SYVN1

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0012505 endomembrane system	IBA GO_REF:0000033	ACCEPT	Summary: IBA annotation placing SYVN1 in the endomembrane system. SYVN1/HRD1 is an ER-resident multi-pass transmembrane protein (PMID:14593114, PMID:12459480). The endomembrane system is a broad parent term that encompasses the ER. This is correct but less specific than the more informative ER membrane (GO:0005789) annotations already present. Reason: Phylogenetically inferred CC term consistent with the well-established ER localization of SYVN1/HRD1. Broad but correct. Supporting Evidence: PMID:14593114 We show that human HRD1 is a non-glycosylated, stable ER protein with a cytosolic RING-H2 finger domain.
GO:0036503 ERAD pathway	IBA GO_REF:0000033	ACCEPT	Summary: IBA annotation for ERAD pathway. SYVN1/HRD1 is the central E3 ubiquitin ligase of the ERAD pathway, a core function established by multiple experimental studies (PMID:14593114, PMID:12459480, PMID:17059562). Reason: ERAD pathway is the core biological process of SYVN1/HRD1. Strongly supported by phylogenetic conservation and extensive experimental evidence. Supporting Evidence: PMID:14593114 Human HRD1 is an E3 ubiquitin ligase involved in degradation of proteins from the endoplasmic reticulum.
GO:0043161 proteasome-mediated ubiquitin-dependent protein catabolic process	IBA GO_REF:0000033	ACCEPT	Summary: IBA annotation for proteasome-mediated ubiquitin-dependent protein catabolism. SYVN1/HRD1 ubiquitinates misfolded ER proteins with K48-linked polyubiquitin chains (PMID:14593114), targeting them for proteasomal degradation. This is the downstream consequence of its E3 ligase activity in the ERAD pathway. Reason: Core function. HRD1-mediated ubiquitination leads to proteasomal degradation of substrates; K48-linked chains are the hallmark of proteasomal targeting. Supporting Evidence: PMID:14593114 In the presence of the ubiquitin-conjugating enzyme UBC7, the RING-H2 finger has in vitro ubiquitination activity for Lys(48)-specific polyubiquitin linkage, suggesting that human HRD1 is an E3 ubiquitin ligase involved in protein degradation
GO:0044322 endoplasmic reticulum quality control compartment	IBA GO_REF:0000033	ACCEPT	Summary: IBA annotation for ER quality control compartment localization. SYVN1/HRD1 localizes to the ERQC, a specialized ER subdomain where misfolded proteins accumulate before degradation. Demonstrated by IDA in PMID:23233672 and PMID:24478453. Reason: Phylogenetically supported and consistent with multiple IDA studies showing HRD1 recruitment to the ERQC. Supporting Evidence: PMID:24478453 Herp localizes to the ERQC, and our results suggest that it recruits HRD1, which targets to ERAD the substrate presented by the OS-9 lectin at the ERQC.
GO:0061630 ubiquitin protein ligase activity	IBA GO_REF:0000033	ACCEPT	Summary: IBA annotation for ubiquitin protein ligase activity. This is the core molecular function of SYVN1/HRD1, established by in vitro ubiquitination assays (PMID:14593114, PMID:12459480, PMID:12975321) and in vivo substrate ubiquitination studies (PMID:17059562, PMID:17170702). Reason: Core molecular function. SYVN1 is a RING-type E3 ubiquitin ligase, its most fundamental catalytic activity. Supporting Evidence: PMID:14593114 In the presence of the ubiquitin-conjugating enzyme UBC7, the RING-H2 finger has in vitro ubiquitination activity for Lys(48)-specific polyubiquitin linkage, suggesting that human HRD1 is an E3 ubiquitin ligase involved in protein degradation
GO:0005789 endoplasmic reticulum membrane	IEA GO_REF:0000044	ACCEPT	Summary: IEA annotation from UniProt subcellular location mapping. SYVN1 is confirmed as an ER membrane multi-pass transmembrane protein by multiple experimental studies (PMID:14593114, PMID:12459480, PMID:16186510). Reason: Correct electronic annotation consistent with extensive experimental evidence of ER membrane localization. Supporting Evidence: PMID:14593114 We show that human HRD1 is a non-glycosylated, stable ER protein with a cytosolic RING-H2 finger domain.
GO:0008270 zinc ion binding	IEA GO_REF:0000043	ACCEPT	Summary: IEA from UniProt keyword mapping. SYVN1 contains a RING-type zinc finger domain (residues 291-330) that coordinates two zinc ions, confirmed by NMR structure (PDB:6A3Z, PMID:30345569). Zinc binding is integral to the RING domain fold required for E3 ligase activity. Reason: Correct. The RING-H2 zinc finger domain of SYVN1 binds two zinc ions, structurally verified by NMR (PMID:30345569). Supporting Evidence: PMID:14593114 We show that human HRD1 is a non-glycosylated, stable ER protein with a cytosolic RING-H2 finger domain.
GO:0016740 transferase activity	IEA GO_REF:0000043	ACCEPT	Summary: IEA from UniProt keyword mapping. SYVN1 is classified as EC 2.3.2.27 (RING-type E3 ubiquitin transferase). This is a very broad parent term; the more specific GO:0061630 (ubiquitin protein ligase activity) is already well-annotated. Reason: Technically correct as a broad parent term since SYVN1 catalyzes ubiquitin transfer, but redundant with the more specific ubiquitin protein ligase activity annotations.
GO:0044322 endoplasmic reticulum quality control compartment	IEA GO_REF:0000117	ACCEPT	Summary: IEA annotation from ARBA machine learning for ERQC localization. Consistent with IBA and IDA annotations for the same term. Reason: Correct electronic annotation, redundant with IBA and IDA evidence for the same term.
GO:0046872 metal ion binding	IEA GO_REF:0000043	ACCEPT	Summary: IEA from UniProt keyword mapping. SYVN1 binds zinc ions through its RING-type zinc finger domain. This is a very broad parent term; the more specific GO:0008270 (zinc ion binding) is already annotated. Reason: Correct but very broad. Redundant with the more specific zinc ion binding annotation.
GO:0050821 protein stabilization	IEA GO_REF:0000117	KEEP AS NON CORE	Summary: IEA from ARBA for protein stabilization. This likely derives from the observation that HRD1 stabilizes SEL1L within the HRD1-SEL1L complex (PMID:21454652). While this is a documented function, the primary role of SYVN1 is protein degradation, not stabilization. The stabilization of SEL1L is a secondary consequence of complex formation. Reason: HRD1 does stabilize SEL1L within the ERAD complex (PMID:21454652), but protein stabilization is not a core function of this E3 ubiquitin ligase. It is a secondary consequence of its role in the HRD1-SEL1L complex. Supporting Evidence: PMID:21454652 Although endogenous SEL1L is a long-lived protein, the half-life of SEL1L was greatly reduced when HRD1 is silenced. Conversely, transiently expressed SEL1L was rapidly degraded but was stabilized when HRD1 was coexpressed.
