Affinage

SYVN1

E3 ubiquitin-protein ligase synoviolin · UniProt Q86TM6

Length
617 aa
Mass
67.7 kDa
Annotated
2026-06-14
100 papers in source corpus 71 papers cited in narrative 72 extracted findings
Cross-family judge vs UniProt: Affinage preferred

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SYVN1 (HRD1) is an ER-resident, multi-spanning E3 ubiquitin ligase that constitutes the catalytic core of the SEL1L-HRD1 ER-associated degradation (ERAD) machinery, coupling recognition of misfolded ER proteins to their ubiquitination and retrotranslocation into the cytosol for proteasomal destruction (PMID:11139575, PMID:20100910). Its cytosolic RING-H2 finger binds the E2 conjugating enzymes Ubc7/UBE2J1 and is strictly required for ubiquitination of soluble and membrane misfolded substrates; the RING is also the regulatory hub of the channel (PMID:11139575, PMID:10218484, PMID:21245296). Reconstitution and structural work establish that HRD1 forms a membrane dimer that, upon autoubiquitination of specific RING-domain lysines, disassembles into active monomers and opens an aqueous, laterally gated pore through which substrate loops are threaded; substrate binding enlarges the pore and deubiquitination closes it, making the autoubiquitination/deubiquitination cycle the gate of retrotranslocation (PMID:27321670, PMID:28682307, PMID:32094691, PMID:35970394). In the assembled complex HRD1 partners with SEL1L (which it reciprocally stabilizes and which recruits UBE2J1, Derlin and the luminal lectins OS-9/XTP3-B that capture glycosylated substrates), together with Der1/Derlin-2 and HERP proteins that form a second half-channel and govern substrate movement (PMID:18264092, PMID:32327568, PMID:21454652, PMID:38365914, PMID:23867461, PMID:24366871). Beyond clearance of misfolded clients, HRD1 ubiquitinates a broad spectrum of folded regulatory proteins to control diverse physiology: it degrades Nrf2, BLIMP1, p27kip1, Fas, the pre-BCR, TGF-β receptor 1, STING, the ER-tethered transcription factor CREBH, MafA, and METTL14, thereby tuning antioxidant responses, immune-cell development and signaling, β-cell identity, and hepatic metabolic gene programs (PMID:24636985, PMID:25366967, PMID:27417417, PMID:27573825, PMID:27568564, PMID:32182217, PMID:30389664, PMID:37142791, PMID:34847358, PMID:32086291). HRD1 expression is induced by the UPR through the IRE1-XBP1 branch, and its ligase activity is itself set by post-translational modification, including S-sulfhydration at Cys115 and UFMylation at Lys610, and by deubiquitinases that stabilize it (PMID:17967421, PMID:27827840, PMID:37795761, PMID:32257542). Disease-causing variants that weaken the SEL1L-HRD1 interaction impair ERAD, and inherited GPI-deficiency PIGK variants are themselves HRD1 substrates, linking this machinery to human Mendelian disease (PMID:38365914, PMID:38253565).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 1999 High

    Established that the RING-H2 motif of Der3/Hrd1p is indispensable for degrading both soluble and membrane misfolded ER proteins, defining HRD1 as a catalytic, not merely scaffolding, ERAD component.

    Evidence Site-directed RING mutagenesis (C399S), in vivo degradation and dominant-negative/genetic suppression assays in S. cerevisiae

    PMID:10218484

    Open questions at the time
    • Did not define the E2 partner or biochemical mechanism
    • Did not establish substrate recognition route
  2. 2001 High

    Defined HRD1 as the E3 ligase of ERAD by mapping its six-TM topology with cytosolic RING and showing direct RING-dependent binding to E2 Ubc7p and in vitro ubiquitination.

    Evidence Topology mapping, in vitro ubiquitination, Ubc7p binding, RING-mutant analysis

    PMID:11139575

    Open questions at the time
    • No structural model of the channel
    • Retrotranslocation mechanism unresolved
  3. 2008 High

    Showed how luminal substrates reach HRD1, identifying OS-9/XTP3-B lectins that bind substrate and dock onto SEL1L via their MRH domains.

    Evidence Reciprocal Co-IP, siRNA degradation assays, domain mutagenesis in mammalian cells

    PMID:18264092

    Open questions at the time
    • How lectin-bound substrate is handed to HRD1 catalysis not shown
    • GRP94 role only correlative
  4. 2010 High

    Defined the architecture and codependence of the mammalian complex: HRD1 stabilizes SEL1L, and disposal of soluble ERAD-L substrates strictly requires HRD1, SEL1L and OS-9/XTP3-B.

    Evidence siRNA knockdown, reciprocal Co-IP, size fractionation, pulse-chase epistasis with defined substrates

    PMID:20100910 PMID:21454652

    Open questions at the time
    • Distinct organization from yeast (Complex I vs II) not mechanistically explained
    • Stoichiometry undefined
  5. 2016 High

    Demonstrated that HRD1 autoubiquitination within its RING domain — not substrate ubiquitination or Cdc48 — triggers retrotranslocation of luminal domains, reordering the canonical ERAD sequence.

    Evidence Proteoliposome reconstitution with purified yeast proteins, RING-lysine mutagenesis, in vivo validation

    PMID:27321670

    Open questions at the time
    • Did not visualize the channel
    • Did not resolve substrate paths through the membrane
  6. 2017 High

    Provided structural proof of a retrotranslocation channel, showing Hrd1 dimerizes with an eight-TM aqueous cavity and lateral gate in complex with Hrd3.

    Evidence Cryo-EM of S. cerevisiae Hrd1-Hrd3

    PMID:28682307

    Open questions at the time
    • Captured an inactive state
    • Did not include Der1 half-channel or substrate
  7. 2020 High

    Unified structure and function: the five-subunit complex shows Hrd1 and Der1 form two opposing half-channels in a thinned membrane while Hrd3/Yos9 build a luminal substrate site, and purified Hrd1 forms a ubiquitination-gated pore enlarged by substrate.

    Evidence Cryo-EM of subcomplexes with crosslinking and MD; pore reconstitution with electrophysiology and RING-lysine mutagenesis

    PMID:32094691 PMID:32327568

    Open questions at the time
    • Dynamics of dimer-to-monomer transition during catalysis not directly observed
    • Mammalian channel structure not solved
  8. 2022 High

    Mapped the substrate path in living cells and showed autoubiquitination disassembles inactive Hrd1 dimers into active monomers, linking the gating cycle to oligomeric state.

    Evidence Site-specific disulfide crosslinking in live yeast integrated with cryo-EM

    PMID:35970394

    Open questions at the time
    • Kinetics of monomer activation not quantified
    • Generality across non-glycosylated substrates untested
  9. 2019 High

    Defined the writer/eraser logic of channel gating: deubiquitinase Ubp1 reverses autoubiquitination, Hrd3 brakes it, and Usa1 attenuates Ubp1, establishing a regulated cycle.

    Evidence Genetic and biochemical ubiquitination/deubiquitination assays with domain mutagenesis in S. cerevisiae

    PMID:31713515

    Open questions at the time
    • Mammalian counterparts of this cycle not mapped here
    • Quantitative balance under stress unknown
  10. 2024 High

    Connected complex assembly to human disease, showing SEL1L-HRD1 binding recruits UBE2J1 and DERLIN and that a pathogenic SEL1L variant disrupts the interaction by electrostatic repulsion at the SEL1L/HRD1 interface.

