Affinage

SYVN1

E3 ubiquitin-protein ligase synoviolin · UniProt Q86TM6

Length
617 aa
Mass
67.7 kDa
Annotated
2026-04-28
100 papers in source corpus 62 papers cited in narrative 62 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SYVN1 (HRD1) is an ER-membrane-spanning RING-H2-finger E3 ubiquitin ligase that serves as the catalytic core of the SEL1L-HRD1 endoplasmic reticulum-associated degradation (ERAD) complex, coupling substrate retrotranslocation across the ER membrane with polyubiquitination and proteasomal disposal of misfolded luminal and membrane proteins (PMID:11139575, PMID:27321670, PMID:32327568). Autoubiquitination of RING-domain lysines opens a transmembrane retrotranslocation channel whose gating is regulated by cycles of autoubiquitination and deubiquitination, with cofactors SEL1L, Derlin-2, Herp, FAM8A1, OS-9, and Yos9 mediating substrate recognition, complex assembly, and pore dynamics (PMID:32094691, PMID:31713515, PMID:18264092, PMID:28827405). Beyond canonical ERAD, HRD1 ubiquitinates diverse cytoplasmic and ER-resident non-ERAD substrates—including Nrf1, Nrf2, CREBH, p27kip1, Fas, TGF-βR1, STING, GSDMD, and ceruloplasmin—to regulate transcription, innate immunity, cell death, metabolic homeostasis, and iron balance in a cell-type-specific manner (PMID:21911472, PMID:27573825, PMID:27417417, PMID:37142791, PMID:30389665, PMID:36595688). Biallelic loss-of-function variants in SYVN1 (and its obligate partner SEL1L) cause neurodevelopmental disorder in humans (PMID:37943610).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 1999 High

    Establishing that the RING-H2 finger domain is the essential catalytic element: a single Cys→Ser mutation abolished ERAD of both soluble and membrane substrates and acted dominant-negatively, defining HRD1 as an E3 ligase required for ER protein quality control.

    Evidence Site-directed mutagenesis with ERAD substrate half-life assays in yeast

    PMID:10218484

    Open questions at the time
    • Mammalian ortholog not yet tested
    • No in vitro ubiquitination to confirm direct E3 activity
    • Substrate recognition mechanism unknown
  2. 2001 High

    Defining the membrane topology and direct E3 activity: Hrd1p spans the ER membrane six times with cytoplasmic termini, its RING domain binds the E2 Ubc7p, and it catalyzes autoubiquitination in vitro, establishing it as a bona fide ER-embedded ubiquitin ligase.

    Evidence Membrane topology mapping, in vitro ubiquitination reconstitution, E2 binding assay in yeast

    PMID:11139575

    Open questions at the time
    • No structural model of TM domain
    • Mechanism of substrate engagement across the membrane unknown
  3. 2008 High

    Defining the substrate recognition hierarchy: OS-9 and XTP3-B bind misfolded glycoproteins and deliver them via the SEL1L adaptor to HRD1, establishing a lectin-adaptor-ligase relay for luminal ERAD substrate selection, while XBP1 directly induces HRD1 transcription through a UPRE-II element.

    Evidence Reciprocal Co-IP, siRNA knockdown with α1-antitrypsin degradation assay; EMSA and promoter deletion in UPR-deficient MEFs

    PMID:18264092 PMID:18664523

    Open questions at the time
    • Structural basis of SEL1L-HRD1 interface unknown
    • Relative contributions of OS-9 vs XTP3-B not resolved
  4. 2010 High

    Demonstrating that the mammalian HRD1-SEL1L complex exists in two biochemically distinct high-molecular-mass assemblies with different cofactor compositions, and that HRD1 is essential for soluble luminal ERAD substrates but dispensable for membrane-tethered versions of the same substrates.

    Evidence Size-exclusion chromatography, systematic siRNA knockdown panel with multiple ERAD substrates

    PMID:20100910 PMID:21454652

    Open questions at the time
    • Functional distinction between the two complex assemblies unclear
    • Mammalian pathway selection rules incomplete
  5. 2016 High

    Establishing autoubiquitination as the trigger for retrotranslocation channel opening: in reconstituted proteoliposomes, Hrd1 autoubiquitination at RING-domain lysines was necessary and sufficient for luminal substrate translocation, independent of Cdc48/p97 ATPase, redefining Hrd1 as both channel and ligase.

    Evidence In vitro reconstitution with purified yeast Hrd1 in proteoliposomes, lysine mutagenesis

    PMID:27321670

    Open questions at the time
    • Mammalian HRD1 channel activity not yet reconstituted
    • Role of cofactors in channel gating not addressed in minimal system
  6. 2016 High

    Expanding HRD1 function beyond canonical ERAD: in vivo conditional knockouts revealed that HRD1 ubiquitinates cytoplasmic substrates p27kip1 (promoting T cell proliferation) and the death receptor Fas (protecting B cells from AICD), while the SEL1L-HRD1 complex degrades pre-BCR to regulate B cell development.

    Evidence Conditional Hrd1/Sel1L knockout mice with ubiquitination assays, genetic rescue experiments, disease models (EAE)

    PMID:27417417 PMID:27568564 PMID:27573825

    Open questions at the time
    • How HRD1 accesses cytoplasmic substrates mechanistically unresolved
    • Whether these are SEL1L-dependent or -independent not fully delineated
  7. 2017 High

    Resolving the structural architecture: cryo-EM of the yeast Hrd1-Hrd3 complex revealed an eight-TM-segment dimer with an aqueous cavity and lateral gate consistent with a retrotranslocation channel, providing the first structural framework for HRD1-mediated substrate translocation.

    Evidence Cryo-electron microscopy with crosslinking validation

    PMID:28682307

    Open questions at the time
    • Mammalian HRD1 structure not determined
    • Substrate trapped in the channel not visualized
  8. 2019 High

    Defining channel gating by autoubiquitination-deubiquitination cycles: Usa1 limits deubiquitination by inhibiting the DUB Ubp1 via its UBL domain, while Hrd3 restrains autoubiquitination, establishing a regulatory circuit that controls Hrd1 channel opening and closing.

