demonstrated SEL1L has ERAD-independent functions, stabilizing the LPL-LMF1 maturation complex to promote lipase secretion, separating chaperone-like roles from HRD1-mediated degradation.

    Evidence Adipocyte-specific knockout mice, co-IP, secretion pulse-chase, and autophagy inhibition

    PMID:25066055

    Open questions at the time
    • Structural basis for SEL1L-LPL/LMF1 binding undefined
    • Extent of other ERAD-independent clients unknown
  7. 2016 High

    Provided first structural insight: SEL1L homodimerizes via domain-swapped SLR motifs and directly contacts HRD1 luminal loops through its SLR-C region; yeast work showed the ortholog is directly required for HRD1 E3 activity beyond stabilization.

    Evidence X-ray crystallography of the SEL1L central domain with co-IP/mutagenesis, and yeast genetic epistasis using a Usa1-based Hrd1-stabilization system

    PMID:27064360 PMID:27170191

    Open questions at the time
    • Full-length mammalian complex architecture not resolved
    • Mechanism by which SEL1L activates HRD1 catalysis unclear
  8. 2017 High

    Cryo-EM of the yeast Hrd1-Hrd3 complex revealed Hrd1 forms a membrane dimer with a lateral-gated aqueous cavity, supporting a retrotranslocation channel model with the SEL1L ortholog on the luminal side.

    Evidence Cryo-electron microscopy of the Hrd1-Hrd3 complex

    PMID:28682307

    Open questions at the time
    • Yeast structure; mammalian complex differs
    • How the channel accommodates folded/disulfide-bonded substrates unclear
  9. 2018 High

    Defined the route 1 retrotranslocon: SEL1L-dependent substrates additionally require Derlin2/3 and Herp1/2, distinguishing them from a second HRD1 route, refining how SEL1L substrates exit the ER.

    Evidence Genetic knockout in DT40 cells with multi-substrate pulse-chase

    PMID:28552883

    Open questions at the time
    • Rules determining route assignment per substrate not defined
    • Physical organization of Derlin/Herp within the complex unresolved
  10. 2023 High

    Expanded the physiological substrate repertoire and disease relevance, showing SEL1L-HRD1 ERAD degrades specific clients (STING, TGFBR1, CREBH, ceruloplasmin, pre-BCR) in an ER-stress-uncoupled manner to control immunity, β-cell identity, metabolism, and B-cell development.

    Evidence Multiple tissue-specific knockout mice with ubiquitination assays, co-IP, proteomics, and functional/physiological readouts

    PMID:27568564 PMID:30389665 PMID:32182217 PMID:36595688 PMID:37142791

    Open questions at the time
    • How specific substrates are selected from the proteome unclear
    • Whether substrate sets overlap or differ across tissues not fully mapped
  11. 2024 High

    Systematic proteomics and tissue-specific knockouts established a >100-substrate landscape (including PIGK, WNT5A, LepRb, fibrinogen chains) and demonstrated SEL1L-HRD1 is a prerequisite for recruiting UBE2J1 and Derlin to HRD1, with human hypomorphic variants causing neurodevelopmental disorders and agammaglobulinemia.

    Evidence Proteomics substrate screens, knock-in and conditional knockout mice, patient-variant biochemical interface mapping, and degradation assays

    PMID:27170191 PMID:36238898 PMID:37943610 PMID:37943617 PMID:38253565 PMID:38365914 PMID:39343970 PMID:39455574

    Open questions at the time
    • Genotype-phenotype basis of distinct human syndromes incompletely explained
    • Selectivity logic for the broad substrate set unresolved
  12. 2025 High

    Cryo-EM of the mammalian core OS9-SEL1L-HRD1 complex resolved a luminal claw-like substrate-engagement platform above a dimeric HRD1 membrane channel and mapped pathogenic variants to specific interfaces.