GO:0061630 ubiquitin protein ligase activity	IEA GO_REF:0000003	ACCEPT	Summary: IEA from EC number mapping (EC 2.3.2.27). Consistent with the core molecular function of SYVN1 as an E3 ubiquitin-protein ligase. Reason: Correct electronic annotation based on EC classification, consistent with extensive experimental evidence.
GO:1902236 negative regulation of endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway	IEA GO_REF:0000117	ACCEPT	Summary: IEA from ARBA for anti-apoptotic role in ER stress. SYVN1/HRD1 overexpression protects cells from ER stress-induced apoptosis (PMID:12459480), and its degradation of Pael-R prevents ER stress-induced cell death in neurons (PMID:17059562). Reason: Correct electronic annotation consistent with experimental evidence from PMID:12459480 and PMID:17059562. Supporting Evidence: PMID:12459480 293 cells stably expressing wild-type HRD1, but not the C329S mutant, afforded resistance to ER stress-induced apoptosis.
GO:0005515 protein binding	IPI PMID:17170702 Cytoplasmic destruction of p53 by the endoplasmic reticulum-...	REMOVE	Summary: IPI for protein binding based on interaction with p53/TP53. PMID:17170702 demonstrated that SYVN1 interacts with p53, sequesters it in the cytoplasm, and promotes its ubiquitination and degradation. This is a functional E3 ligase-substrate interaction, not mere binding. Reason: Protein binding is uninformative. The interaction with TP53 reflects SYVN1's E3 ubiquitin ligase activity targeting p53 for degradation (PMID:17170702). Already covered by ubiquitin protein ligase activity annotations. Supporting Evidence: PMID:17170702 Cytoplasmic destruction of p53 by the endoplasmic reticulum-resident ubiquitin ligase 'Synoviolin'.
GO:0005515 protein binding	IPI PMID:18369366 Synoviolin promotes IRE1 ubiquitination and degradation in s...	REMOVE	Summary: IPI for protein binding based on interaction with IRE1. PMID:18369366 showed SYVN1 interacts with and ubiquitinates IRE1, promoting its degradation. This is an E3 ligase-substrate interaction. Reason: Protein binding is uninformative. The interaction with IRE1 reflects SYVN1's E3 ligase activity in ubiquitinating and degrading IRE1 (PMID:18369366). The correct annotation is ubiquitin protein ligase activity. Supporting Evidence: PMID:18369366 SYVN1 interacts with and catalyses IRE1 ubiquitination and consequently promotes IRE1 degradation.
GO:0005515 protein binding	IPI PMID:19690564 A comprehensive framework of E2-RING E3 interactions of the ...	REMOVE	Summary: IPI for protein binding from a large-scale E2-RING E3 interaction study. This is a high-throughput interaction screen (PMID:19690564) identifying E2-E3 pairs. Reason: Protein binding is uninformative. Interactions between E2 conjugating enzymes and E3 ligases are functional aspects of ubiquitin protein ligase activity, not mere binding.
GO:0005515 protein binding	IPI PMID:21343306 Membrane-associated ubiquitin ligase complex containing gp78...	REMOVE	Summary: IPI for protein binding from a study on sterol-regulated HMGCR degradation. PMID:21343306 identifies SYVN1 as a component of a membrane-associated ubiquitin ligase complex involved in HMGCR degradation. Reason: Protein binding is uninformative. The interaction is in the context of an E3 ligase complex for ERAD substrate degradation.
GO:0005515 protein binding	IPI PMID:22119785 Defining human ERAD networks through an integrative mapping ...	REMOVE	Summary: IPI for protein binding from an integrative ERAD network mapping study. This large-scale study defined human ERAD interaction networks. Reason: Protein binding is uninformative. These interactions represent functional ERAD complex assembly rather than nonspecific binding.
GO:0005515 protein binding	IPI PMID:26551274 IRE1α is an endogenous substrate of endoplasmic-reticulum-as...	REMOVE	Summary: IPI for protein binding based on interaction with IRE1alpha. PMID:26551274 demonstrates that IRE1alpha is an endogenous substrate of HRD1-SEL1L ERAD. The HRD1-SEL1L complex ubiquitinates IRE1alpha to control its protein levels. Reason: Protein binding is uninformative. The interaction reflects IRE1alpha being an endogenous ERAD substrate of SYVN1.
GO:0005515 protein binding	IPI PMID:28827405 Conserved cytoplasmic domains promote Hrd1 ubiquitin ligase ...	REMOVE	Summary: IPI for protein binding from a study on HRD1 complex formation. PMID:28827405 characterized interactions between SYVN1 and complex components SEL1L, FAM8A1, HERPUD1, OS9, and UBE2J1. Reason: Protein binding is uninformative. These are functional interactions within the HRD1 ubiquitin ligase complex for ERAD. Already captured by Hrd1p ubiquitin ligase complex (GO:0000836) annotations.
GO:0005515 protein binding	IPI PMID:31477895 ER-localized Hrd1 ubiquitinates and inactivates Usp15 to pro...	REMOVE	Summary: IPI for protein binding based on interaction with USP15. PMID:31477895 showed HRD1 ubiquitinates and inactivates USP15 to promote TLR4-induced inflammation during bacterial infection. Reason: Protein binding is uninformative. The interaction reflects an E3 ligase-substrate relationship where HRD1 ubiquitinates USP15.
GO:0005515 protein binding	IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling...	REMOVE	Summary: IPI for protein binding from a dual proteome-scale interactome study. High-throughput interaction data. Reason: Protein binding is uninformative for a protein with well-characterized specific binding activities (E3 ligase activity, ERAD complex formation).
GO:0005515 protein binding	IPI PMID:35271311 OpenCell: Endogenous tagging for the cartography of human ce...	REMOVE	Summary: IPI for protein binding from the OpenCell endogenous tagging study. High-throughput interactome data. Reason: Protein binding is uninformative. More specific functional annotations are available.
GO:0140297 DNA-binding transcription factor binding	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: IEA from Ensembl Compara orthology transfer. SYVN1 ubiquitinates transcription factor substrates such as p53/TP53 (PMID:17170702) and NFE2L1 (by similarity), but this interaction is in the context of E3 ligase-mediated degradation, not transcription factor binding in a transcriptional regulatory sense. SYVN1 also ubiquitinates CREB3L3 (by similarity from mouse). Reason: While SYVN1 does physically interact with transcription factors (p53, NFE2L1, CREB3L3), these are E3 ligase-substrate interactions for ubiquitination and degradation, not transcriptional co-regulatory binding. The term implies a role in transcriptional regulation machinery which is misleading for an ER-resident E3 ligase.