    Evidence In vitro ubiquitination/deubiquitination assays and yeast genetic epistasis

    PMID:31713515

    Open questions at the time
    • Mammalian counterpart of Ubp1 (USP19 stabilizes HRD1 but channel gating role unclear)
    • Kinetics of gating cycles in cells unknown
  9. 2020 High

    Near-atomic visualization of the active retrotranslocation complex: cryo-EM of the five-subunit yeast Hrd1 complex showed Hrd1 and Der1 forming two half-channels with a thinned membrane region, and Hrd3-Yos9 creating a luminal substrate-recognition platform; reconstituted pore assays confirmed autoubiquitination opens and deubiquitination closes the channel.

    Evidence Cryo-EM at near-atomic resolution, crosslinking mass spectrometry, MD simulation, in vitro pore formation assay

    PMID:32094691 PMID:32327568

    Open questions at the time
    • Substrate threading in real time not captured
    • No mammalian complex structure
  10. 2022 High

    Mapping the complete substrate trajectory through the channel: site-specific disulfide crosslinking in live yeast cells traced an ERAD-L substrate from the Hrd3-Yos9 luminal groove through Der1 and Hrd1 lateral gates, and showed autoubiquitination disassembles Hrd1 dimers to generate active monomers.

    Evidence Site-specific disulfide crosslinking in live S. cerevisiae, correlated with cryo-EM data

    PMID:35970394

    Open questions at the time
    • Whether monomerization is universally required for all substrate classes unclear
    • Mammalian substrate path not mapped
  11. 2022 High

    Demonstrating that SEL1L-HRD1 ERAD tonically degrades STING independently of ER stress, defining a basal quality-control mechanism that restrains innate immune signaling; macrophage-specific deletion amplified antiviral and antitumor immunity.

    Evidence Macrophage-specific Sel1L/Hrd1 conditional knockout mouse, viral and tumor challenge models, ubiquitination assay

    PMID:37142791

    Open questions at the time
    • Whether all pattern-recognition receptors are similarly regulated unknown
    • Therapeutic window for HRD1 inhibition in immunity unexplored
  12. 2023 High

    Expanding physiological ERAD substrates: SEL1L-HRD1 degrades ceruloplasmin to control systemic iron homeostasis and PIGK to regulate GPI-anchored protein biogenesis; systematic proteomics identified >100 high-confidence endogenous substrates.

    Evidence Hepatocyte-specific Sel1L knockout mouse, SILAC proteomics with machine-learning filtering, ubiquitination assays

    PMID:36595688 PMID:38253565

    Open questions at the time
    • Substrate selection rules for the >100 identified clients not determined
    • Individual physiological roles of most substrates not validated
  13. 2024 High

    Establishing SYVN1 as a disease gene: biallelic variants in both SEL1L and SYVN1 (e.g., HRD1 P398L) impair ERAD at distinct mechanistic steps and cause neurodevelopmental disorder in humans; a SEL1L S658P knock-in mouse replicated the phenotype.

    Evidence Patient variant functional characterization, knock-in mouse, co-immunoprecipitation, ERAD assays

    PMID:37943610 PMID:38365914

    Open questions at the time
    • Full clinical spectrum of SYVN1 deficiency not defined
    • No structural explanation for P398L effect on catalytic activity
    • Genotype-phenotype correlations incomplete

Open questions

Synthesis pass · forward-looking unresolved questions
  • Mammalian HRD1 retrotranslocation channel structure has not been determined, substrate selection rules for the expanding list of non-ERAD cytoplasmic substrates remain undefined, and the therapeutic potential of modulating HRD1 activity in immunity and neurodegeneration is untested.
  • No mammalian HRD1 cryo-EM structure
  • Mechanism of cytoplasmic substrate access unresolved
  • No small-molecule modulators with defined mechanism

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 8 GO:0005215 transporter activity 4 GO:0016874 ligase activity 3
Localization
GO:0005783 endoplasmic reticulum 6
Pathway
R-HSA-392499 Metabolism of proteins 8 R-HSA-168256 Immune System 5 R-HSA-8953897 Cellular responses to stimuli 4 R-HSA-1430728 Metabolism 3 R-HSA-162582 Signal Transduction 3 R-HSA-5357801 Programmed Cell Death 2 R-HSA-1643685 Disease 1
Partners
DERL2FAM8A1HERPUD1OS-9SEL1LUBE2J1UFL1USP19
Complex memberships
Hrd1-Hrd3-Der1-Usa1-Yos9 complexSEL1L-HRD1 ERAD complex