    Evidence Cryo-EM structural determination with mutagenesis, crosslinking, and functional ERAD validation (preprint)

    PMID:40661598

    Open questions at the time
    • Preprint, not yet peer-reviewed
    • Substrate trajectory through the methionine-rich crevices not directly visualized

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the SEL1L-HRD1 complex selects which of its many substrates and tissue contexts to act on, and the mechanistic basis of its noncanonical functions (collagen clearance, SIRT4-regulated ALKBH1 turnover, integrin/insulin secretion), remain open.
  • Substrate selection determinants undefined
  • Noncanonical roles (collagen sensing, ALKBH1) mechanistically incomplete and single-lab
  • Regulation of complex assembly by post-translational modification (e.g. K547 deacetylation) not integrated into structural model

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 5 GO:0140096 catalytic activity, acting on a protein 4
Localization
GO:0005783 endoplasmic reticulum 4
Pathway
R-HSA-392499 Metabolism of proteins 5 R-HSA-168256 Immune System 3 R-HSA-8953897 Cellular responses to stimuli 2
Partners
AUP1DERL2EDEM1ERDJ5HRD1OS-9UBE2J1XTP3-B
Complex memberships
LPL-LMF1 maturation complexOS9-SEL1L-HRD1 core complexSEL1L-HRD1 ERAD complex