    Evidence Interactome proteomics, interface mutagenesis, mouse model of pathogenic variant

    PMID:38365914

    Open questions at the time
    • Full spectrum of affected substrates in patients not defined
    • Other interface mutations untested
  11. 2011 High

    Extended HRD1 ERAD to a physiological glycoprotein, showing HRD1/UBE2J1 dislocate misfolded MHC I heavy chains while sparing assembled heterotrimers, demonstrating substrate discrimination.

    Evidence siRNA screen, Co-IP complex characterization, ubiquitination and dislocation assays

    PMID:21245296

    Open questions at the time
    • Molecular basis of discrimination unresolved
    • Role in antigen presentation only correlative
  12. 2014 High

    Revealed HRD1 as a regulator of folded transcription factors beyond ERAD, degrading Nrf2 (independently of Keap1) and BLIMP1 to control antioxidant responses and dendritic-cell MHC-II expression.

    Evidence Conditional knockout mice, ubiquitination assays, human tissue analysis, T-cell priming assays

    PMID:24636985 PMID:25366967

    Open questions at the time
    • How HRD1 recognizes cytosolic/non-ER substrates unclear
    • Linkage to canonical ERAD machinery not established for these substrates
  13. 2016 High

    Established HRD1 control of immune-cell fate by degrading p27kip1, Fas, and the pre-BCR, with genetic epistasis defining causal substrates for proliferation, survival, and developmental checkpoints.

    Evidence Conditional Hrd1/Sel1L knockouts with p27 and Fas rescue crosses, ubiquitination and signaling assays

    PMID:27417417 PMID:27568564 PMID:27573825

    Open questions at the time
    • Substrate selectivity mechanisms across these clients not defined
    • Localization of these degradation events not resolved
  14. 2020 High

    Demonstrated HRD1/SEL1L control of cell identity and innate immunity, degrading TGF-β receptor 1 (β-cell identity), MafA (insulin secretion), and STING (basal antiviral tone).

    Evidence Tissue-specific knockouts/overexpression, scRNA-seq, ubiquitination assays, viral/tumor and pharmacological rescue models

    PMID:32086291 PMID:32182217 PMID:37142791

    Open questions at the time
    • Whether these substrates use the retrotranslocation channel or a distinct route is unresolved
    • Quantitative contribution relative to other ligases unknown
  15. 2018 High

    Defined a hepatic ERAD-CREBH-FGF21 metabolic axis and a broader metabolic-enzyme degradome (ENTPD5, CPT2, RMND1, HSD17B4), showing HRD1 ubiquitination of CREBH at K294 sets postprandial FGF21 and reprograms hepatic metabolism.

    Evidence Liver-specific knockouts, ubiquitination site mapping, refeeding studies, interactome proteomics, metabolic phenotyping

    PMID:30201971 PMID:30389664 PMID:30389665

    Open questions at the time
    • Direct vs indirect effects on some metabolic enzymes not fully separated
    • Tissue specificity of substrate set unexplained
  16. 2021 High

    Linked HRD1 substrate selection to UPR outcome, showing accumulating misfolded proteins competitively block METTL14 degradation, raising m6A modification of CHOP mRNA to bias cells toward adaptation.

    Evidence Ubiquitination competition assays, m6A analysis, liver-specific knockouts

    PMID:34847358

    Open questions at the time
    • Generality of competitive substrate triage to other clients untested
    • Affinity hierarchy of substrates undefined
  17. 2023 High

    Identified post-translational control of HRD1 activity via UFMylation at Lys610 and discovered new quality-control substrates (PIGK in GPI biogenesis, ceruloplasmin), including disease-relevant variants.

    Evidence UFMylation and ubiquitination assays with K610R mutagenesis; SILAC proteomics with functional and in vivo substrate validation

    PMID:37795761 PMID:38253565

    Open questions at the time
    • Interplay between UFMylation, S-sulfhydration, and autoubiquitination not integrated
    • Full substrate repertoire still expanding

Open questions

Synthesis pass · forward-looking unresolved questions
  • How HRD1 selects and engages its many non-canonical, folded cytosolic substrates relative to the structurally defined luminal retrotranslocation pathway remains unresolved.
  • No structural model for cytosolic substrate engagement
  • Mechanism integrating PTM regulation with substrate triage unknown
  • Tissue-specific substrate repertoire incompletely mapped

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 5 GO:0016874 ligase activity 4 GO:0005198 structural molecule activity 3 GO:0031386 protein tag activity 2 GO:0098772 molecular function regulator activity 2
Localization
GO:0005783 endoplasmic reticulum 4
Pathway
R-HSA-168256 Immune System 5 R-HSA-1430728 Metabolism 4 R-HSA-392499 Metabolism of proteins 4 R-HSA-8953897 Cellular responses to stimuli 3 R-HSA-9609507 Protein localization 3
Partners
DERL2HERPHRD3OS-9SEL1LUBE2J1USP15YOS9
Complex memberships
ERpQC (HRD1-Sec61α-Derlin-1) complexHRD1-Hrd3-Der1-Usa1-Yos9 retrotransloconSEL1L-HRD1 ERAD complex