Evidence

Reading pass · 62 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2001 Der3/Hrd1p (yeast ortholog of SYVN1/HRD1) spans the ER membrane six times with cytoplasmic N- and C-termini; its RING-H2 finger domain is required for ubiquitin ligase (E3) activity, binds Ubc7p, and mediates ubiquitination of misfolded ER proteins in vivo and autoubiquitination in vitro. Membrane topology mapping, in vitro ubiquitination assay, Ubc7p binding assay, in vivo ERAD substrate degradation The Journal of biological chemistry High 11139575
1999 A single point mutation in the RING-H2 finger motif of Der3/Hrd1p (C399S) abolishes its ability to support degradation of soluble and membrane ERAD substrates in yeast without altering ER localization or topology, and acts as a dominant-negative allele. Site-directed mutagenesis, in vivo ERAD substrate half-life assay, dominant-negative analysis FEBS letters High 10218484
2008 OS-9 and XTP3-B/Erlectin are ER-resident glycoproteins that bind ERAD substrates and, through the SEL1L adaptor, recruit the Hrd1 ubiquitin ligase complex; OS-9 also associates with GRP94; both OS-9 and SEL1L/Hrd1 are required for degradation of misfolded α1-antitrypsin. Co-immunoprecipitation, siRNA knockdown with substrate half-life assay Nature cell biology High 18264092
2008 The human HRD1 promoter contains a functional UPR element II to which XBP1 (but not ATF6) directly binds, explaining IRE1-XBP1-pathway-dependent transcriptional induction of HRD1 during ER stress. Promoter deletion analysis, EMSA/gel shift, reporter assay in UPR-deficient MEFs Journal of biochemistry High 18664523
2010 In the mammalian HRD1-SEL1L ERAD complex, SEL1L stability depends on its association with HRD1 (unlike yeast where Hrd1p depends on Hrd3p); SEL1L unassociated with HRD1 is degraded by the ubiquitin-proteasome pathway. The complex forms two distinct high-molecular-mass assemblies with different co-factor compositions (Complex I includes Derlin-1/2, VIMP, and Herp; Complex II does not), yet both support retrotranslocation and degradation of model ERAD substrates. siRNA knockdown, co-immunoprecipitation, size-exclusion chromatography, cycloheximide chase The Journal of biological chemistry High 21454652
2010 Herp directly interacts with Hrd1 and regulates Hrd1-mediated ubiquitylation in a ubiquitin-like (UBL) domain-dependent manner; Herp is rapidly turned over at Hrd1 complexes and is required for efficient ubiquitylation and degradation of the ERAD substrate NHK (α1-antitrypsin null Hong Kong). Co-immunoprecipitation, siRNA/mutant analysis, ERAD substrate degradation assay The Journal of biological chemistry High 21149444
2011 Nrf1 is degraded in the cytoplasm by Hrd1 and VCP/p97 under basal conditions via a cytoplasmic degradation motif (between NHB1 and NHB2 domains), suppressing Nrf1-dependent transcription of proteasome subunit genes; siRNA knockdown of Hrd1 markedly augments Nrf1 target gene expression. siRNA knockdown, co-immunoprecipitation, cycloheximide chase, reporter assay Molecular and cellular biology High 21911472
2016 Autoubiquitination of Hrd1 (yeast) at lysines in its RING-finger domain triggers retrotranslocation of a misfolded luminal protein domain across the ER membrane in reconstituted proteoliposomes; substrate ubiquitination is a subsequent event and Cdc48 ATPase is not required for retrotranslocation itself. In vitro reconstitution with purified proteins in proteoliposomes, mutagenesis of RING-finger lysines Cell High 27321670
2017 Cryo-EM structure of yeast Hrd1 in complex with Hrd3 reveals that Hrd1 forms a dimer with eight TM segments per monomer, an aqueous cavity extending from the cytosol toward the ER lumen, and a lateral gate—features consistent with a retrotranslocation channel. Cryo-electron microscopy, structural modeling Nature High 28682307
2020 Cryo-EM structure of the active yeast Hrd1 complex (Hrd1, Hrd3, Der1, Usa1, Yos9) shows Hrd3 and Yos9 jointly create a luminal substrate-recognition site for glycosylated substrates, while Hrd1 and rhomboid-like Der1 form two 'half-channels' with a thinned membrane region through which a substrate polypeptide loop moves. Cryo-electron microscopy of two subcomplexes, crosslinking mass spectrometry, molecular dynamics simulation Science High 32327568
2020 Hrd1 auto-ubiquitination opens a membrane-spanning pore in purified reconstituted membranes; substrate binding enlarges the pore, while deubiquitination closes it. Two substrate-binding sites were identified: a low-affinity luminal site and a high-affinity cytoplasmic site formed after auto-ubiquitination of specific RING-domain lysines. In vitro pore formation assay with purified Hrd1 in model membranes, site-directed mutagenesis, substrate binding assays Nature cell biology High 32094691
2019 Cycles of autoubiquitination (promoted by Usa1 limiting deubiquitination) and deubiquitination by the transmembrane DUB Ubp1 regulate Hrd1 channel activity; Hrd3 acts as a brake on autoubiquitination, while Usa1 inhibits Ubp1 through its UBL domain. Yeast genetics, in vitro ubiquitination/deubiquitination assays, ERAD substrate degradation assays eLife High 31713515
2022 Disulfide crosslinking in live yeast cells shows that an ERAD-L substrate interacts on the luminal side with a groove in Hrd3 and the lectin domain of Yos9, inserts a loop into the membrane with one side contacting Der1's lateral gate and the other contacting Hrd1's lateral gate; two Hrd1 molecules interact through their lateral gates and autoubiquitination is required to disassemble Hrd1 dimers to generate active monomers. Site-specific disulfide crosslinking in live S. cerevisiae, combined with cryo-EM structural data The Journal of biological chemistry High 35970394
2006 Human HRD1 interacts with and ubiquitinates polyglutamine-expanded huntingtin N-terminal fragment (httN) in a RING-finger-dependent manner; HRD1 recruits httN to the ER, co-localizes with juxtanuclear aggregates, and degradation is p97/VCP-dependent but Ufd1/Npl4-independent; HRD1 expression protects cells from httN-induced death. Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, subcellular fractionation, confocal microscopy, cell viability assay Experimental cell research High 17141218
