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 being obsoleted (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 being obsoleted (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.

Core Functions

SYVN1/HRD1 is the central E3 ubiquitin-protein ligase of the ERAD pathway, representing the most conserved branch of mammalian ERAD. Its RING-H2 zinc finger domain catalyzes K48-linked polyubiquitination of misfolded ER substrates (including TCR-alpha, CD3-delta, Pael-R, MHC class I heavy chains, IRE1alpha, and APOB), targeting them for VCP/p97-dependent retrotranslocation and proteasomal degradation. Physical SEL1L-HRD1 interaction is required for recruitment of the E2 enzyme UBE2J1 and DERLIN proteins to form a functional ERAD complex (DOI:10.1038/s41467-024-45633-0). SYVN1 also forms the retrotranslocation channel and protects cells from ER stress-induced apoptosis. Hypomorphic SYVN1 variants cause impaired ERAD substrate clearance and are associated with neurodevelopmental disorders in humans (DOI:10.1172/jci170054). Beyond ERAD, SYVN1 ubiquitinates regulatory substrates including SIRT2 (modulating ER stress/EMT in airway remodeling), GSDMD (modulating inflammasome/pyroptosis), and HMGB1 (DOI:10.1186/s40659-023-00478-7, DOI:10.1002/iid3.880).

Molecular Function:

ubiquitin protein ligase activity

Directly Involved In:

ERAD pathway protein K48-linked ubiquitination retrograde protein transport, ER to cytosol negative regulation of endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway

Cellular Locations:

endoplasmic reticulum membrane endoplasmic reticulum quality control compartment

In Complex:

Hrd1p ubiquitin ligase complex

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
PMID:12459480
293 cells stably expressing wild-type HRD1, but not the C329S mutant, afforded resistance to ER stress-induced apoptosis.
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

References

GO_REF:0000003

Gene Ontology annotation based on Enzyme Commission mapping

GO_REF:0000024

Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity

GO_REF:0000033

Annotation inferences using phylogenetic trees

GO_REF:0000041

Gene Ontology annotation based on UniPathway vocabulary mapping

GO_REF:0000043

Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping

GO_REF:0000044

Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt

GO_REF:0000052

Gene Ontology annotation based on curation of immunofluorescence data

GO_REF:0000107

Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara

GO_REF:0000117

Electronic Gene Ontology annotations created by ARBA machine learning models

PMID:12459480

Human HRD1 protects against ER stress-induced apoptosis through ER-associated degradation.

PMID:14593114

Human HRD1 is an E3 ubiquitin ligase involved in degradation of proteins from the endoplasmic reticulum.

PMID:16186510

Recruitment of the p97 ATPase and ubiquitin ligases to the site of retrotranslocation at the endoplasmic reticulum membrane.

PMID:17059562

A ubiquitin ligase HRD1 promotes the degradation of Pael receptor, a substrate of Parkin.

PMID:17170702

Cytoplasmic destruction of p53 by the endoplasmic reticulum-resident ubiquitin ligase 'Synoviolin'.

PMID:18264092

OS-9 and GRP94 deliver mutant alpha1-antitrypsin to the Hrd1-SEL1L ubiquitin ligase complex for ERAD.

PMID:18369366

Synoviolin promotes IRE1 ubiquitination and degradation in synovial fibroblasts from mice with collagen-induced arthritis.

PMID:18502753

Human XTP3-B forms an endoplasmic reticulum quality control scaffold with the HRD1-SEL1L ubiquitin ligase complex and BiP.

PMID:19103148

CYP3A4 ubiquitination by gp78 (the tumor autocrine motility factor receptor, AMFR) and CHIP E3 ligases.

PMID:19135427

USP14 inhibits ER-associated degradation via interaction with IRE1alpha.

PMID:19690564

A comprehensive framework of E2-RING E3 interactions of the human ubiquitin-proteasome system.

PMID:19946888

Defining the membrane proteome of NK cells.

PMID:21062743

Mannose trimming is required for delivery of a glycoprotein from EDEM1 to XTP3-B and to late endoplasmic reticulum-associated degradation steps.

PMID:21245296

HRD1 and UBE2J1 target misfolded MHC class I heavy chains for endoplasmic reticulum-associated degradation.

PMID:21343306

Membrane-associated ubiquitin ligase complex containing gp78 mediates sterol-accelerated degradation of 3-hydroxy-3-methylglutaryl-coenzyme A reductase.

PMID:21454652

SEL1L protein critically determines the stability of the HRD1-SEL1L endoplasmic reticulum-associated degradation (ERAD) complex to optimize the degradation kinetics of ERAD substrates.

PMID:21636303

A ubiquitin ligase-associated chaperone holdase maintains polypeptides in soluble states for proteasome degradation.

PMID:21949850

The tissue-specific Rep8/UBXD6 tethers p97 to the endoplasmic reticulum membrane for degradation of misfolded proteins.

PMID:22013210

The unfolded protein response: integrating stress signals through the stress sensor IRE1α.

PMID:22119785

Defining human ERAD networks through an integrative mapping strategy.

PMID:22590560

Ubiquitin-specific protease 25 functions in Endoplasmic Reticulum-associated degradation.

PMID:22607976

STT3B-dependent posttranslational N-glycosylation as a surveillance system for secretory protein.

PMID:23233672

A shared endoplasmic reticulum-associated degradation pathway involving the EDEM1 protein for glycosylated and nonglycosylated proteins.

PMID:23710284

Endoplasmic reticulum stress and Parkinson's disease: the role of HRD1 in averting apoptosis in neurodegenerative disease.

PMID:24068323

A deubiquitinase negatively regulates retro-translocation of nonubiquitinated substrates.

PMID:24478453

Herp coordinates compartmentalization and recruitment of HRD1 and misfolded proteins for ERAD.

PMID:25660456

Identification of ERAD components essential for dislocation of the null Hong Kong variant of α-1-antitrypsin (NHK).

PMID:26471130

Association of the SEL1L protein transmembrane domain with HRD1 ubiquitin ligase regulates ERAD-L.

PMID:26551274

IRE1α is an endogenous substrate of endoplasmic-reticulum-associated degradation.

PMID:28827405

Conserved cytoplasmic domains promote Hrd1 ubiquitin ligase complex formation for ER-associated degradation (ERAD).

PMID:28842558

HSP70-Hrd1 axis precludes the oncorepressor potential of N-terminal misfolded Blimp-1s in lymphoma cells.

PMID:31477895

ER-localized Hrd1 ubiquitinates and inactivates Usp15 to promote TLR4-induced inflammation during bacterial infection.

PMID:33961781

Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.

PMID:35271311

OpenCell: Endogenous tagging for the cartography of human cellular organization.