Evidence

Reading pass · 72 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2001 Der3/Hrd1p (SYVN1) is a six-transmembrane ER membrane protein with cytoplasmic N- and C-termini; its RING-H2 finger domain is required for ubiquitination of misfolded ER proteins, and it directly binds the E2 ubiquitin-conjugating enzyme Ubc7p through this RING domain, establishing it as the E3 ubiquitin ligase of the ERAD pathway. Membrane topology mapping, in vitro ubiquitination assay, Ubc7p binding assay, in vivo RING-finger mutant analysis The Journal of biological chemistry High 11139575
1999 The RING-H2 finger motif of Der3/Hrd1p is essential for ERAD function; a C399S point mutation abolishes degradation of both soluble and integral membrane misfolded ER proteins and acts as a dominant negative, while Hrd3p overexpression suppresses this dominant effect, suggesting competition for Hrd3p interaction. Site-directed mutagenesis, in vivo degradation assay, dominant-allele analysis, genetic suppression FEBS letters High 10218484
2008 OS-9 and XTP3-B (Erlectin) are ER-resident glycoproteins that bind ERAD substrates (mutant α1-antitrypsin) and, through the SEL1L adaptor, deliver them to the HRD1 ubiquitin ligase complex; OS-9 also associates with the ER chaperone GRP94. The MRH domains of OS-9/XTP3-B are required for SEL1L interaction but not for substrate binding. Co-immunoprecipitation, siRNA knockdown with degradation assay, domain mutagenesis Nature cell biology High 18264092
2016 Autoubiquitination of Hrd1 within its RING-finger domain triggers retrotranslocation of misfolded luminal protein domains across the ER membrane in a reconstituted proteoliposome system; substrate ubiquitination is a subsequent event and the Cdc48 ATPase is not required for the retrotranslocation step itself. In vitro reconstitution with purified S. cerevisiae proteins in proteoliposomes, RING-finger lysine mutagenesis, in vivo ERAD assay Cell High 27321670
2017 Cryo-EM structure of S. cerevisiae Hrd1 in complex with Hrd3 shows Hrd1 forms a dimer in the membrane; each Hrd1 molecule has eight transmembrane segments with an aqueous cavity extending from the cytosol nearly to the ER lumen and a lateral gate, consistent with a retrotranslocation channel. Cryo-electron microscopy structural determination Nature High 28682307
2020 Cryo-EM structure of the active five-subunit Hrd1 complex (Hrd1, Hrd3, Der1, Usa1, Yos9) reveals Hrd3 and Yos9 jointly create a luminal substrate-binding site for glycosylated substrates; Hrd1 and the rhomboid-like Der1 form two 'half-channels' with opposing cavities and lateral gates in a thinned membrane region, explaining how a polypeptide loop moves through the membrane during ERAD-L. Cryo-EM of two subcomplexes, crosslinking, molecular dynamics simulation Science (New York, N.Y.) High 32327568
2020 Purified Hrd1 incorporated into model membranes forms a pore whose opening is triggered by autoubiquitination; substrate binding increases pore size and activity; deubiquitination closes the pore. Two substrate-binding sites were identified: a low-affinity luminal site and a high-affinity cytoplasmic site formed after autoubiquitination of specific RING-domain lysines. Reconstitution of purified Hrd1 in model membranes, electrophysiology/pore assay, site-specific mutagenesis of RING-domain lysines Nature cell biology High 32094691
2019 Hrd1 autoubiquitination is counteracted by the deubiquitinating enzyme Ubp1, which requires its N-terminal transmembrane segment for activity toward Hrd1. Hrd3 acts as a brake on autoubiquitination, while Usa1 attenuates Ubp1 deubiquitination through its UBL domain, establishing a cycle of autoubiquitination/deubiquitination that gates the Hrd1 retrotranslocation channel. Genetic and biochemical analysis in S. cerevisiae, ubiquitination/deubiquitination assays, domain mutagenesis eLife High 31713515
2022 Site-specific disulfide crosslinking in live S. cerevisiae cells maps the path of a glycosylated ERAD substrate through the Hrd1 complex: the substrate contacts a groove in Hrd3 and the lectin domain of Yos9 on the luminal side, inserts a loop into the membrane with one side interacting with the Der1 lateral gate and the other with the Hrd1 lateral gate. Hrd1 autoubiquitination is required to disassemble inactive Hrd1 dimers into active monomers. Site-specific disulfide crosslinking in live cells, cryo-EM structure integration The Journal of biological chemistry High 35970394
2010 SEL1L protein stability is critically dependent on HRD1: SEL1L is rapidly degraded when HRD1 is absent, and HRD1 co-expression stabilizes SEL1L. The endogenous HRD1-SEL1L complex (Complex I) associates with Derlin-1/2, VIMP, Herp, and OS-9, while a smaller transiently expressed complex (Complex II) lacks Derlin-1/2, VIMP, and Herp but still supports retrotranslocation. siRNA knockdown, co-immunoprecipitation, size fractionation, degradation assays The Journal of biological chemistry High 21454652
2010 Disposal of soluble ERAD-L substrates (ERAD-LS) in mammalian cells is strictly dependent on HRD1, SEL1L, and either OS-9 or XTP3-B; tethering the same substrate to the membrane (ERAD-LM) renders these factors dispensable, revealing a distinct pathway organization from yeast. siRNA knockdown with pulse-chase degradation assays, genetic epistasis The Journal of cell biology High 20100910
2024 SEL1L-HRD1 interaction is required to form a functional ERAD complex: SEL1L is needed to recruit the E2 enzyme UBE2J1 and DERLIN to HRD1. A disease-causing SEL1L variant (p.Ser658Pro) reduces SEL1L stability and attenuates the SEL1L-HRD1 interaction via electrostatic repulsion between SEL1L F668 and HRD1 Y30, impairing ERAD. Biochemical analysis, proteomic interactome screens, mutagenesis, mouse model with pathogenic variant Nature communications High 38365914
2011 HRD1 acts together with the E2 ubiquitin-conjugating enzyme UBE2J1 to ubiquitinate and dislocate misfolded MHC class I heavy chains from the ER. HRD1, UBE2J1, non-β2m-bound MHC I heavy chains, Derlin-1, and p97 form a complex. HRD1 discriminates misfolded MHC I from properly assembled heterotrimers. siRNA functional screen, Co-immunoprecipitation, ubiquitination assay, dislocation assay Proceedings of the National Academy of Sciences of the United States of America High 21245296
2014 Hrd1 ubiquitinates Nrf2 and targets it for proteasomal degradation independently of the canonical Keap1 pathway. In cirrhotic livers, XBP1 transcriptionally up-regulates Hrd1, which then ubiquitinates Nrf2, suppressing the antioxidant response. Hrd1 conditional knockout mice show elevated Nrf2 levels. Hrd1 conditional knockout mouse model, ubiquitination assay, liver cirrhosis patient tissue analysis, XBP1-Hrd1 transcriptional pathway analysis Genes & development High 24636985
2014 Hrd1 catalyzes ubiquitination and degradation of the transcriptional suppressor BLIMP1 in dendritic cells, thereby promoting MHC-II expression. Hrd1-null DCs fail to prime CD4+ T cells. Hrd1 expression is induced by TLR stimulation. Conditional Hrd1 knockout in DCs, ubiquitination assay, T cell priming assay The Journal of experimental medicine High 25366967
2016 Hrd1 ubiquitinates and degrades the CDK inhibitor p27(kip1) to promote T cell proliferation; genetic deletion of Hrd1 in T cells impairs proliferation and IL-2 production, and deletion of p27(kip1) in Hrd1-null T cells rescues proliferative capacity but not cytokine production. Conditional Hrd1 knockout mouse, genetic rescue (p27 deletion), ubiquitination assay, T cell functional assays Nature communications High 27417417
2016 Hrd1 ubiquitinates and degrades the death receptor Fas/CD95 in B cells, protecting them from activation-induced cell death. Hrd1-null B cells exhibit elevated Fas expression during activation and undergo Fas-mediated apoptosis; Fas mutation in Hrd1 KO mice abrogates the B-cell AICD increase. Conditional Hrd1 knockout mouse, genetic rescue (Fas mutation), ubiquitination assay Proceedings of the National Academy of Sciences of the United States of America High 27573825