2006 Human HRD1 interacts with Pael-R (Parkin substrate) through its proline-rich region, promotes Pael-R ubiquitylation and proteasomal degradation, and siRNA-mediated HRD1 knockdown causes Pael-R accumulation and caspase-3 activation; ATF6-induced HRD1 upregulation accelerates Pael-R degradation. Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, caspase-3 activation assay Journal of neurochemistry High 17059562
2008 The proline-rich domain of HRD1 is required for promoting Pael-R degradation, while the transmembrane domain is required for transferring Pael-R from the ER to the cytosol; a TM-domain mutant HRD1 is markedly unstable. Domain deletion/mutagenesis, ERAD substrate degradation assay Journal of pharmacological sciences Medium 18344614
2010 SEL1L and HRD1 are required for ERAD of unassembled secretory IgM μ chains; both proteins are induced by ER stress and during B cell differentiation. Co-immunoprecipitation, siRNA/overexpression, ERAD substrate half-life assay Journal of cellular physiology Medium 18314878
2010 HRD1, SEL1L, OS-9, and XTP3-B are all strictly required for ERAD-L(S) (soluble luminal substrates) but become dispensable when the same substrates are membrane-tethered (ERAD-L(M)), revealing distinct pathway selection in mammalian vs. yeast ERAD. siRNA knockdown, ERAD substrate degradation assay (multiple substrates), glycosylation analysis The Journal of cell biology High 20100910
2009 HRD1 and gp78 bind cholera toxin CTA1 subunit and protein disulfide isomerase (PDI) in the ER; dominant-negative Hrd1 or Hrd1 knockdown attenuates CTA1 retrotranslocation; toxin association with Hrd1/gp78 is blocked by dominant-negative Derlin-1, suggesting sequential transfer from Derlin-1 to the E3 ligases. Co-immunoprecipitation/binding studies, dominant-negative expression, siRNA knockdown, retrotranslocation assay 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 SHH and NHK; Derlin-2 acts at a post-targeting step for HRD1-dependent retrotranslocation—without Derlin-2, HRD1 oligomer assembly and substrate targeting proceed normally but substrate is trapped in the ER lumen. siRNA knockdown, co-immunoprecipitation, ERAD substrate degradation assay, protease protection assay The Journal of biological chemistry High 23867461
2014 Herp localizes to the ER quality control compartment (ERQC) and recruits HRD1 to the ERQC where it targets misfolded substrates presented by OS-9 lectin for ERAD; PKR-like ER kinase (PERK) UPR branch is required for this compartmentalization. Confocal microscopy, co-immunoprecipitation, siRNA knockdown, ERAD substrate degradation assay Molecular biology of the cell Medium 24478453
2015 PDI reduces disulfide bonds of Akita proinsulin mutant in the ER lumen, priming it for ERAD via the Hrd1-Sel1L membrane complex; p97 ATPase then couples cytosolic arrival of proinsulin with proteasomal degradation; PDI engagement appears linked to Hrd1 availability. siRNA knockdown, co-immunoprecipitation, retrotranslocation assay, cycloheximide chase Molecular biology of the cell Medium 26269577
2015 Hrd1 interacts with IGF-1R and promotes its ubiquitination and proteasomal degradation; HRD1 overexpression inhibits breast cancer cell growth, migration, and invasion in vitro and in vivo. Co-immunoprecipitation, ubiquitination assay, overexpression/knockdown with cell proliferation and invasion assays, in vivo xenograft Oncotarget Medium 26536657
2015 Grp94 uses its middle domain to interact with misfolded GABAA receptor α1 subunits; OS-9 acts downstream of Grp94 in a glycan-dependent manner; this delivers α1 subunits to the Hrd1-mediated ubiquitination and VCP-mediated extraction pathway for ERAD. Co-immunoprecipitation, siRNA knockdown, ERAD substrate half-life assay, domain mapping The Journal of biological chemistry High 26945068
2016 SEL1L-HRD1 ERAD 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, persistent pre-BCR signaling, and a developmental block from large to small pre-B cells. Conditional Sel1L knockout mouse, flow cytometry, co-immunoprecipitation, co-immunofluorescence Cell reports High 27568564
2016 HRD1 is identified as the first E3 ubiquitin ligase for the death receptor Fas; Hrd1-mediated ubiquitination and proteasomal degradation of Fas protects B cells from activation-induced cell death (AICD); Fas mutation in Hrd1-KO mice abrogates increased AICD. Conditional Hrd1 knockout mouse, co-immunoprecipitation, ubiquitination assay, flow cytometry/apoptosis assay, genetic rescue (Fas mutation) Proceedings of the National Academy of Sciences High 27573825
2016 Hrd1 promotes T cell proliferation by mediating ubiquitination and degradation of the cyclin-dependent kinase inhibitor p27kip1; Hrd1 deletion also inhibits IL-2 production independently of p27kip1; T-cell-specific Hrd1 deficiency protects mice from experimental autoimmune encephalomyelitis. Conditional Hrd1 knockout mouse, co-immunoprecipitation, ubiquitination assay, T cell proliferation assay, cytokine ELISA, EAE model Nature communications High 27417417
2016 HRD1-mediated ERAD tunes the level of the ER-bound E2 enzyme UBE2J1 (plant ortholog UBC32) by targeting it for proteasomal degradation; this cross-regulation between HRD1 (E3) and UBE2J1 (E2 of the DOA10 complex) is conserved between plants and mammals. Yeast two-hybrid, co-immunoprecipitation, ubiquitination assay, cycloheximide chase in mammalian cells Nature plants Medium 27322605
2016 USP19, an ER-anchored deubiquitinating enzyme, stabilizes HRD1 by removing K48-linked ubiquitin chains and rescuing it from proteasomal degradation; altered USP19 expression bidirectionally affects steady-state HRD1 levels. Co-immunoprecipitation, deubiquitination assay, overexpression/siRNA with HRD1 stability assay International journal of molecular sciences Medium 27827840
2017 SYVN1/HRD1 promotes degradation of the SERPINA1 Z variant (ATZ) via SQSTM1/p62-dependent selective autophagy; SYVN1 mediates K48-linked polyubiquitination of ATZ, which binds the UBA domain of SQSTM1 to couple ubiquitinated ATZ to the lysosome; autophagy inhibition impairs SYVN1-mediated clearance. Ubiquitination assay, co-immunoprecipitation, autophagy inhibitor/inducer treatment, ATG5-KO cells, SQSTM1 domain mutants, cell viability assay Autophagy High 28121484