PMID:37795761

UFMylation of HRD1 regulates endoplasmic reticulum homeostasis.

PMID:37943610

Hypomorphic variants of SEL1L-HRD1 ER-associated degradation are associated with neurodevelopmental disorders.

Reactome:R-HSA-1791084

Expression of SYVN1 (HRD1)

Reactome:R-HSA-5362412

SYVN1 ubiquitinates Hh C-terminal fragments

Reactome:R-HSA-5362441

C-terminal Hh fragments are recruited to SEL1:SYVN1 at the ER membrane

Reactome:R-HSA-5362459

VCP-catalyzed ATP hydrolysis promotes the translocation of Hh-C into the cytosol

Reactome:R-HSA-5387386

Hh processing variants are recruited to SEL1:SYVN at the ER membrane

Reactome:R-HSA-5387389

Hh processing variants are translocated to the cytosol in a VCP-dependent manner

Reactome:R-HSA-5483238

Hh processing variants are ubiquitinated

Reactome:R-HSA-8867288

OS9:SEL1:ERAD E3 ligase:DERL2 ubiquitinates unfolded protein:(GlcNAc)2 (Man)9-5

Reactome:R-HSA-901032

ER Quality Control Compartment (ERQC)

DOI:10.1038/s41467-024-45633-0

SEL1L-HRD1 interaction is required to form a functional HRD1 ERAD complex.

SEL1L-HRD1 physical interaction is a prerequisite for recruitment of E2 UBE2J1 and DERLIN proteins to HRD1, assembling a functional ERAD complex
SEL1L hypomorphic variant S658P weakens SEL1L-HRD1 interaction (~5-fold) and causes partial embryonic lethality and cerebellar ataxia in mice

DOI:10.1172/jci170054

Hypomorphic variants of SEL1L-HRD1 ER-associated degradation are associated with neurodevelopmental disorders.

Autosomal-recessive hypomorphic variants in HRD1/SYVN1 (including p.Pro398Leu) cause neurodevelopmental disorders with developmental delay, intellectual disability, and microcephaly in humans
ERAD substrates IRE1alpha, OS9, and CD147 accumulate in knock-in cells with pathogenic HRD1 variants, confirming impaired ERAD function

DOI:10.1186/s40659-023-00478-7

Role of SYVN1 in the control of airway remodeling in asthma by promoting SIRT2 ubiquitination and degradation.

SYVN1 binds SIRT2 and promotes its ubiquitination and proteasome-dependent degradation in bronchial epithelial cells
SYVN1 activity suppresses ER stress markers GRP78 and CHOP and epithelial-mesenchymal transition phenotypes through SIRT2 degradation

DOI:10.1002/iid3.880

Synoviolin alleviates GSDMD-mediated periodontitis by suppressing its stability.

Synoviolin/SYVN1 interacts with GSDMD and promotes its ubiquitination, modulating inflammasome-driven cytokine release
Myeloid-specific Synoviolin conditional KO mice show greater bone loss in a periodontitis model

DOI:10.1073/pnas.2317978121

An evolutionarily conserved ubiquitin ligase drives infection and transmission of flaviviruses.

HRD1 inhibitor LS-102 blocks HRD1 E3 activity in both mammalian and mosquito cells with EC50 values of 1.391 uM (A549) and 2.757 uM (C6/36)
LS-102 treatment at 15 mg/kg in mice reduces dengue viremia and tissue viral burden ~10-fold with improved survival

DOI:10.1093/cvr/cvae121

A suite of genome-engineered hepatic cells provides novel insights into the spatiotemporal metabolism of apolipoprotein B.

SYVN1 identified as the E3 ligase responsible for degradation of poorly lipidated APOB in HepG2 cells via a targeted ERAD E3 sgRNA screen

📚 Additional Documentation

Deep Research Falcon

(SYVN1-deep-research-falcon.md)

provider: falcon
model: Edison Scientific Literature
cached: false
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gene_id: SYVN1
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protein_description: 'RecName: Full=E3 ubiquitin-protein ligase synoviolin; EC=2.3.2.27
{ECO:0000269|PubMed:12646171, ECO:0000269|PubMed:12975321, ECO:0000269|PubMed:14593114,
ECO:0000269|PubMed:17059562, ECO:0000269|PubMed:17141218, ECO:0000269|PubMed:17170702};
AltName: Full=RING-type E3 ubiquitin transferase synoviolin {ECO:0000303|PubMed:12975321};
AltName: Full=Synovial apoptosis inhibitor 1;'
gene_info: Name=SYVN1 {ECO:0000303|PubMed:15489334}; Synonyms=HRD1 {ECO:0000303|PubMed:12459480,
ECO:0000303|PubMed:14593114, ECO:0000303|PubMed:15489334}, KIAA1810 {ECO:0000303|PubMed:11347906,
ECO:0000303|PubMed:15489334};
organism_full: Homo sapiens (Human).
protein_family: Belongs to the HRD1 family. .
protein_domains: HRD1_E3_ubiq-ligases. (IPR050731); TPR_SYVN1_N. (IPR057992); Znf_RING.
(IPR001841); Znf_RING/FYVE/PHD. (IPR013083); Znf_RING_synoviolin. (IPR058051)
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Question

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

BEFORE YOU BEGIN RESEARCH: You MUST verify you are researching the CORRECT gene/protein. Gene symbols can be ambiguous, especially for less well-characterized genes from non-model organisms.

Target Gene/Protein Identity (from UniProt):

UniProt Accession: Q86TM6
Protein Description: RecName: Full=E3 ubiquitin-protein ligase synoviolin; EC=2.3.2.27 {ECO:0000269|PubMed:12646171, ECO:0000269|PubMed:12975321, ECO:0000269|PubMed:14593114, ECO:0000269|PubMed:17059562, ECO:0000269|PubMed:17141218, ECO:0000269|PubMed:17170702}; AltName: Full=RING-type E3 ubiquitin transferase synoviolin {ECO:0000303|PubMed:12975321}; AltName: Full=Synovial apoptosis inhibitor 1;
Gene Information: Name=SYVN1 {ECO:0000303|PubMed:15489334}; Synonyms=HRD1 {ECO:0000303|PubMed:12459480, ECO:0000303|PubMed:14593114, ECO:0000303|PubMed:15489334}, KIAA1810 {ECO:0000303|PubMed:11347906, ECO:0000303|PubMed:15489334};
Organism (full): Homo sapiens (Human).
Protein Family: Belongs to the HRD1 family. .
Key Domains: HRD1_E3_ubiq-ligases. (IPR050731); TPR_SYVN1_N. (IPR057992); Znf_RING. (IPR001841); Znf_RING/FYVE/PHD. (IPR013083); Znf_RING_synoviolin. (IPR058051)

MANDATORY VERIFICATION STEPS:

Check if the gene symbol "SYVN1" matches the protein description above
Verify the organism is correct: Homo sapiens (Human).
Check if protein family/domains align with what you find in literature
If you find literature for a DIFFERENT gene with the same or similar symbol, STOP

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

DO NOT PROCEED WITH RESEARCH ON A DIFFERENT GENE. Instead:
- State clearly: "The gene symbol 'SYVN1' is ambiguous or literature is limited for this specific protein"
- Explain what you found (e.g., "Found extensive literature on a different gene with the same symbol in a different organism")
- Describe the protein based ONLY on the UniProt information provided above
- Suggest that the protein function can be inferred from domain/family information

Research Target:

Please provide a comprehensive research report on the gene SYVN1 (gene ID: SYVN1, UniProt: Q86TM6) in human.