2016 Sel1L-Hrd1 ERAD selectively recognizes and targets the pre-B cell receptor (pre-BCR) for proteasomal degradation in a BiP-dependent manner; loss of Sel1L-Hrd1 causes pre-BCR accumulation intracellularly and at the cell surface, leading to persistent pre-BCR signaling and developmental block at the large-to-small pre-B cell transition. Conditional Sel1L knockout in B cell precursors, pre-BCR accumulation analysis, signaling assays Cell reports High 27568564
2020 Sel1L-Hrd1 ERAD controls β cell identity by mediating the degradation of TGF-β receptor 1; Sel1L deficiency leads to loss of β cell identity (not apoptosis) that can be rescued by inhibition of TGF-β signaling, as demonstrated by single-cell RNA-seq and TGF-β receptor 1 protein accumulation. β cell-specific Sel1L conditional knockout, single-cell RNA-seq, TGF-β receptor 1 degradation assay, TGF-β pathway inhibition rescue The Journal of clinical investigation High 32182217
2018 The Sel1L-Hrd1 ERAD complex controls FGF21 transcription by ubiquitinating and degrading the ER-tethered transcription factor CREBH; liver-specific Sel1L deletion elevates CREBH nuclear abundance and markedly increases circulating FGF21, establishing a hepatic ERAD-CREBH-FGF21 metabolic axis. Liver-specific Sel1L knockout mouse, CREBH ubiquitination assay, FGF21 measurement The EMBO journal High 30389664 30389665
2018 HRD1 catalyzes polyubiquitin conjugation onto CREBH at lysine K294, targeting it for proteasomal degradation in the postprandial state to downregulate FGF21 expression in liver. Liver-specific HRD1 knockout mouse, CREBH ubiquitination site mapping (K294), refeeding experiments The EMBO journal High 30389664
2023 The SEL1L-HRD1 ERAD complex ubiquitinates nascent STING protein and targets it for proteasomal degradation in the basal state, limiting the pool of activatable STING and thus suppressing innate immune signaling; SEL1L or HRD1 deficiency in macrophages amplifies STING-dependent antiviral and antitumor immunity. Conditional knockout in macrophages, ubiquitination assay, STING signaling assays, viral infection and tumor models Nature cell biology High 37142791
2006 HRD1 interacts with Parkin-associated endothelin receptor-like receptor (Pael-R) through its proline-rich region, promotes Pael-R ubiquitination and degradation via the proteasome, prevents Pael-R-induced ER stress and neuronal death; ATF6 overexpression induces HRD1 and accelerates Pael-R degradation in an HRD1-dependent manner. Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, ATF6 overexpression, neuronal cell death assay Journal of neurochemistry High 17059562
2010 HRD1 promotes ubiquitination and degradation of amyloid precursor protein (APP) through its proline-rich region interaction; suppression of HRD1 by siRNA causes APP accumulation, increased Aβ production, and ER stress; ATF6/XBP1-induced HRD1 upregulation enhances APP degradation and reduces Aβ production. Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, APP and Aβ measurement The Journal of neuroscience High 20237263
2006 Hrd1 interacts with and ubiquitinates polyglutamine-expanded huntingtin N-terminal fragment (httN) in a RING-finger-dependent manner; Hrd1 recruits httN to the ER and co-localizes with juxtanuclear httN aggregates; Hrd1-mediated httN degradation is p97/VCP-dependent but Ufd1/Npl4-independent; expanded polyQ tracts are preferred substrates. Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, subcellular fractionation, confocal microscopy Experimental cell research High 17141218
2009 Both Hrd1 and gp78 bind cholera toxin CTA1 and protein disulfide isomerase (PDI); dominant-negative Hrd1 or gp78 and Ube2g2 mutants decrease CTA1 retrotranslocation; CT association with Hrd1/gp78 is blocked by dominant-negative Derlin-1, suggesting a sequential handoff from Derlin-1 to Hrd1/gp78 on the ER membrane. Binding studies (Co-immunoprecipitation), dominant-negative mutant expression, retrotranslocation assay, siRNA knockdown Molecular biology of the cell Medium 19864457
2013 Derlin-2, but not Derlin-1 or Derlin-3, is an essential functional partner for HRD1-mediated ERAD of sonic hedgehog (SHH) and NHK substrates; without Derlin-2, HRD1 homo-oligomerization and substrate targeting proceed normally but substrates are trapped in the ER lumen, suggesting Derlin-2 regulates substrate movement through the HRD1 retrotranslocon. siRNA knockdown of individual Derlins, ERAD substrate degradation assay, retrotranslocation assay The Journal of biological chemistry High 23867461
2013 HERP proteins (HERP1/HERP2) are required for HRD1-mediated ERAD; they recruit DERL2 to the HRD1-SEL1L complex, and loss of HERPs traps substrates in the ER lumen and attenuates their ubiquitination. HERP2 is constitutively expressed whereas HERP1 is ER stress-inducible. The UBL domain of HERP1 has an additional function independent of DERL2 recruitment. siRNA knockdown, Co-immunoprecipitation, ERAD substrate degradation/retrotranslocation assay The Journal of biological chemistry High 24366871
2014 Herp localizes to the ER quality control compartment (ERQC) and recruits HRD1 to this compartment; Herp is required for HRD1-mediated ubiquitination of ERAD substrates presented by OS-9 lectin at the ERQC. Confocal microscopy/live imaging, Co-immunoprecipitation, siRNA knockdown with ERAD substrate assay Molecular biology of the cell Medium 24478453
2010 Herp regulates Hrd1-mediated ubiquitylation through its ubiquitin-like (UBL) domain; the UBL domain is required for efficient ubiquitylation of the NHK ERAD substrate and for NHK degradation. Herp undergoes rapid turnover at Hrd1 complexes with multiple copies of Hrd1 per complex. Co-immunoprecipitation, UBL domain mutagenesis, ubiquitylation assay with NHK substrate The Journal of biological chemistry Medium 21149444
2017 Affinity-tagged endogenous Hrd1 in HEK293 cells forms two distinct high-molecular-mass complexes with different interacting proteins and variable stoichiometries, indicating heterogeneity in functional Hrd1 ERAD units; complex composition is strongly influenced by Hrd1 expression levels. Genome-edited endogenous tandem affinity tag, size-exclusion chromatography, immunodepletion, absolute quantification mass spectrometry The Journal of biological chemistry High 28411238
2018 During ER stress, HRD1 associates with the Sec61α translocon and Derlin-1 to form a large pre-emptive quality control (ERpQC) complex; ERpQC substrates are captured by the C-terminal region of Derlin-1 and ubiquitinated by HRD1 prior to cytosolic degradation. Co-immunoprecipitation, ubiquitination assay, ER stress induction Scientific reports Medium 29743537
2016 Grp94 uses its middle domain to interact with GABAA receptor α1 subunits in the ER lumen; OS-9 acts downstream of Grp94 to recognize misfolded α1 subunits in a glycan-dependent manner, delivering them to Hrd1-mediated ubiquitination and VCP-mediated extraction. Co-immunoprecipitation, domain mutagenesis, Grp94 inhibition, ERAD substrate assay The Journal of biological chemistry Medium 26945068
2007 ER stress-induced transcription of HRD1 is mediated by the IRE1-XBP1 pathway, while SEL1 induction is mediated by the ATF6-dependent pathway, revealing differential regulation of these ERAD components by distinct UPR branches. IRE1/ATF6 inhibition, XBP1 overexpression, promoter-linked induction analysis FEBS letters Medium 17967421
2016 USP19, an ER-anchored deubiquitinating enzyme, stabilizes HRD1 by removing K48-linked ubiquitin chains from HRD1, rescuing it from proteasomal degradation; altered USP19 expression affects steady-state HRD1 levels. Co-immunoprecipitation, ubiquitination assay, USP19 overexpression/knockdown International journal of molecular sciences Medium 27827840