2017 A conserved HAF-H domain within the intrinsically disordered cytoplasmic region of Hrd1 is required for interaction with cofactors FAM8A1 and Herp (HERPUD1), and for assembly of higher-order Hrd1 complexes; FAM8A1 enhances Herp binding to Hrd1 and this interaction is required for ERAD. Co-immunoprecipitation, domain deletion/mutagenesis, ERAD substrate degradation assay Journal of cell science High 28827405
2017 Hrd1 interacts with and promotes ubiquitination and proteasomal degradation of tau and phosphorylated tau in a RING-finger E3-activity-dependent manner; HRD1 knockdown stabilizes tau; proteasome inhibition increases Hrd1-mediated tau ubiquitination; Hrd1 overexpression alleviates tau cytotoxicity. Co-immunoprecipitation, ubiquitination assay, siRNA knockdown with cycloheximide chase, cell viability assay Current molecular medicine Medium 22280354
2017 Hrd1 overexpression increases proteasomal degradation and aggresome formation of optineurin (OPTN) at the MTOC; Hrd1 knockdown stabilizes OPTN and inhibits aggresome formation. Overexpression/siRNA, co-immunoprecipitation, ubiquitination assay, immunofluorescence for aggresome Human molecular genetics Medium 28334804
2017 Endogenous Hrd1 complexes in HEK293 cells exist as two distinct high-molecular-mass assemblies with different interacting proteins and variable stoichiometries, identified by CRISPR-tagged endogenous Hrd1 pulldown and absolute quantification mass spectrometry. CRISPR knock-in tandem affinity tag, size-exclusion chromatography, immunodepletion, absolute quantification mass spectrometry The Journal of biological chemistry High 28411238
2018 SYVN1/HRD1 interacts with METTL14 and mediates its ubiquitination and proteasomal degradation under normal conditions; during ER stress (UPR), competition against HRD1-ERAD blocks METTL14 ubiquitination, allowing METTL14 accumulation to promote CHOP mRNA m6A-mediated decay and limit apoptosis. Co-immunoprecipitation, ubiquitination assay, liver-specific METTL14 knockout mouse, m6A-seq, ribosome profiling Molecular cell High 34847358
2018 HRD1 interacts with and promotes ubiquitination and degradation of PTEN in hepatocellular carcinoma cells, promoting cell proliferation, migration, and invasion. Co-immunoprecipitation, ubiquitination assay, siRNA/overexpression with proliferation and invasion assays, in vivo xenograft Cellular signalling Medium 29958993
2018 RNF145 and gp78 independently coordinate HMGCR ubiquitination and degradation; in the absence of both, Hrd1 (a third UBE2G2-dependent E3 ligase) partially regulates HMGCR activity via sterol-accelerated proteasomal degradation. CRISPR/Cas9 genome-wide screen, epistasis analysis, sterol-sensitive endogenous HMGCR reporter eLife Medium 30543180
2018 Hepatic SEL1L-HRD1 ERAD controls FGF21 expression by mediating ubiquitination and turnover of ER-resident transcription factor CREBH, thereby regulating its nuclear abundance and FGF21 transcription; liver-specific Sel1L deletion elevates CREBH and circulating FGF21. Liver-specific Sel1L knockout mouse, co-immunoprecipitation, ubiquitination assay, transcriptional reporter, metabolic phenotyping The EMBO journal High 30389665
2018 HRD1 interacts with and promotes ubiquitination and degradation of SIRT2; HRD1 deficiency induces SIRT2 upregulation and inhibits lung cancer cell growth in vitro and in vivo. Co-immunoprecipitation, ubiquitination assay, siRNA/overexpression with proliferation and tumor formation assays Molecular and cellular biology Medium 31932479
2018 ER-associated HRD1 targets multiple metabolic enzymes (ENTPD5, CPT2, RMND1, HSD17B4) for degradation in the liver; liver-specific HRD1 deletion increases these proteins, hyperactivates AMPK and AKT, and reprograms metabolic gene expression. Liver-specific HRD1 knockout mouse, proteomic interactome analysis, genome-wide mRNA-seq, metabolic phenotyping Nature communications High 30201971
2019 ER-localized Hrd1 interacts directly with deubiquitinase Usp15 and ubiquitinates it, but unlike classical ERAD, Usp15 is not degraded; instead it loses DUB activity toward IκBα, leading to excessive NF-κB activation during TLR4-triggered bacterial infection; Hrd1-deficient macrophages are protected from LPS-induced septic shock. Co-immunoprecipitation, ubiquitination assay, deubiquitination assay, macrophage-specific Hrd1 knockout mouse, LPS/sepsis model Nature microbiology High 31477895
2019 Hrd1 genetic deletion in Treg cells leads to elevated IRE1α and p38 MAPK activation; pharmacological suppression of IRE1α kinase (but not endonuclease) activity rescues Hrd1-null Treg stability; Hrd1 therefore maintains Treg function by suppressing IRE1α-mediated ER stress signaling. Treg-specific Hrd1 conditional knockout mouse, pharmacological IRE1α inhibition, FACS, gene expression analysis JCI insight High 30843874
2020 β-cell-specific deletion of Sel1L-Hrd1 ERAD leads to loss of β cell identity (not apoptosis), mediated through TGF-β signaling; SEL1L-HRD1 ERAD degrades TGF-β receptor 1, and inhibition of TGF-β signaling in Sel1L-deficient β cells restores β cell maturation markers. β-cell-specific Sel1L knockout mouse, single-cell RNA-seq, co-immunoprecipitation, ubiquitination assay, TGF-β signaling inhibition The Journal of clinical investigation High 32182217
2020 HRD1 interacts with and promotes ubiquitination and proteasomal degradation of MafA (a β-cell transcription factor) in diabetic β-cells, leading to cytoplasmic MafA accumulation and impaired β-cell function. Co-immunoprecipitation, ubiquitination assay, proteomic interactome, HRD1 overexpression/knockdown with insulin secretion assay Diabetes Medium 32086291
2020 HRD1 interacts with CPT2 and promotes its K48-linked ubiquitination under glutamine-sufficient conditions; HRD1 knockdown increases CPT2 levels and fatty acid oxidation in TNBC cells, and inhibition of CPT2 suppresses this effect. Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, FAO assay, in vitro and in vivo proliferation assays Molecular oncology Medium 33207079
2021 HRD1 mediates polyubiquitination-dependent proteasomal degradation of Vimentin in breast cancer cells, inhibiting EMT; this is regulated by the circNR3C2/miR-513a-3p/HRD1 axis. Co-immunoprecipitation, in vitro ubiquitination assay, immunoblotting, in vivo xenograft Molecular cancer Medium 33530981
2021 SYVN1 interacts with GSDMD and mediates K27-linked polyubiquitination at K203 and K204 residues of GSDMD, promoting GSDMD-induced pyroptotic cell death; SYVN1 deficiency inhibits pyroptosis and LDH release. Co-immunoprecipitation, site-directed mutagenesis of ubiquitination sites, LDH/PI uptake assays Cell death & disease Medium 35115505