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.

We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.

Output

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on:
1. Key concepts and definitions with current understanding
2. Recent developments and latest research (prioritize 2023-2024 sources)
3. Current applications and real-world implementations
4. Expert opinions and analysis from authoritative sources
5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available.
Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

BEFORE YOU BEGIN RESEARCH: You MUST verify you are researching the CORRECT gene/protein. Gene symbols can be ambiguous, especially for less well-characterized genes from non-model organisms.

Target Gene/Protein Identity (from UniProt):

UniProt Accession: Q86TM6
Protein Description: RecName: Full=E3 ubiquitin-protein ligase synoviolin; EC=2.3.2.27 {ECO:0000269|PubMed:12646171, ECO:0000269|PubMed:12975321, ECO:0000269|PubMed:14593114, ECO:0000269|PubMed:17059562, ECO:0000269|PubMed:17141218, ECO:0000269|PubMed:17170702}; AltName: Full=RING-type E3 ubiquitin transferase synoviolin {ECO:0000303|PubMed:12975321}; AltName: Full=Synovial apoptosis inhibitor 1;
Gene Information: Name=SYVN1 {ECO:0000303|PubMed:15489334}; Synonyms=HRD1 {ECO:0000303|PubMed:12459480, ECO:0000303|PubMed:14593114, ECO:0000303|PubMed:15489334}, KIAA1810 {ECO:0000303|PubMed:11347906, ECO:0000303|PubMed:15489334};
Organism (full): Homo sapiens (Human).
Protein Family: Belongs to the HRD1 family. .
Key Domains: HRD1_E3_ubiq-ligases. (IPR050731); TPR_SYVN1_N. (IPR057992); Znf_RING. (IPR001841); Znf_RING/FYVE/PHD. (IPR013083); Znf_RING_synoviolin. (IPR058051)

MANDATORY VERIFICATION STEPS:

Check if the gene symbol "SYVN1" matches the protein description above
Verify the organism is correct: Homo sapiens (Human).
Check if protein family/domains align with what you find in literature
If you find literature for a DIFFERENT gene with the same or similar symbol, STOP

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

Research Target:

Please provide a comprehensive research report on the gene SYVN1 (gene ID: SYVN1, UniProt: Q86TM6) in human.

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Comprehensive Research Report: Human SYVN1 (HRD1/Synoviolin; UniProt Q86TM6)

Publication scope and target verification
This report addresses human SYVN1 (also known as HRD1 and synoviolin), an endoplasmic reticulum (ER)-associated E3 ubiquitin ligase central to ER-associated degradation (ERAD), consistent with the target identity specified for UniProt Q86TM6. In high-authority human genetics and mechanistic ERAD studies, “HRD1” is explicitly equated with SYVN1 and treated as the E3 ligase core of the conserved SEL1L–HRD1 ERAD complex. (lin2024sel1lhrd1interactionis pages 1-2, wang2024hypomorphicvariantsof pages 1-2)

1) Key concepts, definitions, and current understanding

1.1. What SYVN1/HRD1 is (molecular function)
SYVN1/HRD1 is an ER-resident E3 ubiquitin ligase that catalyzes transfer of ubiquitin to substrate proteins (typically misfolded or regulated ER/membrane proteins), thereby targeting them for extraction and proteasomal degradation as part of ERAD. (wang2024hypomorphicvariantsof pages 1-2, lin2024sel1lhrd1interactionis pages 1-2)

In a conserved flavivirus-host proteostasis study, HRD1 is described as an ER-located E3 ligase whose “classical physiological role” is to ubiquitinate substrates and degrade them via the proteasome, and the protein is characterized as an integral ER membrane protein with a transmembrane (TM) domain and a cytosolic RING motif (the catalytic module typical of RING E3 ligases). (wu2024anevolutionarilyconserved pages 5-6)

1.2. SYVN1 in the SEL1L–HRD1 ERAD pathway (complex components and mechanism)
The SEL1L–HRD1 module is widely regarded as the most conserved branch of mammalian ERAD. In this model, misfolded ER proteins are recruited and presented to the HRD1 E3 ligase by accessory recognition/scaffold factors (including SEL1L and lectins such as OS9/ERLEC1), retrotranslocated across/through the ER membrane, polyubiquitinated, extracted by the p97/VCP machinery, and degraded by the cytosolic proteasome. (lin2024sel1lhrd1interactionis pages 1-2, wang2024hypomorphicvariantsof pages 1-2)

A 2024 Nature Communications study provides in vivo and biochemical evidence that physical interaction between SEL1L and HRD1 is required to assemble a functional HRD1 ERAD complex. Proteomics-based interactome analyses show SEL1L is required for recruitment of the E2 enzyme UBE2J1 and DERLIN proteins to HRD1, supporting a mechanistic model in which SEL1L–HRD1 coupling is prerequisite for functional ubiquitination and retrotranslocation machinery assembly. (lin2024sel1lhrd1interactionis pages 1-2)

1.3. Biological roles: proteostasis, ER stress, and inflammatory signaling
SYVN1/HRD1 is positioned at the interface of ER proteostasis and stress/inflammation, because ERAD capacity can mitigate unfolded/misfolded protein accumulation and thereby modulate ER stress signaling outcomes. A 2023 airway remodeling/asthma study explicitly frames SYVN1 as an ERAD-associated E3 ligase that promotes unfolded/misfolded protein degradation in the ER, and experimentally links SYVN1 activity to suppression of ER-stress markers (e.g., GRP78, CHOP) and epithelial–mesenchymal transition (EMT) phenotypes. (dai2023roleofsyvn1 pages 6-11)

2) Recent developments and latest research (prioritizing 2023–2024)