GO:0005654 nucleoplasm	IDA GO_REF:0000052	REMOVE	Summary: IDA from HPA immunofluorescence data. SYVN1 is an ER membrane-resident multi-pass transmembrane protein. Nuclear localization is not expected and is likely an artifact of antibody cross-reactivity or HPA classification methodology. UniProt does not report nuclear localization. Reason: SYVN1 is a 6-transmembrane domain ER-resident protein. Nucleoplasm localization is inconsistent with its established topology and all literature evidence. Likely a high-throughput data artifact from HPA.
GO:0005783 endoplasmic reticulum	IDA GO_REF:0000052	ACCEPT	Summary: IDA from HPA immunofluorescence data. SYVN1 localization to the ER is well-established (PMID:14593114, PMID:12459480). Reason: Consistent with extensive experimental evidence of ER localization. Supporting Evidence: PMID:14593114 We show that human HRD1 is a non-glycosylated, stable ER protein with a cytosolic RING-H2 finger domain.
GO:0005886 plasma membrane	IDA GO_REF:0000052	REMOVE	Summary: IDA from HPA immunofluorescence data for plasma membrane localization. SYVN1 is an ER membrane-resident protein with no known plasma membrane localization in the literature. This is likely a high-throughput data artifact. Reason: SYVN1 is an ER membrane multi-pass transmembrane protein. Plasma membrane localization is not supported by any targeted study and contradicts its established ER-resident function. Likely HPA artifact.
GO:0061630 ubiquitin protein ligase activity	TAS Reactome:R-HSA-8867288	ACCEPT	Summary: TAS from Reactome pathway for ubiquitination of unfolded glycoproteins by the OS9:SEL1:ERAD E3 ligase:DERL2 complex. Consistent with core function. Reason: Reactome pathway annotation consistent with the well-established E3 ligase activity of SYVN1 in the context of ERAD.
GO:0005515 protein binding	IPI PMID:37943610 Hypomorphic variants of SEL1L-HRD1 ER-associated degradation...	REMOVE	Summary: IPI for protein binding from a study on hypomorphic SEL1L-HRD1 variants associated with neurodevelopmental disorders (PMID:37943610). The interaction is between SYVN1 and SEL1L, a functional ERAD complex component relationship. Reason: Protein binding is uninformative. This is a functional HRD1-SEL1L complex interaction already captured by complex annotations.
GO:0000836 Hrd1p ubiquitin ligase complex	IDA PMID:28827405 Conserved cytoplasmic domains promote Hrd1 ubiquitin ligase ...	ACCEPT	Summary: IDA showing SYVN1 is a component of the Hrd1p ubiquitin ligase complex. PMID:28827405 characterized the HRD1 complex composition including SEL1L, FAM8A1, HERPUD1, OS9, and UBE2J1, and showed how conserved cytoplasmic domains promote complex formation. Reason: Core annotation. SYVN1/HRD1 is the central catalytic component of the Hrd1 ubiquitin ligase complex. Supporting Evidence: PMID:28827405 Conserved cytoplasmic domains promote Hrd1 ubiquitin ligase complex formation for ER-associated degradation (ERAD).
GO:0005783 endoplasmic reticulum	IDA PMID:37795761 UFMylation of HRD1 regulates endoplasmic reticulum homeostas...	ACCEPT	Summary: IDA showing SYVN1 localization to the ER from a study on UFMylation of HRD1 (PMID:37795761). Consistent with established localization. Reason: Consistent with the well-established ER localization of SYVN1. Supporting Evidence: PMID:37795761 HRD1, a ubiquitin ligase of ER-associated protein degradation (ERAD), is a novel substrate of UFM1 conjugation.
GO:0016567 protein ubiquitination	IEA GO_REF:0000041	ACCEPT	Summary: IEA from UniPathway vocabulary mapping. Protein ubiquitination is a core process carried out by SYVN1's E3 ligase activity. Reason: Correct electronic annotation for a fundamental process catalyzed by SYVN1.
GO:0006511 ubiquitin-dependent protein catabolic process	IDA PMID:14593114 Human HRD1 is an E3 ubiquitin ligase involved in degradation...	ACCEPT	Summary: IDA showing SYVN1 involvement in ubiquitin-dependent protein catabolism. PMID:14593114 demonstrated HRD1 ubiquitinates ERAD substrates TCR-alpha and CD3-delta with K48-linked polyubiquitin chains targeting them for proteasomal degradation. Reason: Core function directly demonstrated by in vitro and cell-based assays. Supporting Evidence: PMID:14593114 Human HRD1 is an E3 ubiquitin ligase involved in degradation of proteins from the endoplasmic reticulum.
GO:0006511 ubiquitin-dependent protein catabolic process	IDA PMID:17059562 A ubiquitin ligase HRD1 promotes the degradation of Pael rec...	ACCEPT	Summary: IDA showing SYVN1 promotes ubiquitylation and degradation of Pael receptor (GPR37), demonstrating its role in ubiquitin-dependent protein catabolism (PMID:17059562). Reason: Core function demonstrated by showing HRD1 promotes Pael-R ubiquitylation and degradation. Supporting Evidence: PMID:17059562 HRD1 was expressed in substantia nigra pars compacta (SNC) dopaminergic neurons and interacted with Pael-R through the HRD1 proline-rich region, promoting the ubiquitylation and degradation of Pael-R.
GO:0006511 ubiquitin-dependent protein catabolic process	TAS PMID:23710284 Endoplasmic reticulum stress and Parkinson's disease: the ro...	ACCEPT	Summary: TAS from a review on HRD1 role in ER stress and Parkinson's disease. Consistent with core function. Reason: Review article supporting the well-established role of SYVN1 in ubiquitin-dependent protein catabolism.
GO:0036503 ERAD pathway	IDA PMID:14593114 Human HRD1 is an E3 ubiquitin ligase involved in degradation...	ACCEPT	Summary: IDA demonstrating SYVN1 function in the ERAD pathway. PMID:14593114 showed HRD1 mediates degradation of model ERAD substrates TCR-alpha and CD3-delta. Reason: Core function with direct experimental demonstration. Supporting Evidence: PMID:14593114 We show that human HRD1 is involved in the elimination of two model ER-associated degradation substrates, TCR-alpha and CD3-delta.
GO:0036503 ERAD pathway	IDA PMID:17059562 A ubiquitin ligase HRD1 promotes the degradation of Pael rec...	ACCEPT	Summary: IDA demonstrating SYVN1 function in ERAD by promoting ubiquitylation and degradation of the Pael receptor (PMID:17059562). Reason: Core function supported by direct experimental evidence. Supporting Evidence: PMID:17059562 HRD1 promotes the degradation of Pael receptor, a substrate of Parkin.