2021 SYVN1 interacts with HSP90 and impacts ubiquitination of EEF2K in hepatocellular carcinoma; SYVN1 expression is associated with tumor metastasis. Immunoprecipitation, immunofluorescence, proteomic/ubiquitinomic analysis, SYVN1 knockdown/overexpression with migration/invasion assays Cancer communications Low 34196494
2021 HRD1 interacts with and ubiquitinates PFKP (platelet isoform of phosphofructokinase), targeting it for proteasomal degradation and reducing aerobic glycolysis (Warburg effect) in breast cancer cells; HRD1-PFKP interaction is in the cytoplasm. Mass spectrometry, co-immunoprecipitation, immunofluorescence, ubiquitination assay, glycolysis assay Cell communication and signaling Medium 33588886
2021 HRD1 mediates ubiquitination and degradation of ACSL4, thereby inhibiting ferroptosis in gastric cancer cells; ATF3 downregulates HRD1 transcription and co-immunoprecipitation confirmed HRD1-ACSL4 interaction. Co-immunoprecipitation, ChIP assay, ubiquitination assay, ferroptosis assays Translational oncology Low 36947996
2022 SEL1L-HRD1 ERAD is a negative regulator of STING innate immunity: the SEL1L-HRD1 complex ubiquitinates nascent STING protein for proteasomal degradation in the basal state, independently of ER stress or IRE1α; Hrd1 or Sel1L deficiency in macrophages amplifies STING signaling and antiviral/antitumor immunity. Macrophage-specific Sel1L/Hrd1 conditional knockout mouse, co-immunoprecipitation, ubiquitination assay, viral infection model, tumor model Nature cell biology High 37142791
2022 S100A16 promotes HRD1-mediated ubiquitination and degradation of GSK3β and CK1α, activating Wnt/β-catenin signaling in renal fibroblasts during acute kidney injury. Co-immunoprecipitation, ubiquitination assay, S100A16 knockout mouse (IRI model), siRNA knockdown Cellular and molecular life sciences Medium 35279748
2023 SEL1L-HRD1 ERAD controls systemic iron homeostasis by targeting ceruloplasmin (CP) for proteasomal degradation; in Sel1L-deficient hepatocytes, CP accumulates in the ER and is shunted to refolding leading to elevated secretion; disease-causing CP mutants are also SEL1L-HRD1 ERAD substrates. Hepatocyte-specific Sel1L knockout mouse, proteomic screening, co-immunoprecipitation, ubiquitination assay, iron homeostasis phenotyping Proceedings of the National Academy of Sciences High 36595688
2023 SYVN1 binds and promotes K48-linked ubiquitination and proteasomal degradation of HMGB1 in neurons; SYVN1 overexpression activates NRF2/HO-1 pathway by reducing HMGB1, thereby inhibiting ferroptosis in spinal cord ischemia-reperfusion injury. Co-immunoprecipitation, ubiquitination assay, adenoviral SYVN1 overexpression in rat SCIRI model International immunopharmacology Medium 37591122
2023 SYVN1 mediates ubiquitination and degradation of STAT3, decreasing phospho-STAT3 and VEGF secretion in retinal endothelial cells; SYVN1 overexpression prevents neovascularization in oxygen-induced retinopathy mice. Co-immunoprecipitation, ubiquitination assay, SYVN1 overexpression (adenoviral), OIR mouse model Investigative ophthalmology & visual science Medium 37540175
2023 HRD1 interacts with and ubiquitinates Nrf2 (at a QSLVPDI motif-containing interaction site) under high-glucose conditions, promoting Nrf2 proteasomal degradation; XBP1-induced HRD1 upregulation suppresses Nrf2/HO-1 signaling, promoting ferroptosis-related EMT in diabetic nephropathy. Co-immunoprecipitation, ubiquitination assay, XBP1/HRD1 overexpression, ferroptosis assays, interaction motif mapping Biomedicine & pharmacotherapy Medium 37224754
2023 HRD1 is UFMylated at Lys610 by the UFM1 E3 ligase UFL1 in complex with DDRGK1; UFL1 depletion increases HRD1 stability and reduces its ubiquitination; K610R mutation impairs HRD1's ability to degrade misfolded ER proteins; UFMylation regulates HRD1 ERAD function. Co-immunoprecipitation, UFMylation assay, site-directed mutagenesis (K610R), ERAD substrate degradation assay FASEB journal Medium 37795761
2023 Syvn1 sulfhydration at Cys115 by H2S promotes Syvn1-Keap1 interaction, increasing Keap1 ubiquitination and Nrf2 nuclear translocation to activate Nrf2/GPx4/GSH ferroptosis protection in diabetic hearts. S-sulfhydration assay, co-immunoprecipitation, Syvn1 C115A mutant transfection, ubiquitination assay, db/db mouse model Cell death discovery Medium 37875467
2023 SYVN1 promotes proteasomal degradation of ETS1 via ubiquitination at K318; stA (sculponeatin A) promotes ETS1-SYVN1 interaction to induce ETS1 degradation and reduce xCT/SLC7A11 expression, thereby triggering ferroptosis in breast cancer. Co-immunoprecipitation, ubiquitination assay, K318R mutagenesis, drug-affinity assay, xenograft model Phytomedicine Medium 37327642
2024 SEL1L is required for recruitment of E2 enzyme UBE2J1 and DERLIN to HRD1; a pathogenic SEL1L variant (S658P) attenuates SEL1L-HRD1 interaction (likely via electrostatic repulsion between SEL1L F668 and HRD1 Y30), reducing SEL1L stability and impairing ERAD complex formation, causing neurodevelopmental disease in mice. Knock-in mouse model (SEL1LS658P), proteomic screens of SEL1L and HRD1 interactomes, co-immunoprecipitation, biochemical stability assays, ERAD substrate degradation assay Nature communications High 38365914
2024 Biallelic hypomorphic variants in SEL1L (p.Gly585Asp, p.Met528Arg) and HRD1/SYVN1 (p.Pro398Leu) impair ERAD at distinct steps—substrate recruitment, SEL1L-HRD1 complex formation, and HRD1 catalytic activity, respectively—causing neurodevelopmental disorder in humans. Patient variant functional characterization, biochemical ERAD assays, co-immunoprecipitation, protein stability assays The Journal of clinical investigation High 37943610
2024 SEL1L-HRD1 ERAD attenuates GPI-anchored protein biogenesis by specifically targeting PIGK (catalytic subunit of GPI-transamidase complex) for proteasomal degradation; over 100 high-confidence ERAD substrates were identified in human and mouse cells by proteomics with machine-learning filtering. Quantitative proteomics (SILAC), CRISPR-based substrate screen, machine learning, co-immunoprecipitation, ubiquitination assay, GPI-anchored protein surface expression assay Nature communications High 38253565