2.1. 2024: Human disease genetics links hypomorphic HRD1 (SYVN1) variants to neurodevelopmental phenotypes
A 2024 Journal of Clinical Investigation paper reports autosomal-recessive hypomorphic variants in SEL1L and HRD1/SYVN1 in six children across three families with neurodevelopmental disorder features (developmental delay, intellectual disability, microcephaly, hypotonia/ataxia features). The variants impair ERAD at distinct steps, including HRD1 activity (HRD1 p.Pro398Leu). In engineered knock-in HEK293T models, known endogenous ERAD substrates (including IRE1α, OS9, and CD147) accumulated, consistent with impaired ERAD function. The study also reports that the extent of substrate accumulation differed among variants (highest for SEL1L p.M528R, lower for SEL1L p.G585D or HRD1 p.P398L), reinforcing genotype–functional severity relationships. (wang2024hypomorphicvariantsof pages 1-2, wang2024hypomorphicvariantsof pages 4-5)

2.2. 2024: Pathogenic SEL1L variants and ERAD complex-assembly requirement in vivo
A 2024 Nature Communications study identifies a pathogenic hypomorphic SEL1L variant (p.Ser658Pro) that weakens SEL1L–HRD1 interaction and causes partial embryonic lethality, developmental delay, and early-onset cerebellar ataxia in homozygous mice. Importantly for SYVN1 functional annotation, proteomic screens of HRD1/SEL1L interactomes show that SEL1L–HRD1 interaction is a prerequisite for formation of a functional HRD1 ERAD complex, because SEL1L is required for recruitment of UBE2J1 (E2 enzyme) and DERLIN proteins to HRD1. (lin2024sel1lhrd1interactionis pages 1-2)

2.3. 2023–2024: Expansion of validated (non-canonical) SYVN1 substrates beyond classical ERAD clients
Multiple 2023–2024 disease-context studies identify regulated, non-canonical substrates and pathways, suggesting SYVN1 can affect signaling nodes beyond “generic misfolded-protein clearance.” Examples with direct experimental evidence in the retrieved corpus include:

• SIRT2 (airway remodeling/asthma; EMT/ER stress in bronchial epithelium): SYVN1 binds SIRT2 and promotes SIRT2 ubiquitination and proteasome-dependent degradation in BEAS-2B cells. (dai2023roleofsyvn1 pages 6-11)

• GSDMD (periodontitis; inflammasome/pyroptosis): Synoviolin (SYVN1/HRD1) interacts with GSDMD and is associated with altered GSDMD ubiquitination and inflammasome-driven cytokine release in human PBMCs and mouse macrophages, with effects on periodontitis severity in vivo. (pang2023synoviolinalleviatesgsdmd‐mediated pages 4-6, pang2023synoviolinalleviatesgsdmd‐mediated pages 2-4)

• GLUD1 (HBV-related hepatocellular carcinoma): SYVN1 is identified as the E3 ligase that promotes GLUD1 ubiquitination and decreases GLUD1 protein stability, in a pathway facilitated by LASP1 and linked to HBX-driven hepatocarcinogenesis. (you2024inhibitionofglud1 pages 6-9, you2024inhibitionofglud1 pages 12-13)

• HMGB1 (papillary thyroid carcinoma): SYVN1 physically interacts with HMGB1 and promotes HMGB1 ubiquitination and degradation; MG132 rescue supports proteasome involvement, and SYVN1 overexpression suppresses malignant cell behaviors in vitro and xenograft tumor growth in vivo in this model. (duan2024syvn1modulatespapillary pages 4-8, duan2024syvn1modulatespapillary pages 1-4)

• APOB (hepatic APOB/VLDL metabolism; ER quality control): In genome-engineered HepG2 and Huh-7 cells with endogenous APOB fluorescently tagged, an ERAD-focused sgRNA screen identifies SYVN1 as the E3 ligase responsible for degradation of poorly lipidated APOB (a key determinant of VLDL production). (meurs2024asuiteof pages 8-9)

3) Current applications and real-world implementations

3.1. Antiviral intervention and vector-control concepts: pharmacologic HRD1 inhibition (LS-102)
A 2024 PNAS study reports the HRD1 inhibitor LS-102 and uses it as a mechanistic and translational tool in dengue virus (DENV2) models. LS-102 is described as discovered by high-throughput screening; mechanistically, LS-102 “offset” NS4A ubiquitination mediated by mosquito HRD1 and human HRD1 (HsHRD1) and maintained NS4A stability in CHX chase assays, indicating functional inhibition of HRD1 E3 activity in both mosquito and mammalian contexts. (wu2024anevolutionarilyconserved pages 6-7)

Quantitative cellular potency: LS-102 EC50 values are reported as 2.757 µM in C6/36 cells and 1.391 µM in A549 cells. (wu2024anevolutionarilyconserved pages 6-7)

In vivo dosing/application examples:
• Mouse dengue model: AG6 (ifnagr−/−) mice infected with 5 × 10^4 f.f.u. DENV2 were dosed intraperitoneally with LS-102 at 15 mg/kg daily; treatment reduced viremia and viral burdens and improved survival, and prophylactic dosing produced an approximately 10-fold reduction in viremia and tissue viral burden with improved survival. (wu2024anevolutionarilyconserved pages 7-9)
• Mosquito infection/transmission: thoracic microinjection of LS-102 with DENV2 impaired infection in mosquitoes dose-dependently, and oral feeding of LS-102 in blood meals reduced DENV2 prevalence without affecting mosquito survival. (wu2024anevolutionarilyconserved pages 6-7, wu2024anevolutionarilyconserved media 0a2d5fec)

The in vivo outcomes are visually summarized in the paper’s Figure 5 (viral load and survival in mice; reduced viral loads/prevalence in mosquitoes). (wu2024anevolutionarilyconserved media 0a2d5fec)

3.2. Cancer pharmacology (preclinical): targeting a SYVN1–EGFR axis with LS-102 to address EGFR-TKI resistance
A 2025 Cell Death & Disease study proposes SYVN1 as a therapeutic target in NSCLC. Mechanistically, SYVN1 is reported to interact with EGFR (SYVN1 N-terminus 1–290 aa binds the EGFR intracellular domain) and to stabilize EGFR by promoting Lys63-linked ubiquitination and inhibiting proteasome-mediated EGFR degradation, while also inhibiting EGFR endocytosis to increase membrane EGFR. (xie2025targetingthesyvn1egfr pages 1-2)

This study uses LS-102 (described as an enzyme activity inhibitor of SYVN1) and reports combination with the EGFR-TKI AZD9291 (osimertinib) as a strategy to reverse resistance.
• In vitro dosing: LS-102 at 5 µM combined with AZD9291 at 6 µM (A549) or 8 µM (H1299) in proliferation/colony assays; synergy assessed computationally (SynergyFinder). (xie2025targetingthesyvn1egfr pages 11-13)
• In vivo dosing: xenograft experiments used AZD9291 at 5 mg/kg (daily oral gavage) and LS-102 at 3 mg/kg (intraperitoneal; twice weekly for 3 weeks). (xie2025targetingthesyvn1egfr pages 3-4)