2023 HRD1 is UFMylated at Lys610 by UFL1 and interacts with UFMylation components UFL1 and DDRGK1; UFL1 depletion increases HRD1 stability and reduces its ubiquitination. Mutation of HRD1 K610R impairs its ability to degrade misfolded proteins. During ER stress, UFMylation and ubiquitination of HRD1 are progressively inhibited. Co-immunoprecipitation, UFMylation assay, site-directed mutagenesis (K610R), siRNA knockdown, ERAD substrate degradation assay FASEB journal Medium 37795761
2019 ER-localized Hrd1 directly interacts with the deubiquitinating enzyme Usp15 and inactivates its deubiquitinating activity toward IκBα (without degrading Usp15), resulting in enhanced IκBα ubiquitination and excessive NF-κB activation during TLR4-triggered bacterial infection; Hrd1 deficiency in macrophages protects mice from LPS-induced septic shock. Co-immunoprecipitation, deubiquitinase activity assay, Hrd1 knockout macrophages, septic shock mouse model, rescue with Usp15 knockdown Nature microbiology High 31477895
2019 Hrd1 suppresses ER stress-induced IRE1α-p38 MAPK signaling in regulatory T cells (Tregs); genetic deletion of Hrd1 in Tregs elevates ER stress-responsive genes and IRE1α/p38 activation, destabilizing FoxP3 expression; pharmacological suppression of IRE1α kinase (but not endonuclease) activity rescues Hrd1-null Treg stability. Treg-specific Hrd1 conditional knockout, IRE1α kinase/endonuclease pharmacological inhibition, FoxP3 stability assay, multi-organ inflammation phenotype JCI insight High 30843874
2021 HRD1 ubiquitinates and degrades METTL14; in ER stress, accumulation of unfolded proteins competes with HRD1 to block METTL14 ubiquitination, allowing METTL14 accumulation to promote m6A modification of CHOP mRNA and reduce its translation, thereby shifting UPR toward stress adaptation over apoptosis. HRD1 ERAD machinery competition assay, METTL14 ubiquitination assay, m6A modification analysis, liver-specific METTL14 knockout Molecular cell High 34847358
2021 SYVN1/HRD1 directly interacts with GSDMD and mediates K27-linked polyubiquitination of GSDMD at K203 and K204 residues, promoting GSDMD-induced pyroptotic cell death; SYVN1 deficiency inhibits pyroptosis. Co-immunoprecipitation, in vitro ubiquitination assay with specific ubiquitin linkage analysis, site-directed mutagenesis of GSDMD lysines, LDH/PI uptake cell death assays Cell death & disease Medium 35115505
2017 SYVN1/HRD1 enhances degradation of the ATZ (SERPINA1 E342K) variant through SQSTM1/p62-dependent selective autophagy; SYVN1 mediates K48-linked polyubiquitination of ATZ, which is recognized by the UBA domain of SQSTM1, coupling ubiquitinated ATZ to the lysosome; autophagy inhibition attenuates SYVN1-mediated ATZ clearance. Ubiquitination assay (K48 linkage specific), autophagy inhibition/induction, Atg5 knockout cells, SQSTM1 UBA domain analysis, Co-immunoprecipitation Autophagy High 28121484
2017 Hrd1 interacts with tau and promotes proteasomal degradation of both total tau and phosphorylated tau through its E3 ubiquitin ligase activity; proteasome inhibition increases Hrd1-mediated tau ubiquitination; Hrd1 overexpression alleviates tau cytotoxicity. Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, proteasome inhibitor treatment, cell viability assay Current molecular medicine Medium 22280354
2017 Hrd1 interacts with optineurin (OPTN) and promotes its proteasomal degradation and aggresome formation at the MTOC; Hrd1 overexpression increases OPTN degradation and aggresome formation, while Hrd1 knockdown stabilizes OPTN and inhibits aggresome formation; this applies to both WT and ALS/POAG mutant OPTN. Co-immunoprecipitation, siRNA knockdown, proteasome assay, confocal microscopy of aggresome formation Human molecular genetics Medium 28334804
2016 SYVN1 (HRD1), NEDD8, and FBXO2 each contribute to ubiquitin-mediated proteasomal degradation of ΔF508-CFTR in human cystic fibrosis airway epithelia; knockdown of SYVN1, NEDD8, or FBXO2 partially restores ΔF508-CFTR-mediated Cl- transport; SYVN1 and FBXO2 represent two distinct multiprotein complexes targeting ΔF508-CFTR. siRNA knockdown in primary human airway epithelia, functional CFTR Cl- transport assay, CFTR maturation assay The Journal of biological chemistry Medium 27756846
2009 Silencing of Hrd1 leads to stabilization of gp78 and a decline in gp78 ubiquitination, thereby enhancing CFTRΔf508 degradation; endogenous gp78 co-immunoprecipitates with Hrd1, and Hrd1 acts as an E3 for gp78, negatively regulating CFTRΔf508 degradation. siRNA knockdown, Co-immunoprecipitation, ubiquitination assay, cycloheximide chase The international journal of biochemistry & cell biology Medium 19828134
2018 HRD1 interacts with and ubiquitinates multiple metabolic enzymes including ENTPD5, CPT2, RMND1, and HSD17B4 in the liver; liver-specific HRD1 deletion elevates these proteins and hyperactivates AMPK and AKT pathways, reprogramming hepatic metabolic gene expression to suppress glycogenesis/lipogenesis and upregulate glycolysis/fatty acid oxidation. Liver-specific HRD1 knockout, proteomic interactome analysis, ubiquitination assay, genome-wide mRNA sequencing, metabolic phenotyping Nature communications High 30201971
2020 HRD1 interacts with and ubiquitinates MafA in diabetic β-cells, leading to its cytoplasmic accumulation and proteasomal degradation; HRD1 overexpression triggers impaired insulin secretion via MafA loss, while HRD1 knockdown improves glucose control in diabetic models. Proteomic analysis, Co-immunoprecipitation, ubiquitination assay, β cell-specific HRD1 overexpression and knockdown mouse models Diabetes High 32086291
2017 HRD1 interacts with eIF2α and promotes its ubiquitylation and proteasomal degradation; HRD1 overexpression decreases phosphorylated eIF2α levels and inhibits apoptosis in renal tubular cells exposed to palmitic acid or high glucose; the protective effect of HRD1 is blunted by eIF2α overexpression. Co-immunoprecipitation, ubiquitination assay, HRD1 overexpression/knockdown, apoptosis assay Cell death & disease Medium 29233968
2015 HRD1 interacts with IGF-1R and promotes its ubiquitination and proteasomal degradation in breast cancer cells; NF-κB/p65 binds the HRD1 promoter and inhibits HRD1 expression, explaining IL-6-induced HRD1 downregulation; HRD1 overexpression inhibits breast cancer growth and invasion in vitro and in vivo. Co-immunoprecipitation, ubiquitination assay, promoter binding analysis, overexpression in vitro/in vivo Oncotarget Medium 26536657
2020 HRD1 interacts with and ubiquitinates SIRT2, promoting its proteasomal degradation; HRD1 deficiency induces SIRT2 upregulation and inhibits lung cancer cell growth and tumor formation both in vitro and in vivo. Co-immunoprecipitation, ubiquitination assay, HRD1 knockdown/overexpression, tumor xenograft model Molecular and cellular biology Medium 31932479
2021 HRD1 interacts with and ubiquitinates PFKP, targeting it for proteasomal degradation; HRD1-mediated PFKP degradation reduces aerobic glycolysis (Warburg effect) and inhibits breast cancer cell proliferation and invasion. Mass spectrometry HRD1 interactome, Co-immunoprecipitation, ubiquitylation assay, in vitro/in vivo tumor models Cell communication and signaling Medium 33588886
2020 HRD1 interacts with CPT2 and mediates K48-linked ubiquitination of CPT2, stabilizing (not degrading) it; HRD1-mediated CPT2 stabilization inhibits fatty acid oxidation and TNBC cell proliferation under glutamine-deficient conditions. Co-immunoprecipitation, ubiquitination assay with K48 linkage analysis, CPT2 knockdown rescue, in vivo xenograft Molecular oncology Medium 33207079
2020 Hrd1 interacts with and ubiquitinates LOX-1, promoting its proteasomal degradation in endothelial cells; KLF2 transcription factor binds the HRD1 promoter and positively regulates HRD1 expression; loss of HRD1 causes LOX-1 accumulation and endothelial apoptosis. Co-immunoprecipitation, ubiquitination assay, KLF2 promoter binding analysis, LOX-1 knockdown rescue Cell cycle (Georgetown, Tex.) Medium 32308114