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2008 OS-9 and GRP94 deliver mutant alpha1-antitrypsin to the Hrd1-SEL1L ubiquitin ligase complex for ERAD. Nature cell biology 419 18264092
2020 Structural basis of ER-associated protein degradation mediated by the Hrd1 ubiquitin ligase complex. Science (New York, N.Y.) 190 32327568
2016 Autoubiquitination of the Hrd1 Ligase Triggers Protein Retrotranslocation in ERAD. Cell 164 27321670
2017 Cryo-EM structure of the protein-conducting ERAD channel Hrd1 in complex with Hrd3. Nature 160 28682307
2010 Stringent requirement for HRD1, SEL1L, and OS-9/XTP3-B for disposal of ERAD-LS substrates. The Journal of cell biology 147 20100910
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
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 112 26137860
2021 CircNR3C2 promotes HRD1-mediated tumor-suppressive effect via sponging miR-513a-3p in triple-negative breast cancer. Molecular cancer 102 33530981
2013 Endoplasmic reticulum stress and Parkinson's disease: the role of HRD1 in averting apoptosis in neurodegenerative disease. Oxidative medicine and cellular longevity 102 23710284
2023 Endoplasmic reticulum stress-triggered ferroptosis via the XBP1-Hrd1-Nrf2 pathway induces EMT progression in diabetic nephropathy. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 95 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 91 17141218
2018 The sterol-responsive RNF145 E3 ubiquitin ligase mediates the degradation of HMG-CoA reductase together with gp78 and Hrd1. eLife 90 30543180
2011 Dual regulation of the transcriptional activity of Nrf1 by β-TrCP- and Hrd1-dependent degradation mechanisms. Molecular and cellular biology 87 21911472
2023 SEL1L-HRD1 endoplasmic reticulum-associated degradation controls STING-mediated innate immunity by limiting the size of the activable STING pool. Nature cell biology 80 37142791
2018 Hepatic Sel1L-Hrd1 ER-associated degradation (ERAD) manages FGF21 levels and systemic metabolism via CREBH. The EMBO journal 80 30389665
2008 Human HRD1 promoter carries a functional unfolded protein response element to which XBP1 but not ATF6 directly binds. Journal of biochemistry 80 18664523
2020 Sel1L-Hrd1 ER-associated degradation maintains β cell identity via TGF-β signaling. The Journal of clinical investigation 79 32182217
2006 A ubiquitin ligase HRD1 promotes the degradation of Pael receptor, a substrate of Parkin. Journal of neurochemistry 78 17059562
2020 Hrd1 forms the retrotranslocation pore regulated by auto-ubiquitination and binding of misfolded proteins. Nature cell biology 67 32094691
2021 HRD1-mediated METTL14 degradation regulates m6A mRNA modification to suppress ER proteotoxic liver disease. Molecular cell 65 34847358
2016 The Sel1L-Hrd1 Endoplasmic Reticulum-Associated Degradation Complex Manages a Key Checkpoint in B Cell Development. Cell reports 65 27568564
2014 Herp coordinates compartmentalization and recruitment of HRD1 and misfolded proteins for ERAD. Molecular biology of the cell 65 24478453
2009 Intrinsic conformational determinants signal protein misfolding to the Hrd1/Htm1 endoplasmic reticulum-associated degradation system. Molecular biology of the cell 64 19458187
2009 The E3 ubiquitin ligases Hrd1 and gp78 bind to and promote cholera toxin retro-translocation. Molecular biology of the cell 63 19864457
2018 ER-associated ubiquitin ligase HRD1 programs liver metabolism by targeting multiple metabolic enzymes. Nature communications 62 30201971
2017 Conserved cytoplasmic domains promote Hrd1 ubiquitin ligase complex formation for ER-associated degradation (ERAD). Journal of cell science 62 28827405
2010 Herp regulates Hrd1-mediated ubiquitylation in a ubiquitin-like domain-dependent manner. The Journal of biological chemistry 60 21149444
2015 gp78 functions downstream of Hrd1 to promote degradation of misfolded proteins of the endoplasmic reticulum. Molecular biology of the cell 59 26424800
2012 Aberrant substrate engagement of the ER translocon triggers degradation by the Hrd1 ubiquitin ligase. The Journal of cell biology 59 22689655
2009 Differential regulation of CFTRDeltaF508 degradation by ubiquitin ligases gp78 and Hrd1. The international journal of biochemistry & cell biology 56 19828134
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 55 31490085
2016 The ER membrane-anchored ubiquitin ligase Hrd1 is a positive regulator of T-cell immunity. Nature communications 55 27417417
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
2010 Modularity of the Hrd1 ERAD complex underlies its diverse client range. The Journal of cell biology 52 20212318
2023 Exogenous H2S initiating Nrf2/GPx4/GSH pathway through promoting Syvn1-Keap1 interaction in diabetic hearts. Cell death discovery 51 37875467
2020 HRD1, an Important Player in Pancreatic β-Cell Failure and Therapeutic Target for Type 2 Diabetic Mice. Diabetes 50 32086291
2022 E3 ubiquitin ligase SYVN1 is a key positive regulator for GSDMD-mediated pyroptosis. Cell death & disease 49 35115505
2021 Downregulation of XBP1 protects kidney against ischemia-reperfusion injury via suppressing HRD1-mediated NRF2 ubiquitylation. Cell death discovery 48 33654072
2020 E3 Ubiquitin Ligase HRD1 Promotes Lung Tumorigenesis by Promoting Sirtuin 2 Ubiquitination and Degradation. Molecular and cellular biology 48 31932479
2019 ER-localized Hrd1 ubiquitinates and inactivates Usp15 to promote TLR4-induced inflammation during bacterial infection. Nature microbiology 48 31477895
2007 ER E3 ubiquitin ligase HRD-1 and its specific partner chaperone BiP play important roles in ERAD and developmental growth in Caenorhabditis elegans. Genes to cells : devoted to molecular & cellular mechanisms 48 17825049
2017 HRD1 prevents apoptosis in renal tubular epithelial cells by mediating eIF2α ubiquitylation and degradation. Cell death & disease 47 29233968