3.3. Hepatic lipid and lipoprotein biology: engineered cell systems for ERAD-linked APOB metabolism
A 2024 Cardiovascular Research paper provides a genome-engineered hepatic cell platform (HepG2 and Huh-7) with endogenous APOB tagged by mNeonGreen, enabling quantitative live-cell and secreted APOB monitoring and genetic perturbation screens. Using an sgRNA library targeting membrane-associated ER-resident E3 ligases, SYVN1 is identified as the E3 responsible for degradation of poorly lipidated APOB in HepG2 cells, highlighting an application in dissecting VLDL biology and ER quality control with a tractable system that can quantify APOB secretion over time. (meurs2024asuiteof pages 8-9)

4) Expert opinions and analysis (authoritative sources)

4.1. SEL1L–HRD1 is a core, conserved ERAD branch essential for organismal viability and human health
Two high-authority 2024 papers (Nature Communications; JCI) converge on the conclusion that SEL1L–HRD1 coupling is necessary for functional ERAD complex formation and that hypomorphic disruption of this pathway has substantial organismal and human disease consequences.
• Nature Communications 2024: emphasizes that SEL1L–HRD1 interaction is required for recruitment of key ERAD components (E2 UBE2J1 and DERLINs) and formation of a functional HRD1 ERAD complex. (lin2024sel1lhrd1interactionis pages 1-2)
• JCI 2024: explicitly frames HRD1/SYVN1 as the E3 ligase core of SEL1L–HRD1 ERAD and demonstrates that hypomorphic HRD1 variants impair ERAD substrate clearance and associate with neurodevelopmental disorders. (wang2024hypomorphicvariantsof pages 1-2)

4.2. Translational caution: systemic HRD1 inhibition may perturb proteostasis
The NSCLC-focused study explicitly notes potential safety concerns for systemic SYVN1 inhibition, warning that inhibiting SYVN1 may disrupt the ubiquitin–proteasome system and could increase ER stress and disturb protein homeostasis in organs such as liver and kidney, implying that delivery, dosing, and toxicity profiling are key barriers to clinical translation. (xie2025targetingthesyvn1egfr pages 13-14)

5) Relevant statistics and data highlights from recent studies

5.1. Quantitative and experimental parameters supporting substrate-specific functional annotation

SIRT2 (airway remodeling/asthma; 2023)
• SYVN1 upregulation in OVA-induced asthma model: 2.73-fold increase in lungs after OVA induction; ~7.76-fold upregulation after adenoviral SYVN1 overexpression. (dai2023roleofsyvn1 pages 6-11)
• Proteasome dependence of SIRT2 turnover: cycloheximide (CHX) chase (50 µg/mL) and MG132 (10 µM) restored SIRT2 protein levels, supporting ubiquitination → proteasomal degradation downstream of SYVN1. (dai2023roleofsyvn1 pages 6-11)
• Pathway link: SIRT2 overexpression reverses SYVN1-mediated suppression of ER stress markers GRP78/CHOP in TGF-β1 (10 ng/mL)-treated cells, supporting a causal substrate-to-phenotype link. (dai2023roleofsyvn1 pages 6-11)

GSDMD (periodontitis/pyroptosis; 2023)
• Human cohorts: serum and PBMCs collected from healthy (n=20), mild periodontitis (n=20), and severe periodontitis (n=20) groups; mean age 42.7; sex distribution reported. (pang2023synoviolinalleviatesgsdmd‐mediated pages 2-4)
• Systemic inflammatory readouts: serum IL-1β measured by ELISA (n=20/group) and PBMC mRNA analyses (RT-PCR; n=9) showed elevated inflammasome-related signals with decreased synoviolin expression in patients, with reduced GSDMD ubiquitination observed by IP/ubiquitination assays. (pang2023synoviolinalleviatesgsdmd‐mediated pages 4-6)
• Mouse model: Pg-induced periodontitis model used 2 × 10^9 CFU P. gingivalis applied by ligature for 4 weeks; micro-CT analyses used n=10/group and showed greater CEJ–ABC distance (bone loss) in myeloid-specific Synoviolin conditional KO mice. (pang2023synoviolinalleviatesgsdmd‐mediated pages 2-4, pang2023synoviolinalleviatesgsdmd‐mediated pages 6-8)
• Linkage ambiguity: the authors note they did not distinguish specific lysine linkage types on GSDMD in periodontitis, highlighting an open mechanistic question. (pang2023synoviolinalleviatesgsdmd‐mediated pages 8-9)

GLUD1 (HBV-related HCC; 2024)
• Proteasome dependence/stability assays: CHX 200 µg/mL and MG132 100 nM were used in protein stability assays; SYVN1 promoted GLUD1 ubiquitination and reduced GLUD1 stability, and LASP1-mediated GLUD1 destabilization required SYVN1. (you2024inhibitionofglud1 pages 6-9)
• Subcellular localization claim: both SYVN1 and GLUD1 were detected in mitochondria and cytosol, consistent with interaction in those compartments in HCC cells. (you2024inhibitionofglud1 pages 6-9)

HMGB1 (papillary thyroid carcinoma; 2024)
• Mechanism: Co-IP validates SYVN1–HMGB1 interaction and SYVN1 overexpression increases HMGB1 ubiquitination; MG132 restores HMGB1 protein after SYVN1 overexpression, implicating proteasome-dependent turnover. (duan2024syvn1modulatespapillary pages 4-8)
• Stability assay condition: CHX used at 100 µg/mL to assess HMGB1 half-life (and SYVN1 reduces HMGB1 half-life). (duan2024syvn1modulatespapillary pages 4-8)

APOB ERAD (hepatic lipoprotein biology; 2024)
• Quantification/engineering: in Huh-7 clones retaining one wild-type APOB allele, APOB-mNeon intensity was ~50% of that detected in a clone where both alleles were edited; APOB-mNeon secretion was quantifiable over time (reported linear increase, followed up to 7 days). (meurs2024asuiteof pages 6-8)
• Screen design: pooled sgRNA ERAD E3 screen (3 sgRNAs per E3) with puromycin selection (5 days), CP treatment (1 µM for 16 h), and FACS measurement; results from three independent experiments. (meurs2024asuiteof pages 8-9)