GO:0036503 ERAD pathway	TAS PMID:22013210 The unfolded protein response: integrating stress signals th...	ACCEPT	Summary: TAS from a review on the unfolded protein response and IRE1alpha. Discusses HRD1 in context of ERAD. Reason: Review article supporting the core ERAD function of SYVN1.
GO:0036503 ERAD pathway	TAS PMID:23710284 Endoplasmic reticulum stress and Parkinson's disease: the ro...	ACCEPT	Summary: TAS from a review on HRD1 in ER stress and Parkinson's disease. Reason: Consistent with core ERAD function.
GO:0061630 ubiquitin protein ligase activity	IDA PMID:14593114 Human HRD1 is an E3 ubiquitin ligase involved in degradation...	ACCEPT	Summary: IDA demonstrating SYVN1 E3 ubiquitin ligase activity. PMID:14593114 showed the RING-H2 finger domain has in vitro ubiquitination activity for K48-linked polyubiquitin chains in the presence of UBC7. Reason: Core molecular function demonstrated by direct in vitro assay. Supporting Evidence: PMID:14593114 In the presence of the ubiquitin-conjugating enzyme UBC7, the RING-H2 finger has in vitro ubiquitination activity for Lys(48)-specific polyubiquitin linkage, suggesting that human HRD1 is an E3 ubiquitin ligase involved in protein degradation
GO:0070936 protein K48-linked ubiquitination	IDA PMID:14593114 Human HRD1 is an E3 ubiquitin ligase involved in degradation...	ACCEPT	Summary: IDA demonstrating that SYVN1 catalyzes K48-linked polyubiquitination. PMID:14593114 directly showed K48-specific ubiquitin linkage by HRD1. K48-linked chains are the canonical signal for proteasomal degradation. Reason: Core annotation with direct biochemical evidence. K48-linked ubiquitination is the mechanism by which SYVN1 targets substrates for proteasomal degradation. Supporting Evidence: PMID:14593114 In the presence of the ubiquitin-conjugating enzyme UBC7, the RING-H2 finger has in vitro ubiquitination activity for Lys(48)-specific polyubiquitin linkage, suggesting that human HRD1 is an E3 ubiquitin ligase involved in protein degradation
GO:1904380 endoplasmic reticulum mannose trimming	TAS Reactome:R-HSA-901032	MARK AS OVER ANNOTATED	Summary: TAS from Reactome for ER mannose trimming. SYVN1/HRD1 is involved in the ERQC pathway where mannose-trimmed glycoproteins are delivered to the HRD1 complex for ERAD (PMID:21062743). However, SYVN1 does not directly perform mannose trimming; it is a downstream recipient of mannose-trimmed substrates. Reason: SYVN1/HRD1 receives mannose-trimmed substrates for ubiquitination but does not itself catalyze mannose trimming. The mannose trimming is performed by ER mannosidases (ERManI). HRD1 functions downstream in the pathway. The annotation conflates the overall ERQC pathway with the specific mannose trimming step. Supporting Evidence: PMID:21062743 In contrast, substrate association with XTP3-B and with the E3 ubiquitin ligases HRD1 and SCF(Fbs2) was inhibited
GO:0044322 endoplasmic reticulum quality control compartment	IDA PMID:23233672 A shared endoplasmic reticulum-associated degradation pathwa...	ACCEPT	Summary: IDA demonstrating SYVN1 localization to the ERQC. PMID:23233672 showed HRD1 colocalizes with ERAD substrates at the ERQC and is recruited there for ubiquitination of both glycosylated and nonglycosylated substrates. Reason: Direct experimental evidence for ERQC localization consistent with SYVN1's ERAD function. Supporting Evidence: PMID:23233672 Proteasomal inhibition induced accumulation of the nonglycosylated proteins and ERAD machinery in the endoplasmic reticulum-derived quality control compartment.
GO:0044322 endoplasmic reticulum quality control compartment	IDA PMID:24478453 Herp coordinates compartmentalization and recruitment of HRD...	ACCEPT	Summary: IDA demonstrating SYVN1 recruitment to the ERQC by Herp/HERPUD1. PMID:24478453 showed Herp coordinates HRD1 compartmentalization at the ERQC for ERAD substrate processing. Reason: Direct experimental evidence for ERQC localization. Supporting Evidence: PMID:24478453 Herp localizes to the ERQC, and our results suggest that it recruits HRD1, which targets to ERAD the substrate presented by the OS-9 lectin at the ERQC.
GO:0061630 ubiquitin protein ligase activity	IMP PMID:28842558 HSP70-Hrd1 axis precludes the oncorepressor potential of N-t...	ACCEPT	Summary: IMP demonstrating SYVN1 E3 ligase activity through degradation of misfolded N-terminal Blimp-1 mutants in lymphoma cells. PMID:28842558 showed that Hrd1-mediated cytoplasmic sequestration and ubiquitination accelerates degradation of lymphoma-associated Blimp-1 mutants. Reason: Core molecular function demonstrated by mutant phenotype analysis in the context of lymphoma pathogenesis. Supporting Evidence: PMID:28842558 The degradation of lymphoma-associated mutants is accelerated by subversion of this pathway to Hrd1-mediated cytoplasmic sequestration and ubiquitination.
GO:0002327 immature B cell differentiation	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: ISS annotation transferred from mouse ortholog. UniProt notes that in early B cell development, HRD1 is required for degradation of the pre-BCR complex, supporting further differentiation into mature B cells (by similarity with mouse Q9DBY1). Reason: Based on mouse ortholog data showing HRD1 is required for pre-BCR degradation during B cell development. This is a tissue-specific developmental role downstream of SYVN1's core E3 ligase activity, not a core function of the protein itself.
GO:0000839 Hrd1p ubiquitin ligase ERAD-L complex	IDA PMID:28827405 Conserved cytoplasmic domains promote Hrd1 ubiquitin ligase ...	ACCEPT	Summary: IDA showing SYVN1 is a component of the ERAD-L complex, which handles luminal ERAD substrates. PMID:28827405 characterized HRD1 complex assembly including the luminal substrate recognition machinery. Reason: Core annotation. SYVN1/HRD1 is the central E3 ligase of both the Hrd1 complex and its ERAD-L subcomplex. Supporting Evidence: PMID:28827405 Conserved cytoplasmic domains promote Hrd1 ubiquitin ligase complex formation for ER-associated degradation (ERAD).
GO:0036503 ERAD pathway	IMP PMID:28827405 Conserved cytoplasmic domains promote Hrd1 ubiquitin ligase ...	ACCEPT	Summary: IMP demonstrating SYVN1 function in ERAD. PMID:28827405 showed that mutation of HRD1 cytoplasmic domains impairs ERAD substrate degradation. Reason: Core function demonstrated by mutant phenotype analysis.