Evidence

Reading pass · 40 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; shRNA knockdown of SEL1L inhibits degradation of misfolded ribophorin fragment (RI332) and discriminates between HCMV US11 and US2 dislocation pathways, placing SEL1L in the mammalian ERAD dislocation machinery. shRNA knockdown, pulse-chase degradation assay, functional discrimination of viral dislocation pathways The Journal of cell biology High 17043138
2008 SEL1L nucleates a protein complex for dislocation of misfolded glycoproteins, interacting with AUP1, UBXD8, UBC6e, and OS9 as functionally important components; mutagenesis and dominant-negative versions confirmed the functional importance of these interactions. Biochemical pulldown/co-IP of SEL1L-interacting proteins, mass spectrometry, mutagenesis, dominant-negative constructs Proceedings of the National Academy of Sciences of the United States of America High 18711132
2008 OS-9 and XTP3-B bind ERAD substrates and, through the SEL1L adaptor, connect to the ER-membrane-embedded ubiquitin ligase Hrd1; the MRH domains of OS-9/XTP3-B are required for interaction with SEL1L but not substrate; GRP94, together with Hrd1 and SEL1L, is required for degradation of mutant alpha1-antitrypsin. Co-immunoprecipitation, siRNA knockdown, ERAD substrate degradation assay 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; this large complex also incorporates OS-9 but not gp78. Immunoprecipitation, sucrose density gradient centrifugation, ERAD substrate degradation assay The Journal of biological chemistry High 18502753
2009 EDEM1 binds nonnative proteins in a glycan-independent manner and uses its mannosidase-like domain (not catalytic activity) to associate with the ER membrane adaptor SEL1L; mutation of the EDEM1 mannosidase-like domain diminishes its association with SEL1L, linking substrate recognition to delivery to the SEL1L-containing dislocation complex. Co-immunoprecipitation, site-directed mutagenesis, kifunensine treatment, ERAD degradation assay Molecular cell High 19524542
2010 Disposal of soluble ERAD-L substrates (ERAD-LS) is strictly dependent on HRD1, SEL1L, and the ER lectins OS-9 and XTP3-B; tethering the same substrates to the membrane (ERAD-LM) renders these factors dispensable, revealing pathway-selective roles for SEL1L. siRNA knockdown, pulse-chase degradation assay with defined ERAD-LS and ERAD-LM substrates The Journal of cell biology High 20100910
2011 In mammalian cells (unlike yeast), SEL1L is the unstable partner: its half-life is reduced when HRD1 is silenced, and transiently expressed SEL1L is rapidly degraded unless HRD1 is coexpressed; HRD1 association stabilizes SEL1L via interaction at the SEL1L transmembrane domain; free SEL1L is degraded by the ubiquitin-proteasome pathway via an E3 ligase other than HRD1. siRNA knockdown, cycloheximide chase, co-immunoprecipitation, proteasome inhibitor treatment The Journal of biological chemistry High 21454652
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 misfolded polypeptides inhibits SEL1L:LC3-I-mediated segregation, raising ERAD activity without UPR induction. Co-immunoprecipitation, vesicle fractionation, siRNA knockdown, live-cell imaging Molecular cell High 22633958
2013 ATF6 (a transmembrane UPR sensor/transducer) is an ERAD substrate that requires SEL1L for proteasomal degradation despite its transmembrane nature; degradation is dependent on the luminal region of ATF6 and on mannose trimming (inhibited by kifunensine), defining a novel ERAD-LM subclass requiring SEL1L. Gene knockout (DT40 cells), pulse-chase assay, chimeric protein analysis, kifunensine pharmacological 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; SEL1L itself binds cholera toxin CTA subunit and facilitates its retrotranslocation; EDEM1 and OS-9 do not play significant roles in CTA1 retrotranslocation. Loss-of-function and gain-of-function approaches, co-immunoprecipitation, domain mapping Molecular biology of the cell Medium 23363602
2014 Sel1L is required for Hrd1 protein stability in mammalian cells (unlike the reciprocal relationship in yeast); acute Sel1L loss in mice causes rapid Hrd1 degradation, impaired ERAD function, ER stress, translational attenuation, and ribosomal subunit aggregation, leading to pancreatic atrophy and death within 3 weeks. Inducible knockout mouse model, biochemical fractionation, mass spectrometry, pulse-chase ERAD assay Proceedings of the National Academy of Sciences of the United States of America High 24453213