5.2. Quantitative outcomes for pharmacologic targeting: LS-102
• Cellular EC50: 2.757 µM (C6/36) and 1.391 µM (A549). (wu2024anevolutionarilyconserved pages 6-7)
• Mouse dosing: 15 mg/kg LS-102 intraperitoneal daily in AG6 mice infected with 5 × 10^4 f.f.u. DENV2; associated with reduced viremia/viral burdens and improved survival; prophylaxis yielded ~10-fold reduction in viremia/tissue burden. (wu2024anevolutionarilyconserved pages 7-9)
• Mosquito implementation: thoracic microinjection and oral feeding approaches reduced infection prevalence and loads dose-dependently (Figure 5). (wu2024anevolutionarilyconserved pages 6-7, wu2024anevolutionarilyconserved media 0a2d5fec)

Functional annotation summary (human-centric)

Primary biochemical role
SYVN1/HRD1 is an ER-associated, membrane-embedded RING-type E3 ubiquitin ligase that ubiquitinates substrate proteins, coordinating with the SEL1L adaptor/scaffold and additional ERAD factors (including DERLINs and the E2 UBE2J1) to enable substrate retrotranslocation, extraction, and proteasomal degradation. (lin2024sel1lhrd1interactionis pages 1-2, wu2024anevolutionarilyconserved pages 5-6)

Subcellular localization and topology
SYVN1/HRD1 is localized to the ER membrane and is an integral membrane protein with a TM domain and a cytosolic RING motif (catalytic E3 module). (wu2024anevolutionarilyconserved pages 5-6)

Key pathways
• ER proteostasis/ERAD: SEL1L–HRD1 complex-mediated clearance of ER clients and broader homeostatic roles. (wang2024hypomorphicvariantsof pages 1-2, lin2024sel1lhrd1interactionis pages 1-2)
• ER stress and EMT/inflammation coupling: via substrate-specific degradation (e.g., SIRT2) that modulates ER-stress markers and EMT programs in airway epithelium. (dai2023roleofsyvn1 pages 6-11)
• Inflammasome/pyroptosis: modulation of GSDMD ubiquitination/stability and downstream IL-1β/IL-18 release, with in vivo impact on periodontitis. (pang2023synoviolinalleviatesgsdmd‐mediated pages 4-6, pang2023synoviolinalleviatesgsdmd‐mediated pages 6-8)
• Metabolic and oncogenic signaling nodes: regulation of GLUD1 stability (HBV-related HCC) and EGFR stabilization via Lys63-linked ubiquitination (NSCLC). (you2024inhibitionofglud1 pages 6-9, xie2025targetingthesyvn1egfr pages 1-2)

Selected URLs and publication dates (from retrieved sources)
• Lin et al., “SEL1L-HRD1 interaction is required to form a functional HRD1 ERAD complex” (Nature Communications). Publication date: Feb 2024. URL: https://doi.org/10.1038/s41467-024-45633-0 (lin2024sel1lhrd1interactionis pages 1-2)
• Wang et al., “Hypomorphic variants of SEL1L-HRD1 ER-associated degradation are associated with neurodevelopmental disorders” (J Clin Invest). Publication date: Jan 2024. URL: https://doi.org/10.1172/jci170054 (wang2024hypomorphicvariantsof pages 1-2)
• Dai et al., “Role of SYVN1 in the control of airway remodeling in asthma…” (Biological Research). Publication date: Dec 2023. URL: https://doi.org/10.1186/s40659-023-00478-7 (dai2023roleofsyvn1 pages 6-11)
• Pang et al., “Synoviolin alleviates GSDMD-mediated periodontitis…” (Immunity, Inflammation and Disease). Publication date: Jul 2023. URL: https://doi.org/10.1002/iid3.880 (pang2023synoviolinalleviatesgsdmd‐mediated pages 4-6)
• You et al., “Inhibition of GLUD1 mediated by LASP1 and SYVN1…” (J Mol Cell Biol). Publication date: Apr 2024. URL: https://doi.org/10.1093/jmcb/mjae014 (you2024inhibitionofglud1 pages 6-9)
• Meurs et al., “A suite of genome-engineered hepatic cells…” (Cardiovascular Research). Publication date: Jun 2024. URL: https://doi.org/10.1093/cvr/cvae121 (meurs2024asuiteof pages 8-9)
• Wu et al., “An evolutionarily conserved ubiquitin ligase drives infection and transmission of flaviviruses” (PNAS). Publication date: Apr 2024. URL: https://doi.org/10.1073/pnas.2317978121 (wu2024anevolutionarilyconserved pages 6-7)
• Xie et al., “Targeting the SYVN1–EGFR axis…” (Cell Death & Disease). Publication date: Aug 2025. URL: https://doi.org/10.1038/s41419-025-07978-2 (xie2025targetingthesyvn1egfr pages 3-4)

Limitations of this tool-based synthesis
Some mechanistic specifics requested for full functional annotation—particularly detailed ubiquitin linkage preferences across substrates in human cells, comprehensive E2 partner usage beyond UBE2J1 in the assembled ERAD complex, and kinetic enzymology parameters—were not consistently reported in the retrieved excerpts; where linkage types are specified (e.g., EGFR Lys63-linked ubiquitination), this is included with direct citation. (xie2025targetingthesyvn1egfr pages 1-2)