GO:0050821 protein stabilization	IMP PMID:21454652 SEL1L protein critically determines the stability of the HRD...	KEEP AS NON CORE	Summary: IMP showing HRD1 stabilizes SEL1L. PMID:21454652 demonstrated that SEL1L half-life was greatly reduced when HRD1 was silenced, and transiently expressed SEL1L was stabilized when HRD1 was coexpressed. This is a secondary consequence of HRD1-SEL1L complex formation. Reason: While experimentally validated, protein stabilization of SEL1L is a secondary consequence of ERAD complex assembly, not a core function of the E3 ligase. SYVN1's primary role is protein degradation, not stabilization. Supporting Evidence: PMID:21454652 Although endogenous SEL1L is a long-lived protein, the half-life of SEL1L was greatly reduced when HRD1 is silenced. Conversely, transiently expressed SEL1L was rapidly degraded but was stabilized when HRD1 was coexpressed.
GO:0000839 Hrd1p ubiquitin ligase ERAD-L complex	IMP PMID:26471130 Association of the SEL1L protein transmembrane domain with H...	ACCEPT	Summary: IMP showing SYVN1 forms the ERAD-L complex dependent on SEL1L transmembrane domain interaction. PMID:26471130 demonstrated that SEL1L TM domain association with HRD1 regulates ERAD-L. Reason: Core complex annotation supported by mutant phenotype analysis. Supporting Evidence: PMID:26471130 Association of the SEL1L protein transmembrane domain with HRD1 ubiquitin ligase regulates ERAD-L.
GO:0005515 protein binding	IPI PMID:26471130 Association of the SEL1L protein transmembrane domain with H...	REMOVE	Summary: IPI for protein binding based on interaction with SEL1L. This is a functional complex component interaction within the ERAD machinery. Reason: Protein binding is uninformative. The SEL1L interaction is a functional ERAD complex assembly interaction already captured by Hrd1p ubiquitin ligase complex annotations.
GO:0036503 ERAD pathway	IMP PMID:26471130 Association of the SEL1L protein transmembrane domain with H...	ACCEPT	Summary: IMP demonstrating SYVN1 function in ERAD, showing SEL1L TM domain interaction with HRD1 is required for ERAD-L function. Reason: Core function supported by mutant phenotype analysis.
GO:0005789 endoplasmic reticulum membrane	NAS PMID:14593114 Human HRD1 is an E3 ubiquitin ligase involved in degradation...	ACCEPT	Summary: NAS annotation for ER membrane localization from PMID:14593114. The paper directly demonstrated that HRD1 is an ER-resident protein with multiple transmembrane domains. Reason: Correct annotation well-supported by the cited reference and consistent with extensive experimental evidence. Supporting Evidence: PMID:14593114 We show that human HRD1 is a non-glycosylated, stable ER protein with a cytosolic RING-H2 finger domain.
GO:0000836 Hrd1p ubiquitin ligase complex	TAS PMID:21454652 SEL1L protein critically determines the stability of the HRD...	ACCEPT	Summary: TAS for Hrd1 ubiquitin ligase complex from PMID:21454652. This study characterized the endogenous HRD1-SEL1L complex (Complex I) and its association with ERAD components including OS-9, Derlin-1/2, VIMP, and Herp. Reason: Core complex annotation supported by the cited study. Supporting Evidence: PMID:21454652 Endogenous HRD1-SEL1L formed a large ERAD complex (Complex I) associating with numerous ERAD components including ERAD lectin OS-9, membrane-spanning Derlin-1/2, VIMP, and Herp, whereas transiently expressed HRD1-SEL1L formed a smaller complex (Complex II) that was associated with OS-9 but not with Derlin-1/2, VIMP, or Herp
GO:0036513 Derlin-1 retrotranslocation complex	IDA PMID:21454652 SEL1L protein critically determines the stability of the HRD...	ACCEPT	Summary: IDA showing SYVN1 is a component of the Derlin-1 retrotranslocation complex. PMID:21454652 demonstrated that the endogenous HRD1-SEL1L complex associates with Derlin-1 in the retrotranslocation machinery. Reason: Well-supported by experimental evidence. SYVN1 functions together with Derlin-1 in the retrotranslocation channel for ERAD substrates. Supporting Evidence: PMID:21454652 Endogenous HRD1-SEL1L formed a large ERAD complex (Complex I) associating with numerous ERAD components including ERAD lectin OS-9, membrane-spanning Derlin-1/2, VIMP, and Herp, whereas transiently expressed HRD1-SEL1L formed a smaller complex (Complex II) that was associated with OS-9 but not with Derlin-1/2, VIMP, or Herp
GO:0016567 protein ubiquitination	IDA PMID:22590560 Ubiquitin-specific protease 25 functions in Endoplasmic Reti...	ACCEPT	Summary: IDA demonstrating SYVN1 catalyzes protein ubiquitination. PMID:22590560 showed HRD1 increases ubiquitination of CD3delta and that USP25 counteracts this by deubiquitinating HRD1-associated ubiquitinated species. Reason: Core function with direct experimental evidence. Supporting Evidence: PMID:22590560 HRD1 increases ubiquitination of CD3δ in cells. The presence of USP25 significantly reduces levels of ubiquitinated CD3δ
GO:0036503 ERAD pathway	IDA PMID:22590560 Ubiquitin-specific protease 25 functions in Endoplasmic Reti...	ACCEPT	Summary: IDA for ERAD pathway from PMID:22590560. The study demonstrates HRD1 as an ERAD component by showing it ubiquitinates ERAD substrates and interacts with other ERAD components VCP and USP25. Reason: Core function supported by experimental evidence.
GO:0051117 ATPase binding	IPI PMID:22590560 Ubiquitin-specific protease 25 functions in Endoplasmic Reti...	ACCEPT	Summary: IPI showing SYVN1 interacts with the AAA ATPase VCP/p97. PMID:22590560 demonstrated co-immunoprecipitation of HRD1 with VCP. This functional interaction is essential for ERAD substrate extraction from the ER membrane. Reason: Functionally informative binding annotation. VCP/p97 interaction is essential for SYVN1's ERAD function, coupling ubiquitination to substrate extraction. Supporting Evidence: PMID:22590560 Conversely, HRD1 interacts with USP25 and VCP/p97 (Figure 1D)
GO:0061630 ubiquitin protein ligase activity	NAS PMID:22590560 Ubiquitin-specific protease 25 functions in Endoplasmic Reti...	ACCEPT	Summary: NAS for ubiquitin protein ligase activity from PMID:22590560. The paper describes HRD1 as an ER-resident ubiquitin ligase throughout. Reason: Consistent with core molecular function.