2014 SEL1L physically interacts with and stabilizes the LPL–LMF1 maturation complex in the ER, promoting LPL secretion independent of its Hrd1-mediated ERAD function; in Sel1L-deficient adipocytes, LPL is retained in the ER, forms aggregates, and is degraded by autophagy rather than ERAD. Adipocyte-specific knockout mouse, co-immunoprecipitation, pulse-chase secretion assay, autophagy inhibitor treatment Cell metabolism High 25066055
2015 The inherent instability of human SEL1L resides in its transmembrane domain; association of HRD1 with the SEL1L transmembrane domain restores SEL1L stability; the SEL1L luminal domain retains misfolded cargo in the ER and can inhibit HRD1-mediated degradation when overexpressed without the transmembrane domain. Deletion mutagenesis, co-immunoprecipitation, cycloheximide chase, ERAD substrate degradation assay The FEBS journal Medium 26471130
2015 The Hrd1-Sel1L membrane complex conducts Akita proinsulin (MIDY mutant) from the ER lumen to the cytosol for proteasomal degradation via p97; PDI reduces proinsulin disulfide bonds and primes Akita for ERAD; efficient PDI engagement is linked to Hrd1 availability, suggesting retrotranslocation coordination on the lumenal side. siRNA knockdown, co-immunoprecipitation, pulse-chase retrotranslocation assay, PDI redox assay Molecular biology of the cell Medium 26269577
2016 Crystal structure of the mouse SEL1L central domain (SLR motifs 5–9) reveals a homodimer with two-fold head-to-tail symmetry mediated by domain-swapped SLR motif 9; the SLR-C region (SLR motifs 10–11) directly interacts with the N-terminus luminal loops of HRD1; full-length SEL1L forms self-oligomers via the central domain in mammalian cells. X-ray crystallography, co-immunoprecipitation, mutagenesis Scientific reports High 27064360
2016 Yeast Hrd3 (SEL1L ortholog) has a direct and critical role in ERAD beyond stabilizing Hrd1; using a Usa1-based approach to maintain Hrd1 in the absence of Hrd3, Hrd3 was shown to be required for E3 activity of Hrd1, rather than substrate or E2 recruitment to Hrd1. Genetic epistasis in yeast (Saccharomyces cerevisiae), Usa1-based Hrd1 stabilization system, ERAD substrate degradation assay Proceedings of the National Academy of Sciences of the United States of America High 27170191
2016 The Sel1L-Hrd1 ERAD complex selectively recognizes and targets the pre-B cell receptor (pre-BCR) for proteasomal degradation in a BiP-dependent manner; loss of Sel1L in B cell precursors 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 knockout mouse, co-immunoprecipitation, flow cytometry, cell surface staining Cell reports High 27568564
2017 Cryo-EM structure of yeast Hrd1 (SEL1L ortholog Hrd3 complex) reveals Hrd1 forms a dimer within the membrane with one or two Hrd3 molecules on the luminal side; each Hrd1 molecule has 8 transmembrane segments forming an aqueous cavity extending from the cytosol almost to the ER lumen with a lateral gate, suggesting Hrd1 forms a retro-translocation channel. Cryo-electron microscopy structural determination Nature High 28682307
2017 SEL1L-dependent ERAD substrates require Derlin2/3 and Herp1/2 for degradation, defining an HRD1-engaged retrotranslocon route 1 (requiring SEL1L, Derlin2 or Derlin3, and Herp1 or Herp2), distinct from a second HRD1-engaged route that does not require these factors. Gene knockout in chicken DT40 cells, pulse-chase ERAD degradation assay, multiple substrate analysis Cell structure and function High 28552883
2018 The Sel1L-Hrd1 ERAD complex controls FGF21 transcription by regulating ubiquitination and turnover of ER-resident transcription factor CREBH, thereby controlling nuclear abundance of CREBH; hepatic Sel1L deletion elevates circulating FGF21 via CREBH accumulation, while PPARα-mediated Fgf21 transcription is unaffected. Liver-specific knockout mouse, ubiquitination assay, nuclear fractionation, reporter assay The EMBO journal High 30389665
2018 HCMV UL148 interacts with SEL1L by mass spectrometry co-immunoprecipitation; knockdown of SEL1L or Hrd1 stabilizes viral glycoprotein gO, demonstrating gO is a constitutive ERAD substrate of the SEL1L-Hrd1 complex; gO interaction with OS-9 is also stabilized by SEL1L silencing. Mass spectrometry co-immunoprecipitation, siRNA knockdown, pulse-chase assay Journal of virology Medium 29997207
2020 Sel1L-Hrd1 ERAD controls β cell identity via TGF-β signaling by mediating the degradation of TGF-β receptor 1 (TGFBR1); Sel1L deficiency is not associated with β cell apoptosis but loss of β cell identity; inhibition of TGF-β signaling in Sel1L-deficient β cells restores expression of β cell maturation markers and insulin content. β cell-specific knockout mouse, single-cell RNA-seq, TGF-β receptor stability assay, pharmacological TGF-β inhibition The Journal of clinical investigation High 32182217