2016 HRD1-mediated ERAD tuning of ER-bound E2 is conserved between plants and mammals. Nature plants 46 27322605
2020 Endoplasmic reticulum-associated degradation and beyond: The multitasking roles for HRD1 in immune regulation and autoimmunity. Journal of autoimmunity 45 32057541
2015 PDI reductase acts on Akita mutant proinsulin to initiate retrotranslocation along the Hrd1/Sel1L-p97 axis. Molecular biology of the cell 45 26269577
2013 Derlin2 protein facilitates HRD1-mediated retro-translocation of sonic hedgehog at the endoplasmic reticulum. The Journal of biological chemistry 45 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) 42 34196494
2020 HRD1 inhibits fatty acid oxidation and tumorigenesis by ubiquitinating CPT2 in triple-negative breast cancer. Molecular oncology 40 33207079
2020 Ginsenoside Rb1 alleviates colitis in mice via activation of endoplasmic reticulum-resident E3 ubiquitin ligase Hrd1 signaling pathway. Acta pharmacologica Sinica 39 33268823
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
2023 Downregulation of miR-221-3p promotes the ferroptosis in gastric cancer cells via upregulation of ATF3 to mediate the transcription inhibition of GPX4 and HRD1. Translational oncology 36 36947996
2015 HRD1 suppresses the growth and metastasis of breast cancer cells by promoting IGF-1R degradation. Oncotarget 36 26536657
2018 The endoplasmic reticulum-resident E3 ubiquitin ligase Hrd1 controls a critical checkpoint in B cell development in mice. The Journal of biological chemistry 35 29907570
2008 Novel functions of ubiquitin ligase HRD1 with transmembrane and proline-rich domains. Journal of pharmacological sciences 35 18344614
2008 Immunohistochemical localization of a ubiquitin ligase HRD1 in murine brain. Journal of neuroscience research 34 18241051
2017 A critical role of Hrd1 in the regulation of optineurin degradation and aggresome formation. Human molecular genetics 33 28334804
2024 SEL1L-HRD1 interaction is required to form a functional HRD1 ERAD complex. Nature communications 32 38365914
2021 Anti-Warburg effect by targeting HRD1-PFKP pathway may inhibit breast cancer progression. Cell communication and signaling : CCS 31 33588886
2023 SYVN1 attenuates ferroptosis and alleviates spinal cord ischemia-reperfusion injury in rats by regulating the HMGB1/NRF2/HO-1 axis. International immunopharmacology 30 37591122
2020 Exogenous H2S Induces Hrd1 S-sulfhydration and Prevents CD36 Translocation via VAMP3 Ubiquitylation in Diabetic Hearts. Aging and disease 30 32257542
2011 HRD1 levels increased by zonisamide prevented cell death and caspase-3 activation caused by endoplasmic reticulum stress in SH-SY5Y cells. Journal of molecular neuroscience : MN 30 21892618
2009 Degradation of sterol regulatory element-binding protein precursor requires the endoplasmic reticulum-associated degradation components Ubc7 and Hrd1 in fission yeast. The Journal of biological chemistry 30 19520858
2024 Hypomorphic variants of SEL1L-HRD1 ER-associated degradation are associated with neurodevelopmental disorders. The Journal of clinical investigation 29 37943610
2015 Proteasomal Degradation of Proinsulin Requires Derlin-2, HRD1 and p97. PloS one 29 26107514
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 28 34562065
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 27 37392829
2022 S100A16 promotes acute kidney injury by activating HRD1-induced ubiquitination and degradation of GSK3β and CK1α. Cellular and molecular life sciences : CMLS 27 35279748
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
2020 HRD1 prevents atherosclerosis-mediated endothelial cell apoptosis by promoting LOX-1 degradation. Cell cycle (Georgetown, Tex.) 25 32308114
2014 Effects of oxidative stress on the solubility of HRD1, a ubiquitin ligase implicated in Alzheimer's disease. PloS one 25 24788773
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 Sculponeatin A promotes the ETS1-SYVN1 interaction to induce SLC7A11/xCT-dependent ferroptosis in breast cancer. Phytomedicine : international journal of phytotherapy and phytopharmacology 22 37327642
2023 SLC35F2-SYVN1-TRIM59 axis critically regulates ferroptosis of pancreatic cancer cells by inhibiting endogenous p53. Oncogene 22 37740007
2012 Hrd1 facilitates tau degradation and promotes neuron survival. Current molecular medicine 22 22280354
2004 Induction of murine HRD1 in experimental cerebral ischemia. Brain research. Molecular brain research 22 15519674
2023 Hepatic SEL1L-HRD1 ER-associated degradation regulates systemic iron homeostasis via ceruloplasmin. Proceedings of the National Academy of Sciences of the United States of America 21 36595688
2022 SEL1L-HRD1 ER-associated degradation suppresses hepatocyte hyperproliferation and liver cancer. iScience 21 36238898
2018 Both thapsigargin- and tunicamycin-induced endoplasmic reticulum stress increases expression of Hrd1 in IRE1-dependent fashion. Neurological research 20 30475171
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
2024 Proteomic screens of SEL1L-HRD1 ER-associated degradation substrates reveal its role in glycosylphosphatidylinositol-anchored protein biogenesis. Nature communications 19 38253565
2023 UFMylation of HRD1 regulates endoplasmic reticulum homeostasis. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 19 37795761
2022 Disulfide-crosslink analysis of the ubiquitin ligase Hrd1 complex during endoplasmic reticulum-associated protein degradation. The Journal of biological chemistry 19 35970394
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
2023 SYVN1 Promotes STAT3 Protein Ubiquitination and Exerts Antiangiogenesis Effects in Retinopathy of Prematurity Development. Investigative ophthalmology & visual science 18 37540175