GO:1990381 ubiquitin-specific protease binding	IPI PMID:22590560 Ubiquitin-specific protease 25 functions in Endoplasmic Reti...	ACCEPT	Summary: IPI showing SYVN1 interacts with USP25. PMID:22590560 demonstrated co-immunoprecipitation of endogenous HRD1 with USP25. USP25 counteracts HRD1 ubiquitination of ERAD substrates. Reason: Functionally informative binding annotation. USP25 interaction represents a regulatory mechanism for HRD1's E3 ligase activity in ERAD. Supporting Evidence: PMID:22590560 Importantly, HRD1 and endogenous USP25 interact in cells (Figure 1E), but USP25 does not interact with other ubiquitin ligases implicated in ERAD
GO:0044322 endoplasmic reticulum quality control compartment	TAS PMID:21062743 Mannose trimming is required for delivery of a glycoprotein ...	ACCEPT	Summary: TAS for ERQC localization from PMID:21062743. This study showed HRD1 association with ERAD substrates at the ERQC depends on mannose trimming. Reason: Consistent with HRD1's established ERQC localization. Supporting Evidence: PMID:21062743 In contrast, substrate association with XTP3-B and with the E3 ubiquitin ligases HRD1 and SCF(Fbs2) was inhibited
GO:0061630 ubiquitin protein ligase activity	TAS PMID:21062743 Mannose trimming is required for delivery of a glycoprotein ...	ACCEPT	Summary: TAS for ubiquitin protein ligase activity from PMID:21062743. The paper references HRD1 as an E3 ubiquitin ligase in the context of mannose trimming-dependent ERAD. Reason: Consistent with core molecular function.
GO:0005515 protein binding	IPI PMID:24068323 A deubiquitinase negatively regulates retro-translocation of...	REMOVE	Summary: IPI for protein binding from a study on the deubiquitinase YOD1 and retrotranslocation of nonubiquitinated substrates (PMID:24068323). Reason: Protein binding is uninformative. Already captured by more specific ubiquitin-specific protease binding annotations.
GO:1990381 ubiquitin-specific protease binding	IPI PMID:24068323 A deubiquitinase negatively regulates retro-translocation of...	ACCEPT	Summary: IPI showing SYVN1 interacts with the deubiquitinase YOD1. PMID:24068323 demonstrated that YOD1 negatively controls retrotranslocation of ERAD substrates by acting on ERAD components including HRD1. Reason: Functionally informative binding annotation. YOD1 is an ERAD-associated DUB that acts on the HRD1 complex machinery.
GO:0005783 endoplasmic reticulum	IDA PMID:14593114 Human HRD1 is an E3 ubiquitin ligase involved in degradation...	ACCEPT	Summary: IDA demonstrating SYVN1 localization to the ER. PMID:14593114 showed HRD1 is a stable ER protein using immunofluorescence and biochemical fractionation. Reason: Core localization with direct experimental evidence. Supporting Evidence: PMID:14593114 We show that human HRD1 is a non-glycosylated, stable ER protein with a cytosolic RING-H2 finger domain.
GO:0005783 endoplasmic reticulum	IDA PMID:17059562 A ubiquitin ligase HRD1 promotes the degradation of Pael rec...	ACCEPT	Summary: IDA demonstrating SYVN1 localization to the ER from PMID:17059562. Consistent with established localization. Reason: Core localization confirmed by immunofluorescence.
GO:0051082 unfolded protein binding	IPI PMID:17059562 A ubiquitin ligase HRD1 promotes the degradation of Pael rec...	REMOVE	Summary: This annotation was made because HRD1 physically interacts with the Pael receptor (GPR37, UniProtKB:O15354), which is a misfolded protein substrate. However, GO:0051082 (unfolded protein binding) is now formally obsolete (go-ontology#30962) and is defined in the context of chaperone-like activity that assists in protein folding. SYVN1/HRD1 is an E3 ubiquitin ligase; its interaction with misfolded substrates serves the purpose of substrate recognition for ubiquitylation and subsequent proteasomal degradation via ERAD, not to assist in protein folding. The paper (PMID:17059562) clearly demonstrates that HRD1 promotes ubiquitylation and degradation of Pael-R, functioning as an E3 ligase in the ERAD pathway. This is analogous to the case of yeast SAN1, discussed in go-ontology#30962, which recognizes misfolded proteins as a ubiquitin ligase rather than as a chaperone. The correct molecular function for SYVN1 is ubiquitin protein ligase activity (GO:0061630), which is already well-annotated with multiple lines of experimental evidence (IDA from PMID:14593114, PMID:17059562, PMID:12459480, and others). Reason: SYVN1/HRD1 is an E3 ubiquitin-protein ligase, not a chaperone. Its physical interaction with the misfolded Pael receptor (PMID:17059562) is substrate recognition for ERAD-mediated ubiquitylation and degradation, not chaperone-mediated unfolded protein binding. The term GO:0051082 is now formally obsolete (go-ontology#30962) because it conflates substrate recognition by ubiquitin ligases with chaperone-mediated binding. The correct annotation for SYVN1 is ubiquitin protein ligase activity (GO:0061630), which it already has from multiple experimental sources. Supporting Evidence: PMID:17059562 HRD1 was expressed in substantia nigra pars compacta (SNC) dopaminergic neurons and interacted with Pael-R through the HRD1 proline-rich region, promoting the ubiquitylation and degradation of Pael-R.
GO:0051087 protein-folding chaperone binding	IPI PMID:21636303 A ubiquitin ligase-associated chaperone holdase maintains po...	ACCEPT	Summary: IPI showing SYVN1 interacts with the chaperone holdase BAG6. PMID:21636303 demonstrated that BAG6 forms a complex with HRD1 to maintain retrotranslocated polypeptides in soluble states for proteasome degradation. BAG6 is a chaperone holdase that associates with the HRD1 E3 ligase complex. Reason: Functionally informative binding annotation. BAG6 is a bona fide chaperone holdase (not just a chaperone client), and its binding to HRD1 is essential for maintaining ERAD substrate solubility during retrotranslocation. Supporting Evidence: PMID:21636303 We identify a ubiquitin ligase-associated multiprotein complex comprising Bag6, Ubl4A, and Trc35, which chaperones retrotranslocated polypeptides en route to the proteasome to improve ERAD efficiency.
GO:0061630 ubiquitin protein ligase activity	IDA PMID:17059562 A ubiquitin ligase HRD1 promotes the degradation of Pael rec...	ACCEPT	Summary: IDA demonstrating SYVN1 E3 ligase activity. PMID:17059562 showed HRD1 promotes ubiquitylation and degradation of Pael-R, with RING finger activity required. Reason: Core molecular function with direct experimental evidence. Supporting Evidence: PMID:17059562 This study shows that HRD1 was expressed in substantia nigra pars compacta (SNC) dopaminergic neurons and interacted with Pael-R through the HRD1 proline-rich region, promoting the ubiquitylation and degradation of Pael-R
GO:1902236 negative regulation of endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway	IDA PMID:17059562 A ubiquitin ligase HRD1 promotes the degradation of Pael rec...	ACCEPT	Summary: IDA showing SYVN1 protects against ER stress-induced apoptosis. PMID:17059562 demonstrated that HRD1 knockdown induces Pael-R accumulation and caspase-3 activation, while HRD1 expression prevents ER stress-induced cell death in neurons. Reason: Well-supported annotation. HRD1 protects against ER stress-induced apoptosis by promoting degradation of toxic misfolded substrates. Supporting Evidence: PMID:17059562 The disruption of endogenous HRD1 by small interfering RNA (siRNA) induced Pael-R accumulation and caspase-3 activation.