2021 Cytomegalovirus M50 protein mediates IRE1 degradation by tethering IRE1 to SEL1L, facilitating SEL1L-HRD1/p97-dependent proteasomal degradation of IRE1; M50 binds both IRE1 and SEL1L simultaneously; genetic ablation of SEL1L blocks M50-dependent IRE1 degradation. SEL1L genetic ablation, co-immunoprecipitation, proteasome and p97 inhibitor treatment, pulse-chase assay Journal of virology Medium 33472927
2022 SEL1L-HRD1 ERAD suppresses hepatocyte proliferation and tumorigenesis by degrading WNT5A; nascent WNT5A is misfolding-prone and a quality-control ERAD substrate; in ERAD-deficient cells WNT5A accumulates as high-molecular-weight aggregates in the ER, causing loss-of-function and loss of WNT5A-mediated suppression of hepatocyte proliferation. Hepatocyte-specific knockout mouse, proteomics screen, co-immunoprecipitation, substrate stability assay iScience Medium 36238898
2023 SEL1L-HRD1 ERAD ubiquitinates and targets nascent STING protein for proteasomal degradation in the basal state, limiting the size of the activable STING pool; this ERAD-mediated regulation of STING is uncoupled from ER stress and IRE1α; SEL1L or HRD1 deficiency in macrophages amplifies STING signaling and antiviral/antitumor immunity. Macrophage-specific knockout mouse, ubiquitination assay, co-immunoprecipitation, viral infection and tumor growth assays Nature cell biology High 37142791
2023 SEL1L-HRD1 ERAD in hepatocytes controls systemic iron homeostasis by degrading ceruloplasmin (CP); CP is a bona fide ERAD substrate that, in the absence of ERAD, accumulates in the ER and is shunted to refolding, leading to elevated secretion and altered iron distribution; SEL1L-HRD1 also degrades disease-causing CP mutants. Hepatocyte-specific knockout mouse, proteomics, co-immunoprecipitation, substrate stability assay, iron homeostasis measurements Proceedings of the National Academy of Sciences of the United States of America High 36595688
2023 SEL1L deficiency in CD8+ T cells leads to excessive PERK-ATF4-CHOP-Bim-mediated ER stress and aberrant mTORC1/c-MYC activation via enhanced IL-15 receptor α and β chain expression; PERK inhibition rescues SEL1L-deficient CD8+ T cell survival defects; IRE1α deficiency decreases mTORC1 signaling in Sel1l-/- naïve CD8+ T cells by downregulating IL-15 receptor α chain. T cell-specific conditional knockout, single-cell transcriptomics, PERK inhibitor treatment, adoptive transfer Cellular & molecular immunology Medium 37644166
2024 SEL1L variant p.Ser658Pro is a pathogenic hypomorphic mutation that reduces SEL1L protein stability and attenuates SEL1L-HRD1 interaction (likely via electrostatic repulsion between SEL1L F668 and HRD1 Y30); SEL1L is required for recruitment of E2 enzyme UBE2J1 and DERLIN to HRD1, establishing SEL1L-HRD1 interaction as a prerequisite for functional ERAD complex formation. Knock-in mouse model, biochemical co-immunoprecipitation, proteomics interactome screen, mutagenesis Nature communications High 38365914
2024 Three biallelic missense variants in SEL1L (p.Gly585Asp, p.Met528Arg) and HRD1 (p.Pro398Leu) impair ERAD function at distinct steps: p.Gly585Asp disrupts substrate recruitment, p.Met528Arg disrupts SEL1L-HRD1 complex formation, and p.Pro398Leu impairs HRD1 activity; these hypomorphic variants establish the importance of SEL1L-HRD1 ERAD in human neurodevelopment. Biochemical co-immunoprecipitation, ERAD substrate degradation assay, patient-derived variant functional analysis The Journal of clinical investigation High 37943610
2024 The SEL1L variant p.Cys141Tyr disrupts a disulfide bond in the luminal fibronectin II domain of SEL1L, largely abolishing SEL1L-HRD1 ERAD function in part via proteasomal-mediated HRD1 self-destruction; loss of this disulfide bond leads to agammaglobulinemia (no mature B cells) and early death, establishing SEL1L fibronectin II domain as functionally critical. Patient variant characterization, biochemical stability assay, co-immunoprecipitation, B cell development analysis The Journal of clinical investigation High 37943617