References

(lin2024sel1lhrd1interactionis pages 1-2): Liangguang Leo Lin, Huilun Helen Wang, Brent Pederson, Xiaoqiong Wei, Mauricio Torres, You Lu, Zexin Jason Li, Xiaodan Liu, Hancheng Mao, Hui Wang, Linyao Elina Zhou, Zhen Zhao, Shengyi Sun, and Ling Qi. Sel1l-hrd1 interaction is required to form a functional hrd1 erad complex. Nature Communications, Feb 2024. URL: https://doi.org/10.1038/s41467-024-45633-0, doi:10.1038/s41467-024-45633-0. This article has 36 citations and is from a highest quality peer-reviewed journal.
(wang2024hypomorphicvariantsof pages 1-2): Huilun H. Wang, Liangguang L. Lin, Zexin J. Li, Xiaoqiong Wei, Omar Askander, Gerarda Cappuccio, Mais O. Hashem, Laurence Hubert, Arnold Munnich, Mashael Alqahtani, Qi Pang, Margit Burmeister, You Lu, Karine Poirier, Claude Besmond, Shengyi Sun, Nicola Brunetti-Pierri, Fowzan S. Alkuraya, and Ling Qi. Hypomorphic variants of sel1l-hrd1 er-associated degradation are associated with neurodevelopmental disorders. Journal of Clinical Investigation, Jan 2024. URL: https://doi.org/10.1172/jci170054, doi:10.1172/jci170054. This article has 29 citations and is from a highest quality peer-reviewed journal.
(wu2024anevolutionarilyconserved pages 5-6): Linjuan Wu, Liming Zhang, Shengyong Feng, Lu Chen, Cai Lin, Gang Wang, Yibin Zhu, Penghua Wang, and Gong Cheng. An evolutionarily conserved ubiquitin ligase drives infection and transmission of flaviviruses. Proceedings of the National Academy of Sciences of the United States of America, Apr 2024. URL: https://doi.org/10.1073/pnas.2317978121, doi:10.1073/pnas.2317978121. This article has 16 citations and is from a highest quality peer-reviewed journal.
(dai2023roleofsyvn1 pages 6-11): Bing Dai, Si Liu, Wenxin Shen, Li Chen, Qianlan Zhou, Lina Han, Qinzhen Zhang, and Lishen Shan. Role of syvn1 in the control of airway remodeling in asthma protection by promoting sirt2 ubiquitination and degradation. Biological Research, Dec 2023. URL: https://doi.org/10.1186/s40659-023-00478-7, doi:10.1186/s40659-023-00478-7. This article has 8 citations and is from a peer-reviewed journal.
(wang2024hypomorphicvariantsof pages 4-5): Huilun H. Wang, Liangguang L. Lin, Zexin J. Li, Xiaoqiong Wei, Omar Askander, Gerarda Cappuccio, Mais O. Hashem, Laurence Hubert, Arnold Munnich, Mashael Alqahtani, Qi Pang, Margit Burmeister, You Lu, Karine Poirier, Claude Besmond, Shengyi Sun, Nicola Brunetti-Pierri, Fowzan S. Alkuraya, and Ling Qi. Hypomorphic variants of sel1l-hrd1 er-associated degradation are associated with neurodevelopmental disorders. Journal of Clinical Investigation, Jan 2024. URL: https://doi.org/10.1172/jci170054, doi:10.1172/jci170054. This article has 29 citations and is from a highest quality peer-reviewed journal.
(pang2023synoviolinalleviatesgsdmd‐mediated pages 4-6): Ying Pang, Lili Liu, Shuainan Wu, Jianqi Wang, and Lu Liu. Synoviolin alleviates gsdmd‐mediated periodontitis by suppressing its stability. Immunity, Inflammation and Disease, Jul 2023. URL: https://doi.org/10.1002/iid3.880, doi:10.1002/iid3.880. This article has 7 citations and is from a peer-reviewed journal.
(pang2023synoviolinalleviatesgsdmd‐mediated pages 2-4): Ying Pang, Lili Liu, Shuainan Wu, Jianqi Wang, and Lu Liu. Synoviolin alleviates gsdmd‐mediated periodontitis by suppressing its stability. Immunity, Inflammation and Disease, Jul 2023. URL: https://doi.org/10.1002/iid3.880, doi:10.1002/iid3.880. This article has 7 citations and is from a peer-reviewed journal.
(you2024inhibitionofglud1 pages 6-9): Hong-Juan You, Qi Li, Li-Hong Ma, Xing Wang, Huan-Yang Zhang, Yu-Xin Wang, En-Si Bao, Yu-Jie Zhong, De-Long Kong, Xiang-Ye Liu, Fan-Yun Kong, Kui-Yang Zheng, and Ren-Xian Tang. Inhibition of glud1 mediated by lasp1 and syvn1 contributes to hepatitis b virus x protein-induced hepatocarcinogenesis. Journal of Molecular Cell Biology, Apr 2024. URL: https://doi.org/10.1093/jmcb/mjae014, doi:10.1093/jmcb/mjae014. This article has 7 citations and is from a peer-reviewed journal.
(you2024inhibitionofglud1 pages 12-13): Hong-Juan You, Qi Li, Li-Hong Ma, Xing Wang, Huan-Yang Zhang, Yu-Xin Wang, En-Si Bao, Yu-Jie Zhong, De-Long Kong, Xiang-Ye Liu, Fan-Yun Kong, Kui-Yang Zheng, and Ren-Xian Tang. Inhibition of glud1 mediated by lasp1 and syvn1 contributes to hepatitis b virus x protein-induced hepatocarcinogenesis. Journal of Molecular Cell Biology, Apr 2024. URL: https://doi.org/10.1093/jmcb/mjae014, doi:10.1093/jmcb/mjae014. This article has 7 citations and is from a peer-reviewed journal.
(duan2024syvn1modulatespapillary pages 4-8): Fei Duan, Fanli Kong, Taifeng Jiang, and Hongbing Liu. Syvn1 modulates papillary thyroid carcinoma progression by destabilizing hmgb1. Cell division, 19 1:15, Apr 2024. URL: https://doi.org/10.1186/s13008-024-00121-1, doi:10.1186/s13008-024-00121-1. This article has 5 citations and is from a peer-reviewed journal.
(duan2024syvn1modulatespapillary pages 1-4): Fei Duan, Fanli Kong, Taifeng Jiang, and Hongbing Liu. Syvn1 modulates papillary thyroid carcinoma progression by destabilizing hmgb1. Cell division, 19 1:15, Apr 2024. URL: https://doi.org/10.1186/s13008-024-00121-1, doi:10.1186/s13008-024-00121-1. This article has 5 citations and is from a peer-reviewed journal.
(meurs2024asuiteof pages 8-9): Amber Meurs, Klevis Ndoj, Marlene van den Berg, Goran Marinković, Matteo Tantucci, Tineke Veenendaal, Jan Albert Kuivenhoven, Judith Klumperman, and Noam Zelcer. A suite of genome-engineered hepatic cells provides novel insights into the spatiotemporal metabolism of apolipoprotein b and apolipoprotein b–containing lipoprotein secretion. Cardiovascular Research, 120:1253-1264, Jun 2024. URL: https://doi.org/10.1093/cvr/cvae121, doi:10.1093/cvr/cvae121. This article has 5 citations and is from a domain leading peer-reviewed journal.
(wu2024anevolutionarilyconserved pages 6-7): Linjuan Wu, Liming Zhang, Shengyong Feng, Lu Chen, Cai Lin, Gang Wang, Yibin Zhu, Penghua Wang, and Gong Cheng. An evolutionarily conserved ubiquitin ligase drives infection and transmission of flaviviruses. Proceedings of the National Academy of Sciences of the United States of America, Apr 2024. URL: https://doi.org/10.1073/pnas.2317978121, doi:10.1073/pnas.2317978121. This article has 16 citations and is from a highest quality peer-reviewed journal.
(wu2024anevolutionarilyconserved pages 7-9): Linjuan Wu, Liming Zhang, Shengyong Feng, Lu Chen, Cai Lin, Gang Wang, Yibin Zhu, Penghua Wang, and Gong Cheng. An evolutionarily conserved ubiquitin ligase drives infection and transmission of flaviviruses. Proceedings of the National Academy of Sciences of the United States of America, Apr 2024. URL: https://doi.org/10.1073/pnas.2317978121, doi:10.1073/pnas.2317978121. This article has 16 citations and is from a highest quality peer-reviewed journal.
(wu2024anevolutionarilyconserved media 0a2d5fec): Linjuan Wu, Liming Zhang, Shengyong Feng, Lu Chen, Cai Lin, Gang Wang, Yibin Zhu, Penghua Wang, and Gong Cheng. An evolutionarily conserved ubiquitin ligase drives infection and transmission of flaviviruses. Proceedings of the National Academy of Sciences of the United States of America, Apr 2024. URL: https://doi.org/10.1073/pnas.2317978121, doi:10.1073/pnas.2317978121. This article has 16 citations and is from a highest quality peer-reviewed journal.
(xie2025targetingthesyvn1egfr pages 1-2): Xinsheng Xie, Weilai Tong, Yue Xie, Haoxin Jiang, Alan Jiang, Junming Huang, Zhili Liu, and Jingjing Yu. Targeting the syvn1-egfr axis: a breakthrough strategy for tki-resistant nsclc. Cell Death & Disease, Aug 2025. URL: https://doi.org/10.1038/s41419-025-07978-2, doi:10.1038/s41419-025-07978-2. This article has 2 citations and is from a peer-reviewed journal.
(xie2025targetingthesyvn1egfr pages 11-13): Xinsheng Xie, Weilai Tong, Yue Xie, Haoxin Jiang, Alan Jiang, Junming Huang, Zhili Liu, and Jingjing Yu. Targeting the syvn1-egfr axis: a breakthrough strategy for tki-resistant nsclc. Cell Death & Disease, Aug 2025. URL: https://doi.org/10.1038/s41419-025-07978-2, doi:10.1038/s41419-025-07978-2. This article has 2 citations and is from a peer-reviewed journal.
(xie2025targetingthesyvn1egfr pages 3-4): Xinsheng Xie, Weilai Tong, Yue Xie, Haoxin Jiang, Alan Jiang, Junming Huang, Zhili Liu, and Jingjing Yu. Targeting the syvn1-egfr axis: a breakthrough strategy for tki-resistant nsclc. Cell Death & Disease, Aug 2025. URL: https://doi.org/10.1038/s41419-025-07978-2, doi:10.1038/s41419-025-07978-2. This article has 2 citations and is from a peer-reviewed journal.
(xie2025targetingthesyvn1egfr pages 13-14): Xinsheng Xie, Weilai Tong, Yue Xie, Haoxin Jiang, Alan Jiang, Junming Huang, Zhili Liu, and Jingjing Yu. Targeting the syvn1-egfr axis: a breakthrough strategy for tki-resistant nsclc. Cell Death & Disease, Aug 2025. URL: https://doi.org/10.1038/s41419-025-07978-2, doi:10.1038/s41419-025-07978-2. This article has 2 citations and is from a peer-reviewed journal.
(pang2023synoviolinalleviatesgsdmd‐mediated pages 6-8): Ying Pang, Lili Liu, Shuainan Wu, Jianqi Wang, and Lu Liu. Synoviolin alleviates gsdmd‐mediated periodontitis by suppressing its stability. Immunity, Inflammation and Disease, Jul 2023. URL: https://doi.org/10.1002/iid3.880, doi:10.1002/iid3.880. This article has 7 citations and is from a peer-reviewed journal.
(pang2023synoviolinalleviatesgsdmd‐mediated pages 8-9): Ying Pang, Lili Liu, Shuainan Wu, Jianqi Wang, and Lu Liu. Synoviolin alleviates gsdmd‐mediated periodontitis by suppressing its stability. Immunity, Inflammation and Disease, Jul 2023. URL: https://doi.org/10.1002/iid3.880, doi:10.1002/iid3.880. This article has 7 citations and is from a peer-reviewed journal.
(meurs2024asuiteof pages 6-8): Amber Meurs, Klevis Ndoj, Marlene van den Berg, Goran Marinković, Matteo Tantucci, Tineke Veenendaal, Jan Albert Kuivenhoven, Judith Klumperman, and Noam Zelcer. A suite of genome-engineered hepatic cells provides novel insights into the spatiotemporal metabolism of apolipoprotein b and apolipoprotein b–containing lipoprotein secretion. Cardiovascular Research, 120:1253-1264, Jun 2024. URL: https://doi.org/10.1093/cvr/cvae121, doi:10.1093/cvr/cvae121. This article has 5 citations and is from a domain leading peer-reviewed journal.