2020 Hrd1 interacts with and ubiquitinates Acly (ATP citrate lyase), reducing its protein level and suppressing acetyl-CoA production and lipogenesis in hepatocytes; Hrd1 overexpression in db/db mice ameliorates hepatic steatosis and improves insulin sensitivity. Co-IP-based mass spectrometry, Co-immunoprecipitation, ubiquitination assay, adenovirus overexpression in db/db mice Metabolism: clinical and experimental Medium 32888949
2018 HRD1 interacts with PTEN and promotes its ubiquitination and proteasomal degradation in hepatocellular carcinoma; HRD1 suppression inhibits HCC growth, migration, and invasion. Proteomic approach, Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, in vitro/in vivo tumor models Cellular signalling Medium 29958993
2023 SYVN1/HRD1 interacts with and ubiquitinates HMGB1, promoting its degradation; SYVN1-mediated HMGB1 degradation activates the NRF2/HO-1 pathway and inhibits ferroptosis in spinal cord neurons during ischemia-reperfusion injury. Co-immunoprecipitation, ubiquitination assay, MG132 proteasome inhibition, in vivo SCIRI rat model, adenovirus overexpression International immunopharmacology Medium 37591122
2023 SYVN1 promotes ubiquitination and degradation of STAT3 in retinal microvascular endothelial cells; SYVN1 overexpression reduces phospho-STAT3, VEGF secretion, and neovascularization in an OIR mouse model, with effects rescued by STAT3 activator treatment. Co-immunoprecipitation, ubiquitination assay, intravitreal adenovirus injection, retinal flatmount analysis, electroretinogram Investigative ophthalmology & visual science Medium 37540175
2020 Exogenous H2S (NaHS) induces S-sulfhydration of Hrd1 at Cys115, enhancing Hrd1 interaction with VAMP3 and promoting VAMP3 ubiquitylation; Hrd1 C115A mutant abolishes VAMP3 ubiquitylation, CD36 membrane retention, and lipid droplet reduction in diabetic cardiomyocytes. S-sulfhydration assay, site-directed mutagenesis (C115A), Co-immunoprecipitation, LC-MS/MS ubiquitylation analysis, db/db mouse model Aging and disease Medium 32257542
2021 H2S-induced S-sulfhydration of Hrd1 at Cys115 enhances Hrd1 interaction with DGAT1 and DGAT2, promoting their ubiquitylation and reducing lipid droplet accumulation in diabetic cardiac tissue; Hrd1 C115A mutation abolishes this interaction and effect. S-sulfhydration assay, site-directed mutagenesis (C115A), Co-immunoprecipitation, ubiquitylation assay, db/db mouse model Journal of cellular and molecular medicine Medium 34562065
2023 Exogenous H2S promotes S-sulfhydration of Syvn1 at Cys115, facilitating Syvn1-Keap1 interaction and Keap1 ubiquitination, which activates Nrf2 nuclear translocation and the Nrf2/GPx4/GSH pathway to suppress ferroptosis in diabetic cardiomyocytes; Syvn1 C115A mutant partially attenuates these effects. S-sulfhydration assay, Syvn1 C115A mutagenesis, Co-immunoprecipitation, ubiquitination assay, db/db mouse model, Nrf2 nuclear translocation assay Cell death discovery Medium 37875467
2022 SYVN1 competitively interacts with TRIM59, preventing SYVN1-mediated TRIM59 ubiquitination and stabilizing TRIM59 expression; stable TRIM59 then promotes p53 degradation, thereby inhibiting ferroptosis in pancreatic cancer cells. Co-immunoprecipitation, ubiquitination assay, competitive binding assay, in vitro and in vivo tumor models Oncogene Medium 37740007
2021 SYVN1 interacts with ETS1 and promotes its ubiquitination at K318, leading to proteasomal degradation of ETS1 and downregulation of xCT/SLC7A11 transcription, thereby inducing ferroptosis in breast cancer cells; a small molecule (sculponeatin A) promotes the ETS1-SYVN1 interaction to enhance this effect. Co-immunoprecipitation, ubiquitination site mapping (K318), Western blot, ferroptosis assays, in vivo mouse tumor model Phytomedicine Medium 37327642
2015 HRD1 transmembrane domain transfers Pael-R from the ER to the cytosol, while the proline-rich domain is required to promote Pael-R degradation; the transmembrane domain also stabilizes HRD1 itself. Domain deletion mutagenesis, Pael-R degradation assay, HRD1 stability analysis Journal of pharmacological sciences Medium 18344614
2022 SEL1L-HRD1 ERAD degrades nascent WNT5A in a quality-control capacity; in the absence of ERAD, WNT5A misfolds and forms high-molecular-weight ER aggregates (loss of function), attenuating WNT5A-mediated suppression of hepatocyte proliferation and promoting tumorigenesis. Hepatocyte-specific Sel1L/Hrd1 knockout, proteomics substrate screen, WNT5A aggregation analysis, tumor mouse model iScience Medium 36238898
2023 SEL1L-HRD1 ERAD degrades ceruloplasmin (CP), a key ferroxidase for systemic iron distribution; in the absence of ERAD, CP accumulates in the ER, is shunted to refolding, and is secreted at elevated levels, altering systemic iron homeostasis in a manner independent of ER stress. Hepatocyte-specific Sel1L knockout, proteomics substrate screen, CP secretion assay, iron homeostasis phenotyping in mice Proceedings of the National Academy of Sciences of the United States of America Medium 36595688
2023 SEL1L-HRD1 ERAD degrades the GPI-transamidase catalytic subunit PIGK, attenuating the biogenesis of GPI-anchored proteins; disease-causing PIGK variants in inherited GPI deficiency disorders are also SEL1L-HRD1 ERAD substrates. SILAC-based quantitative proteomics with machine learning filtering, ERAD substrate validation (PIGK), GPI-anchored protein functional assay, in vitro and in vivo models Nature communications High 38253565
2021 SYVN1/HRD1 interacts with HSP90 and impacts ubiquitination of eukaryotic elongation factor 2 kinase (EEF2K) in hepatocellular carcinoma cells; SYVN1 knockdown inhibits HCC migration and invasion. Co-IP-based proteomics/mass spectrometry, immunofluorescence, Co-immunoprecipitation, ubiquitination assay Cancer communications (London, England) Low 34196494
2013 Hrd1 regulates collagen I maturation in renal fibrosis via the Sec23A-dependent ER-to-Golgi trafficking pathway; Hrd1 overexpression increases secreted and mature collagen I, while Hrd1 knockdown predominantly reduces mature collagen I; Sec23A knockdown blocks the Hrd1-mediated increase in collagen secretion. siRNA knockdown (Hrd1 and Sec23A), overexpression, collagen I secretion/maturation measurement, epistasis via double knockdown Molecular and cellular biochemistry Medium 24114659
2023 Xbp1-induced Hrd1 ubiquitinates Nrf2, leading to its degradation and reduced antioxidant response in renal tubular cells; the QSLVPDI motif on Nrf2 constitutes the active site for its interaction with Hrd1; downregulation of XBP1 reduces Hrd1 expression and enhances Nrf2/HO-1 function to protect against renal ischemia-reperfusion injury. Co-immunoprecipitation, ubiquitination assay, XBP1 heterozygous knockout mouse, Nrf2 interaction domain mapping Cell death discovery Medium 33654072
2017 SYVN1, an ERAD E3 ubiquitin ligase, promotes intra-ER degradation of GABAAα1 in the dorsal striatum; SYVN1 knockdown increases GABAAα1 protein levels within the ER; this is associated with methamphetamine-induced conditioned place preference. siRNA knockdown in primary neurons and in vivo, proteasome inhibitor treatment (MG132), subcellular (intra/extra-ER) fractionation Frontiers in molecular neuroscience Medium 29051727
2016 Aβ42 oligomers enhance XBP-1s, which transcriptionally upregulates HRD1; HRD1 then acts as an endogenous downregulator of BACE1, reducing BACE1 expression and activity to lower Aβ production. XBP-1s overexpression, HRD1 knockdown, BACE1 activity assay, Aβ42 oligomer treatment Scientific reports Medium 27853315
2021 HRD1-mediated METTL14 degradation is blocked when competing unfolded/misfolded proteins accumulate during ER stress, establishing a mechanism by which protein load competes with HRD1 substrate selection to switch UPR toward adaptation. METTL14 ubiquitination competition assay, ER stress induction, liver-specific knockout Molecular cell Medium 34847358