2024 A proteomics strategy identified over 100 high-confidence SEL1L-HRD1 ERAD substrates in human HEK293T cells and mouse brown adipose tissue; PIGK (catalytic subunit of GPI-transamidase complex) is a shared substrate, and SEL1L-HRD1 ERAD attenuates GPI-anchored protein biogenesis by targeting PIGK for proteasomal degradation. Proteomics substrate screen with machine learning filtering, co-immunoprecipitation, substrate degradation assay, GPI-anchored protein surface staining Nature communications High 38253565
2024 SEL1L-HRD1 ERAD in POMC-expressing neurons degrades misfolded nascent leptin receptor long isoform (LepRb), both wildtype and disease-associated Cys604Ser variant; loss of SEL1L causes ER retention of LepRb in an ER stress-independent manner, attenuating leptin signaling and predisposing mice to diet-induced obesity. POMC neuron-specific knockout mouse, co-immunoprecipitation, substrate stability and localization assay, leptin signaling assay Nature communications High 39343970
2024 Purkinje cell-specific deletion of SEL1L causes early-onset progressive cerebellar ataxia with Purkinje cell loss, dilated ER, and fragmented nuclei, establishing SEL1L-HRD1 ERAD as specifically required in Purkinje cells for cerebellar homeostasis. Purkinje cell-specific (Pcp2-Cre) knockout mouse, transmission electron microscopy, behavioral motor testing, immunohistochemistry JCI insight High 39352758
2024 SEL1L-HRD1 ERAD is required for fibrinogen biogenesis: degradation of misfolded endogenous fibrinogen Aα, Bβ, and γ chains by SEL1L-HRD1 is indispensable for formation of a functional fibrinogen complex; in ERAD-deficient hepatocytes, fibrinogen subunits accumulate as inclusion body components; disease-causing fibrinogen γ mutants are also SEL1L-HRD1 substrates. Hepatocyte-specific knockout mouse, proteomics, co-immunoprecipitation, substrate stability and secretion assay Nature communications High 39455574
2024 Genome-wide CRISPR screens identified SEL1L as an intracellular regulator of collagen clearance via a noncanonical function distinct from its canonical ERAD role; SEL1L senses collagen biosynthesis and negatively regulates extracellular collagen clearance as a homeostatic feedback mechanism. Genome-wide CRISPR screen, loss-of-function validation, collagen clearance assay Nature communications Medium 38378719
2024 SEL1L is required for optimal CD8+ T cell bioenergetics and c-Myc expression following viral activation; loss of Sel1L limits CD8+ T cell function and memory formation after acute viral infection. T cell-specific conditional knockout mouse, viral infection model, metabolic profiling, adoptive transfer Cell reports Medium 38687642
2025 Cryo-EM structure of the core mammalian ERAD complex comprising OS9, SEL1L, and HRD1 reveals a dimeric assembly: SEL1L and OS9 form a claw-like configuration in the ER lumen mediating substrate engagement, while HRD1 dimerizes within the membrane for substrate translocation; pathogenic SEL1L mutations at SEL1L-OS9 (Gly585Asp) and SEL1L-HRD1 (Ser658Pro) interfaces disrupt complex formation; HRD1 variant Ala91Asp impairs HRD1 dimerization; two methionine-rich crevices flank the HRD1 dimer as putative substrate-conducting channels. Cryo-EM structural determination, mutagenesis, crosslinking assays, functional ERAD validation bioRxivpreprint High 40661598
2011 SEL1L co-immunoprecipitates with β1-integrin in pancreatic β-cells; downmodulation of SEL1L negatively influences cell adhesion on matrix components and cell proliferation via altered ERK signaling; SEL1L absence strongly inhibits glucose-stimulated insulin secretion in isolated pancreatic islets, a phenotype rescued by ectopic β1-integrin expression. Co-immunoprecipitation, siRNA knockdown, adhesion assay, ERK signaling assay, insulin secretion assay, rescue experiment PloS one Medium 24324549
2021 Excess free SEL1L (not associated with HRD1) generates cytosolic degradation intermediates when proteasome activity is inhibited; these C-terminal Pro-rich region fragments stimulate aggregation of polyglutamine-expanded Huntingtin protein by interacting with aggregation-prone proteins; OS-9 and XTP3-B inhibit SEL1L degradation. Proteasome inhibitor treatment, co-immunoprecipitation, co-aggregation assay, deletion mutagenesis The FEBS journal Medium 33576152
2023 SIRT4 deacetylates SEL1L at lysine 547, which increases HRD1 protein levels and the SEL1L-HRD1 complex; increased SEL1L-HRD1 complex reduces stability of mitochondrial protein ALKBH1, leading to blocked transcription of mitochondrial DNA-coded genes and mitochondrial damage in pancreatic cancer cells. Co-immunoprecipitation, deacetylation assay, siRNA knockdown, ALKBH1 stability assay Biochimica et biophysica acta. Gene regulatory mechanisms Medium 37146713