GO:0030970 retrograde protein transport, ER to cytosol	IMP PMID:25660456 Identification of ERAD components essential for dislocation ...	ACCEPT	Summary: IMP showing SYVN1 is required for retrotranslocation (dislocation) of the ERAD substrate NHK (null Hong Kong variant of alpha-1-antitrypsin) from the ER to the cytosol. SYVN1/HRD1 forms part of the retrotranslocation channel and its ubiquitination activity is coupled to substrate extraction. Reason: SYVN1 functions as part of the retrotranslocation channel, and its E3 ligase activity is essential for substrate dislocation from the ER to the cytosol. Recent cryo-EM structures confirm HRD1 forms the protein-conducting channel.
GO:0005790 smooth endoplasmic reticulum	IDA PMID:16186510 Recruitment of the p97 ATPase and ubiquitin ligases to the s...	ACCEPT	Summary: IDA showing SYVN1 localizes to smooth ER. PMID:16186510 demonstrated that HRD1 and VCP/p97 are recruited to the site of retrotranslocation at the ER membrane. The smooth ER designation may reflect ER subdomains involved in retrotranslocation. Reason: Experimentally supported localization consistent with retrotranslocation sites at the ER membrane.
GO:0051117 ATPase binding	IPI PMID:16186510 Recruitment of the p97 ATPase and ubiquitin ligases to the s...	ACCEPT	Summary: IPI showing SYVN1 interacts with the p97/VCP ATPase. PMID:16186510 demonstrated that p97 interacts directly with several ubiquitin ligases including HRD1 and facilitates their recruitment to Derlin-1. Reason: Functionally informative binding annotation. VCP/p97 is the essential ATPase that provides the mechanical force for substrate extraction in ERAD, coupled to HRD1's ubiquitination activity. Supporting Evidence: PMID:16186510 p97 interacts directly with several ubiquitin ligases and facilitates their recruitment to Derlin-1.
GO:0016567 protein ubiquitination	IDA PMID:12459480 Human HRD1 protects against ER stress-induced apoptosis thro...	ACCEPT	Summary: IDA demonstrating SYVN1 catalyzes protein ubiquitination. PMID:12459480 showed human HRD1 was localized to the ER and ubiquitinated its substrates, and that the C329S RING finger mutant lacked this activity. Reason: Core function with direct experimental evidence including mutant analysis. Supporting Evidence: PMID:12459480 Human HRD1 was localized to the ER and ubiquitinated its substrates.
GO:0061630 ubiquitin protein ligase activity	IDA PMID:12459480 Human HRD1 protects against ER stress-induced apoptosis thro...	ACCEPT	Summary: IDA demonstrating SYVN1 E3 ubiquitin ligase activity. PMID:12459480 showed HRD1 acts as a ubiquitin ligase with a RING finger motif, and the C329S mutant abolishes activity. Reason: Core molecular function with direct evidence including mutagenesis. Supporting Evidence: PMID:12459480 Yeast Hrd1p is an ER stress-inducible ER membrane protein that acts as a ubiquitin ligase (E3) with a RING finger motif and plays a role in the ubiquitination of proteins in the ER.
GO:1902236 negative regulation of endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway	IDA PMID:12459480 Human HRD1 protects against ER stress-induced apoptosis thro...	ACCEPT	Summary: IDA showing SYVN1 protects against ER stress-induced apoptosis. PMID:12459480 demonstrated that HRD1 wild-type (but not C329S mutant) confers resistance to ER stress-induced apoptosis. Reason: Well-supported annotation from the foundational paper on HRD1's anti-apoptotic function. Requires E3 ligase activity (RING finger). Supporting Evidence: PMID:12459480 293 cells stably expressing wild-type HRD1, but not the C329S mutant, afforded resistance to ER stress-induced apoptosis.
GO:0000836 Hrd1p ubiquitin ligase complex	TAS PMID:23710284 Endoplasmic reticulum stress and Parkinson's disease: the ro...	ACCEPT	Summary: TAS for Hrd1 ubiquitin ligase complex from a review on HRD1 in ER stress and Parkinson's disease. Reason: Consistent with core complex annotation.
GO:0005783 endoplasmic reticulum	TAS PMID:23710284 Endoplasmic reticulum stress and Parkinson's disease: the ro...	ACCEPT	Summary: TAS for ER localization from a review on HRD1 in Parkinson's disease. Reason: Consistent with established ER localization.
GO:0016567 protein ubiquitination	TAS PMID:23710284 Endoplasmic reticulum stress and Parkinson's disease: the ro...	ACCEPT	Summary: TAS for protein ubiquitination from a review discussing HRD1's E3 ligase function. Reason: Consistent with core function.
GO:0061630 ubiquitin protein ligase activity	TAS PMID:23710284 Endoplasmic reticulum stress and Parkinson's disease: the ro...	ACCEPT	Summary: TAS for ubiquitin protein ligase activity from a review on HRD1. Reason: Consistent with core molecular function.
GO:1902236 negative regulation of endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway	TAS PMID:23710284 Endoplasmic reticulum stress and Parkinson's disease: the ro...	ACCEPT	Summary: TAS for anti-apoptotic signaling from a review on HRD1 in ER stress and Parkinson's disease. The review discusses how HRD1 averts apoptosis in neurodegenerative disease. Reason: Consistent with HRD1's established anti-apoptotic function.
GO:0005515 protein binding	IPI PMID:19135427 USP14 inhibits ER-associated degradation via interaction wit...	REMOVE	Summary: IPI for protein binding from a study on USP14 inhibiting ERAD via interaction with IRE1alpha (PMID:19135427). The interaction with HRD1 is in the context of ERAD regulation. Reason: Protein binding is uninformative. The interaction reflects ERAD regulatory mechanisms already captured by ERAD pathway and complex annotations.
GO:0036503 ERAD pathway	IMP PMID:21245296 HRD1 and UBE2J1 target misfolded MHC class I heavy chains fo...	ACCEPT	Summary: IMP demonstrating SYVN1 is required for ERAD of misfolded MHC class I heavy chains. PMID:21245296 used siRNA functional screening to identify HRD1 as essential for ubiquitination and dislocation of misfolded MHC class I heavy chains. Reason: Core function demonstrated by loss-of-function analysis in a physiologically important ERAD substrate pathway. Supporting Evidence: PMID:21245296 Using an siRNA functional screen in beta2m-depleted cells, we identify an essential role for the E3 ligase HRD1 (Synoviolin) together with the E2 ubiquitin-conjugating enzyme UBE2J1 in the ubiquitination and dislocation of misfolded MHC class I heavy chains.