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
2014 Hrd1 suppresses Nrf2-mediated cellular protection during liver cirrhosis. Genes & development 313 24636985
2020 Structural basis of ER-associated protein degradation mediated by the Hrd1 ubiquitin ligase complex. Science (New York, N.Y.) 196 32327568
2003 Synoviolin/Hrd1, an E3 ubiquitin ligase, as a novel pathogenic factor for arthropathy. Genes & development 168 12975321
2016 Autoubiquitination of the Hrd1 Ligase Triggers Protein Retrotranslocation in ERAD. Cell 164 27321670
2010 Loss of HRD1-mediated protein degradation causes amyloid precursor protein accumulation and amyloid-beta generation. The Journal of neuroscience : the official journal of the Society for Neuroscience 162 20237263
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
2001 Membrane topology and function of Der3/Hrd1p as a ubiquitin-protein ligase (E3) involved in endoplasmic reticulum degradation. The Journal of biological chemistry 144 11139575
2011 HRD1 and UBE2J1 target misfolded MHC class I heavy chains for endoplasmic reticulum-associated degradation. Proceedings of the National Academy of Sciences of the United States of America 120 21245296
2020 LncRNA SNHG7/miR-34a-5p/SYVN1 axis plays a vital role in proliferation, apoptosis and autophagy in osteoarthritis. Biological research 117 32066502
2015 Hrd1 and ER-Associated Protein Degradation, ERAD, are Critical Elements of the Adaptive ER Stress Response in Cardiac Myocytes. Circulation research 113 26137860
2021 CircNR3C2 promotes HRD1-mediated tumor-suppressive effect via sponging miR-513a-3p in triple-negative breast cancer. Molecular cancer 104 33530981
2013 Endoplasmic reticulum stress and Parkinson's disease: the role of HRD1 in averting apoptosis in neurodegenerative disease. Oxidative medicine and cellular longevity 103 23710284
2023 Endoplasmic reticulum stress-triggered ferroptosis via the XBP1-Hrd1-Nrf2 pathway induces EMT progression in diabetic nephropathy. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 102 37224754
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
2006 Ubiquitin ligase Hrd1 enhances the degradation and suppresses the toxicity of polyglutamine-expanded huntingtin. Experimental cell research 92 17141218
2014 Hrd1-mediated BLIMP-1 ubiquitination promotes dendritic cell MHCII expression for CD4 T cell priming during inflammation. The Journal of experimental medicine 86 25366967
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
2006 A ubiquitin ligase HRD1 promotes the degradation of Pael receptor, a substrate of Parkin. Journal of neurochemistry 78 17059562
2007 A different pathway in the endoplasmic reticulum stress-induced expression of human HRD1 and SEL1 genes. FEBS letters 72 17967421
2020 Hrd1 forms the retrotranslocation pore regulated by auto-ubiquitination and binding of misfolded proteins. Nature cell biology 67 32094691
2016 The Sel1L-Hrd1 Endoplasmic Reticulum-Associated Degradation Complex Manages a Key Checkpoint in B Cell Development. Cell reports 67 27568564
2021 HRD1-mediated METTL14 degradation regulates m6A mRNA modification to suppress ER proteotoxic liver disease. Molecular cell 66 34847358
2014 Herp coordinates compartmentalization and recruitment of HRD1 and misfolded proteins for ERAD. Molecular biology of the cell 65 24478453
2018 ER-associated ubiquitin ligase HRD1 programs liver metabolism by targeting multiple metabolic enzymes. Nature communications 63 30201971
2009 The E3 ubiquitin ligases Hrd1 and gp78 bind to and promote cholera toxin retro-translocation. Molecular biology of the cell 63 19864457
2010 Herp regulates Hrd1-mediated ubiquitylation in a ubiquitin-like domain-dependent manner. The Journal of biological chemistry 60 21149444
2018 HRD1-ERAD controls production of the hepatokine FGF21 through CREBH polyubiquitination. The EMBO journal 59 30389664
2019 Octyl itaconate inhibits osteoclastogenesis by suppressing Hrd1 and activating Nrf2 signaling. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 57 31490085
2020 Hrd1-mediated ACLY ubiquitination alleviate NAFLD in db/db mice. Metabolism: clinical and experimental 56 32888949
2009 Differential regulation of CFTRDeltaF508 degradation by ubiquitin ligases gp78 and Hrd1. The international journal of biochemistry & cell biology 56 19828134
2016 The ER membrane-anchored ubiquitin ligase Hrd1 is a positive regulator of T-cell immunity. Nature communications 55 27417417
2023 Exogenous H2S initiating Nrf2/GPx4/GSH pathway through promoting Syvn1-Keap1 interaction in diabetic hearts. Cell death discovery 53 37875467
2019 The E3 ligase Hrd1 stabilizes Tregs by antagonizing inflammatory cytokine-induced ER stress response. JCI insight 53 30843874
2017 Ubiquitin ligase SYVN1/HRD1 facilitates degradation of the SERPINA1 Z variant/α-1-antitrypsin Z variant via SQSTM1/p62-dependent selective autophagy. Autophagy 53 28121484
2022 E3 ubiquitin ligase SYVN1 is a key positive regulator for GSDMD-mediated pyroptosis. Cell death & disease 52 35115505
2021 Downregulation of XBP1 protects kidney against ischemia-reperfusion injury via suppressing HRD1-mediated NRF2 ubiquitylation. Cell death discovery 52 33654072
2020 HRD1, an Important Player in Pancreatic β-Cell Failure and Therapeutic Target for Type 2 Diabetic Mice. Diabetes 51 32086291
2017 HRD1 prevents apoptosis in renal tubular epithelial cells by mediating eIF2α ubiquitylation and degradation. Cell death & disease 50 29233968
2020 E3 Ubiquitin Ligase HRD1 Promotes Lung Tumorigenesis by Promoting Sirtuin 2 Ubiquitination and Degradation. Molecular and cellular biology 49 31932479
2019 ER-localized Hrd1 ubiquitinates and inactivates Usp15 to promote TLR4-induced inflammation during bacterial infection. Nature microbiology 48 31477895
2020 Endoplasmic reticulum-associated degradation and beyond: The multitasking roles for HRD1 in immune regulation and autoimmunity. Journal of autoimmunity 47 32057541
2013 Derlin2 protein facilitates HRD1-mediated retro-translocation of sonic hedgehog at the endoplasmic reticulum. The Journal of biological chemistry 46 23867461
2019 Cycles of autoubiquitination and deubiquitination regulate the ERAD ubiquitin ligase Hrd1. eLife 44 31713515
1999 A RING-H2 finger motif is essential for the function of Der3/Hrd1 in endoplasmic reticulum associated protein degradation in the yeast Saccharomyces cerevisiae. FEBS letters 44 10218484
2021 Integrative proteomics reveals the role of E3 ubiquitin ligase SYVN1 in hepatocellular carcinoma metastasis. Cancer communications (London, England) 43 34196494
2013 Role of HERP and a HERP-related protein in HRD1-dependent protein degradation at the endoplasmic reticulum. The Journal of biological chemistry 43 24366871
2020 HRD1 inhibits fatty acid oxidation and tumorigenesis by ubiquitinating CPT2 in triple-negative breast cancer. Molecular oncology 41 33207079
2016 Grp94 Protein Delivers γ-Aminobutyric Acid Type A (GABAA) Receptors to Hrd1 Protein-mediated Endoplasmic Reticulum-associated Degradation. The Journal of biological chemistry 39 26945068
2016 Endoplasmic reticulum-resident E3 ubiquitin ligase Hrd1 controls B-cell immunity through degradation of the death receptor CD95/Fas. Proceedings of the National Academy of Sciences of the United States of America 39 27573825