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 420 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 230 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 190 24453213
2006 SEL1L, the homologue of yeast Hrd3p, is involved in protein dislocation from the mammalian ER. The Journal of cell biology 187 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 148 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 110 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 88 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 84 37142791
2020 Sel1L-Hrd1 ER-associated degradation maintains β cell identity via TGF-β signaling. The Journal of clinical investigation 80 32182217
2018 Hepatic Sel1L-Hrd1 ER-associated degradation (ERAD) manages FGF21 levels and systemic metabolism via CREBH. The EMBO journal 80 30389665
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 67 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 60 22719266
2015 Epithelial Sel1L is required for the maintenance of intestinal homeostasis. Molecular biology of the cell 52 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 44 11809711
2006 SEL1L a multifaceted protein playing a role in tumor progression. Journal of cellular physiology 42 16331677
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
2008 SEL1L and HRD1 are involved in the degradation of unassembled secretory Ig-mu chains. Journal of cellular physiology 39 18314878
2003 SEL1L expression in pancreatic adenocarcinoma parallels SMAD4 expression and delays tumor growth in vitro and in vivo. Oncogene 38 14508516
2013 Putative tumor suppressor gene SEL1L was downregulated by aberrantly upregulated hsa-mir-155 in human pancreatic ductal adenocarcinoma. Molecular carcinogenesis 37 23661430
2013 The ERdj5-Sel1L complex facilitates cholera toxin retrotranslocation. Molecular biology of the cell 36 23363602
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.) 35 16331889
2024 SEL1L-HRD1 interaction is required to form a functional HRD1 ERAD complex. Nature communications 34 38365914
2012 Role of the SEL1L:LC3-I complex as an ERAD tuning receptor in the mammalian ER. Molecular cell 34 22633958
2024 Hypomorphic variants of SEL1L-HRD1 ER-associated degradation are associated with neurodevelopmental disorders. The Journal of clinical investigation 32 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
2024 Biallelic Cys141Tyr variant of SEL1L is associated with neurodevelopmental disorders, agammaglobulinemia, and premature death. The Journal of clinical investigation 28 37943617
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
2000 SEL1L, the human homolog of C. elegans sel-1: refined physical mapping, gene structure and identification of polymorphic markers. Human genetics 25 10746565
2022 SEL1L-HRD1 ER-associated degradation suppresses hepatocyte hyperproliferation and liver cancer. iScience 24 36238898
2005 Protein profile changes in the human breast cancer cell line MCF-7 in response to SEL1L gene induction. Proteomics 24 15880780
2024 Proteomic screens of SEL1L-HRD1 ER-associated degradation substrates reveal its role in glycosylphosphatidylinositol-anchored protein biogenesis. Nature communications 23 38253565
2012 SEL1L, an UPR response protein, a potential marker of colonic cell transformation. Digestive diseases and sciences 23 22350780
2006 A novel polymorphism in SEL1L confers susceptibility to Alzheimer's disease. Neuroscience letters 23 16412574
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 22 36595688
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
2002 Production of a monoclonal antibody directed against the recombinant SEL1L protein. The International journal of biological markers 22 12113576
1999 Identification of SEC12, SED4, truncated SEC16, and EKS1/HRD3 as multicopy suppressors of ts mutants of Sar1 GTPase. Journal of biochemistry 22 9880808
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
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
2004 SEL1L and squamous cell carcinoma of the esophagus. Clinical cancer research : an official journal of the American Association for Cancer Research 20 15355917
2000 The expression of SEL1L and TAN-1 in normal and neoplastic cells. The International journal of biological markers 20 10763137
2025 SEL1L-HRD1-mediated ERAD in mammals. Nature cell biology 18 40562846
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
2024 Regulation of leptin signaling and diet-induced obesity by SEL1L-HRD1 ER-associated degradation in POMC expressing neurons. Nature communications 15 39343970
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 15 37146713
2024 Genome-wide screens identify SEL1L as an intracellular rheostat controlling collagen turnover. Nature communications 14 38378719
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
2006 SEL1L expression in non-small cell lung cancer. Human pathology 14 16647946
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
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 13 37644166
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 hepatic inclusions and fibrinogen biogenesis by SEL1L-HRD1 ERAD. Nature communications 12 39455574
2023 Luteolin Protects Against 6-Hydoroxydopamine-Induced Cell Death via an Upregulation of HRD1 and SEL1L. Neurochemical research 12 37632637
2001 No evidence for SEL1L as a candidate gene for IDDM11-conferred susceptibility. Diabetes/metabolism research and reviews 12 11544613
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
2019 SEL1L plays a major role in human malignant gliomas. The journal of pathology. Clinical research 11 31111685
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
2024 ER-associated degradation adapter Sel1L is required for CD8+ T cell function and memory formation following acute viral infection. Cell reports 10 38687642
2024 Purkinje cell-specific deficiency in SEL1L-hrd1 endoplasmic reticulum-associated degradation causes progressive cerebellar ataxia in mice. JCI insight 10 39352758
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 10 31921048
2013 SEL1L regulates adhesion, proliferation and secretion of insulin by affecting integrin signaling. PloS one 10 24324549
2017 Quantitative proteomics in A30P*A53T α-synuclein transgenic mice reveals upregulation of Sel1l. PloS one 9 28771510
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
2024 The HRD1-SEL1L ubiquitin ligase regulates stress granule homeostasis in couple with distinctive signaling branches of ER stress. iScience 5 38979013
2002 Notch signal transduction is not regulated by SEL1L in leukaemia and lymphoma cells in culture. Anticancer research 5 12553058
2024 Role of SEL1L in the progression of solid tumors, with a special focus on its recent therapeutic potential. Cell biology international 4 39364680
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 Modulation of Sel1L can alleviate altered ER homeostasis towards white matter damage in CKD-stroke complex. Communications biology 3 40301526
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
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 Bromodomain proteins IBD1 and IBD2 link histone acetylation to SWR1- and INO80-mediated H2A.Z regulation in Tetrahymena. Epigenetics & chromatin 2 40764940

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