GO:0061630 ubiquitin protein ligase activity	IMP PMID:21245296 HRD1 and UBE2J1 target misfolded MHC class I heavy chains fo...	ACCEPT	Summary: IMP demonstrating SYVN1 E3 ligase activity in ubiquitinating misfolded MHC class I heavy chains. PMID:21245296 showed HRD1 depletion prevents MHC class I ubiquitination and degradation. Reason: Core molecular function demonstrated by loss-of-function analysis. Supporting Evidence: PMID:21245296 HRD1 is also required for the ubiquitination and degradation of the naturally occurring hemochromatosis-associated HFE-C282Y mutant, which is unable to bind β2m
GO:0061630 ubiquitin protein ligase activity	IDA PMID:19103148 CYP3A4 ubiquitination by gp78 (the tumor autocrine motility ...	UNDECIDED	Summary: IDA for ubiquitin protein ligase activity from PMID:19103148. However, this paper is about CYP3A4 ubiquitination by gp78 and CHIP, not HRD1. The reference may be incorrectly assigned to SYVN1, or HRD1 may be mentioned as a comparator. Reason: The cited reference (PMID:19103148) primarily studies gp78 and CHIP E3 ligases in CYP3A4 ubiquitination, not HRD1. Unable to verify specific relevance to SYVN1 without full text access.
GO:0016020 membrane	HDA PMID:19946888 Defining the membrane proteome of NK cells.	ACCEPT	Summary: HDA annotation from a proteomics study defining the membrane proteome of NK cells. SYVN1 is indeed a multi-pass transmembrane protein. Reason: Correct but very broad. SYVN1 is a multi-pass transmembrane protein. More specific ER membrane annotations are already present.
GO:0005515 protein binding	IPI PMID:21949850 The tissue-specific Rep8/UBXD6 tethers p97 to the endoplasmi...	REMOVE	Summary: IPI for protein binding from a study on Rep8/UBXD6 tethering p97 to the ER membrane (PMID:21949850). HRD1 interaction with UBXD6 is in the context of p97-dependent ERAD. Reason: Protein binding is uninformative. The interaction is within the ERAD machinery context already captured by more specific annotations.
GO:0005789 endoplasmic reticulum membrane	TAS Reactome:R-HSA-1791084	ACCEPT	Summary: TAS from Reactome for expression of SYVN1 at the ER membrane. Reason: Correct annotation consistent with ER membrane localization.
GO:0005789 endoplasmic reticulum membrane	TAS Reactome:R-HSA-5362412	ACCEPT	Summary: TAS from Reactome for SYVN1 ubiquitination of Hedgehog C-terminal fragments at the ER membrane. Reason: Correct annotation in context of Hedgehog processing ERAD pathway.
GO:0005789 endoplasmic reticulum membrane	TAS Reactome:R-HSA-5362441	ACCEPT	Summary: TAS from Reactome for recruitment of Hedgehog fragments to SEL1:SYVN1 at the ER membrane. Reason: Correct annotation.
GO:0005789 endoplasmic reticulum membrane	TAS Reactome:R-HSA-5362459	ACCEPT	Summary: TAS from Reactome for VCP-catalyzed translocation of Hedgehog-C at the ER membrane. Reason: Correct annotation.
GO:0005789 endoplasmic reticulum membrane	TAS Reactome:R-HSA-5387386	ACCEPT	Summary: TAS from Reactome for recruitment of Hedgehog processing variants to SEL1:SYVN at the ER membrane. Reason: Correct annotation.
GO:0005789 endoplasmic reticulum membrane	TAS Reactome:R-HSA-5387389	ACCEPT	Summary: TAS from Reactome for VCP-dependent translocation of Hedgehog processing variants at the ER membrane. Reason: Correct annotation.
GO:0005789 endoplasmic reticulum membrane	TAS Reactome:R-HSA-5483238	ACCEPT	Summary: TAS from Reactome for ubiquitination of Hedgehog processing variants at the ER membrane. Reason: Correct annotation.
GO:0005789 endoplasmic reticulum membrane	TAS Reactome:R-HSA-8867288	ACCEPT	Summary: TAS from Reactome for OS9:SEL1:ERAD E3 ligase:DERL2 ubiquitination of unfolded glycoproteins at the ER membrane. Reason: Correct annotation.
GO:0036503 ERAD pathway	IMP PMID:22607976 STT3B-dependent posttranslational N-glycosylation as a surve...	ACCEPT	Summary: IMP demonstrating SYVN1 function in ERAD. PMID:22607976 studied STT3B-dependent posttranslational N-glycosylation as an ERAD surveillance system and showed HRD1 involvement in degradation of misfolded transthyretin. Reason: Core function demonstrated in the context of glycosylation-dependent ERAD quality control.
GO:0005515 protein binding	IPI PMID:18502753 Human XTP3-B forms an endoplasmic reticulum quality control ...	REMOVE	Summary: IPI for protein binding from a study on XTP3-B/ERLEC1 forming an ERQC scaffold with the HRD1-SEL1L complex and BiP (PMID:18502753). Reason: Protein binding is uninformative. The interaction is a functional ERAD complex assembly already captured by Hrd1 complex and ERQC annotations.
GO:0005515 protein binding	IPI PMID:18264092 OS-9 and GRP94 deliver mutant alpha1-antitrypsin to the Hrd1...	REMOVE	Summary: IPI for protein binding from a study on OS-9 and GRP94 delivering mutant alpha1-antitrypsin to the Hrd1-SEL1L complex (PMID:18264092). Reason: Protein binding is uninformative. The interaction is functional ERAD substrate delivery to the HRD1 complex.
GO:0005783 endoplasmic reticulum	IDA PMID:12459480 Human HRD1 protects against ER stress-induced apoptosis thro...	ACCEPT	Summary: IDA demonstrating SYVN1 localization to the ER. PMID:12459480 showed HRD1 was localized to the ER by immunofluorescence. Reason: Core localization with direct experimental evidence. Supporting Evidence: PMID:12459480 Human HRD1 was localized to the ER and ubiquitinated its substrates.
GO:0036503 ERAD pathway	IDA PMID:12459480 Human HRD1 protects against ER stress-induced apoptosis thro...	ACCEPT	Summary: IDA demonstrating SYVN1 function in the ERAD pathway. PMID:12459480 showed HRD1 protects against ER stress through ER-associated degradation. Reason: Core function from the foundational paper on human HRD1. Supporting Evidence: PMID:12459480 Human HRD1 protects against ER stress-induced apoptosis through ER-associated degradation.

Gene Description

Existing Annotations Review

Core Functions

References

Deep Research

Falcon

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