2008 SEL1L and HRD1 are involved in the degradation of unassembled secretory Ig-mu chains. Journal of cellular physiology 39 18314878
2018 Molecular mechanism of ER stress-induced pre-emptive quality control involving association of the translocon, Derlin-1, and HRD1. Scientific reports 38 29743537
2018 HRD1-mediated PTEN degradation promotes cell proliferation and hepatocellular carcinoma progression. Cellular signalling 37 29958993
2017 Characterization of protein complexes of the endoplasmic reticulum-associated degradation E3 ubiquitin ligase Hrd1. The Journal of biological chemistry 37 28411238
2015 HRD1 suppresses the growth and metastasis of breast cancer cells by promoting IGF-1R degradation. Oncotarget 37 26536657
2008 Novel functions of ubiquitin ligase HRD1 with transmembrane and proline-rich domains. Journal of pharmacological sciences 35 18344614
2024 SEL1L-HRD1 interaction is required to form a functional HRD1 ERAD complex. Nature communications 34 38365914
2018 Long non-coding RNA CASC2 inhibits breast cancer cell growth and metastasis through the regulation of the miR-96-5p/SYVN1 pathway. International journal of oncology 34 30106139
2008 Immunohistochemical localization of a ubiquitin ligase HRD1 in murine brain. Journal of neuroscience research 34 18241051
2021 Anti-Warburg effect by targeting HRD1-PFKP pathway may inhibit breast cancer progression. Cell communication and signaling : CCS 33 33588886
2017 A critical role of Hrd1 in the regulation of optineurin degradation and aggresome formation. Human molecular genetics 33 28334804
2024 Hypomorphic variants of SEL1L-HRD1 ER-associated degradation are associated with neurodevelopmental disorders. The Journal of clinical investigation 32 37943610
2023 SYVN1 attenuates ferroptosis and alleviates spinal cord ischemia-reperfusion injury in rats by regulating the HMGB1/NRF2/HO-1 axis. International immunopharmacology 32 37591122
2020 Exogenous H2S Induces Hrd1 S-sulfhydration and Prevents CD36 Translocation via VAMP3 Ubiquitylation in Diabetic Hearts. Aging and disease 32 32257542
2021 Hydrogen sulphide reduced the accumulation of lipid droplets in cardiac tissues of db/db mice via Hrd1 S-sulfhydration. Journal of cellular and molecular medicine 30 34562065
2016 SYVN1, NEDD8, and FBXO2 Proteins Regulate ΔF508 Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Ubiquitin-mediated Proteasomal Degradation. The Journal of biological chemistry 29 27756846
2023 Down-regulation of Hrd1 protects against myocardial ischemia-reperfusion injury by regulating PPARα to prevent oxidative stress, endoplasmic reticulum stress, and cellular apoptosis. European journal of pharmacology 28 37392829
2022 S100A16 promotes acute kidney injury by activating HRD1-induced ubiquitination and degradation of GSK3β and CK1α. Cellular and molecular life sciences : CMLS 28 35279748
2020 HRD1 prevents atherosclerosis-mediated endothelial cell apoptosis by promoting LOX-1 degradation. Cell cycle (Georgetown, Tex.) 27 32308114
2016 HRD1-Mediated IGF-1R Ubiquitination Contributes to Renal Protection of Resveratrol in db/db Mice. Molecular endocrinology (Baltimore, Md.) 27 27082896
2016 USP19-Mediated Deubiquitination Facilitates the Stabilization of HRD1 Ubiquitin Ligase. International journal of molecular sciences 26 27827840
2021 Regulation of hepatic circadian metabolism by the E3 ubiquitin ligase HRD1-controlled CREBH/PPARα transcriptional program. Molecular metabolism 25 33592335
2013 Hrd1 participates in the regulation of collagen I synthesis in renal fibrosis. Molecular and cellular biochemistry 25 24114659
2022 SEL1L-HRD1 ER-associated degradation suppresses hepatocyte hyperproliferation and liver cancer. iScience 24 36238898
2024 Proteomic screens of SEL1L-HRD1 ER-associated degradation substrates reveal its role in glycosylphosphatidylinositol-anchored protein biogenesis. Nature communications 23 38253565
2023 Sculponeatin A promotes the ETS1-SYVN1 interaction to induce SLC7A11/xCT-dependent ferroptosis in breast cancer. Phytomedicine : international journal of phytotherapy and phytopharmacology 23 37327642
2023 SLC35F2-SYVN1-TRIM59 axis critically regulates ferroptosis of pancreatic cancer cells by inhibiting endogenous p53. Oncogene 23 37740007
2018 Proteomic characterization of endogenous substrates of mammalian ubiquitin ligase Hrd1. Cell & bioscience 23 30167107
2018 Upregulation of HRD1 promotes cell migration and invasion in colon cancer. Molecular and cellular biochemistry 23 30306455
2012 Molecular approaches to the treatment, prophylaxis, and diagnosis of Alzheimer's disease: possible involvement of HRD1, a novel molecule related to endoplasmic reticulum stress, in Alzheimer's disease. Journal of pharmacological sciences 23 22382662
2010 Correlation between decrease in protein levels of ubiquitin ligase HRD1 and amyloid-beta production. Journal of pharmacological sciences 23 20606367
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
2018 Both thapsigargin- and tunicamycin-induced endoplasmic reticulum stress increases expression of Hrd1 in IRE1-dependent fashion. Neurological research 22 30475171
2012 Hrd1 facilitates tau degradation and promotes neuron survival. Current molecular medicine 22 22280354
2023 UFMylation of HRD1 regulates endoplasmic reticulum homeostasis. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 21 37795761
2016 Aβ42 oligomers modulate β-secretase through an XBP-1s-dependent pathway involving HRD1. Scientific reports 20 27853315
2015 Experimental study of the protective effects of SYVN1 against diabetic retinopathy. Scientific reports 20 26358086
2015 Association of the SEL1L protein transmembrane domain with HRD1 ubiquitin ligase regulates ERAD-L. The FEBS journal 20 26471130
2023 HRD1 functions as a tumor suppressor in ovarian cancer by facilitating ubiquitination-dependent SLC7A11 degradation. Cell cycle (Georgetown, Tex.) 19 36809917
2022 HRD1 in human malignant neoplasms: Molecular mechanisms and novel therapeutic strategy for cancer. Life sciences 19 35533759
2022 Disulfide-crosslink analysis of the ubiquitin ligase Hrd1 complex during endoplasmic reticulum-associated protein degradation. The Journal of biological chemistry 19 35970394
2021 Epigenetic Regulator KDM4D Restricts Tumorigenesis via Modulating SYVN1/HMGB1 Ubiquitination Axis in Esophageal Squamous Cell Carcinoma. Frontiers in oncology 19 34820329
2017 SYVN1, an ERAD E3 Ubiquitin Ligase, Is Involved in GABAAα1 Degradation Associated with Methamphetamine-Induced Conditioned Place Preference. Frontiers in molecular neuroscience 19 29051727
2016 Neuroprotection by Endoplasmic Reticulum Stress-Induced HRD1 and Chaperones: Possible Therapeutic Targets for Alzheimer's and Parkinson's Disease. Medical sciences (Basel, Switzerland) 19 29083378
2025 SEL1L-HRD1-mediated ERAD in mammals. Nature cell biology 18 40562846
2023 SYVN1 Promotes STAT3 Protein Ubiquitination and Exerts Antiangiogenesis Effects in Retinopathy of Prematurity Development. Investigative ophthalmology & visual science 18 37540175
2017 HRD1 sensitizes breast cancer cells to Tamoxifen by promoting S100A8 degradation. Oncotarget 18 28423597

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