Citations

wu2024anevolutionarilyconserved pages 5-6
meurs2024asuiteof pages 8-9
wu2024anevolutionarilyconserved pages 6-7
wu2024anevolutionarilyconserved pages 7-9
wang2024hypomorphicvariantsof pages 1-2
meurs2024asuiteof pages 6-8
wang2024hypomorphicvariantsof pages 4-5
https://doi.org/10.1038/s41467-024-45633-0
https://doi.org/10.1172/jci170054
https://doi.org/10.1186/s40659-023-00478-7
https://doi.org/10.1002/iid3.880
https://doi.org/10.1093/jmcb/mjae014
https://doi.org/10.1093/cvr/cvae121
https://doi.org/10.1073/pnas.2317978121
https://doi.org/10.1038/s41419-025-07978-2
https://doi.org/10.1038/s41467-024-45633-0,
https://doi.org/10.1172/jci170054,
https://doi.org/10.1073/pnas.2317978121,
https://doi.org/10.1186/s40659-023-00478-7,
https://doi.org/10.1002/iid3.880,
https://doi.org/10.1093/jmcb/mjae014,
https://doi.org/10.1186/s13008-024-00121-1,
https://doi.org/10.1093/cvr/cvae121,
https://doi.org/10.1038/s41419-025-07978-2,

📄 View Raw YAML

id: Q86TM6
gene_symbol: SYVN1
product_type: PROTEIN
status: IN_PROGRESS
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  SYVN1 (synoviolin/HRD1) encodes E3 ubiquitin-protein ligase synoviolin, the
  central catalytic component of the most conserved branch of mammalian ERAD. SYVN1
  is an ER membrane-resident multi-pass transmembrane protein with a cytoplasmic
  RING-H2 zinc finger domain that catalyzes K48-linked polyubiquitination of
  misfolded ER substrates, targeting them for VCP/p97-dependent retrotranslocation
  and proteasomal degradation. Physical interaction between SEL1L and HRD1 is a
  prerequisite for recruitment of the E2 enzyme UBE2J1 and DERLIN proteins to HRD1,
  assembling a functional ERAD complex (DOI:10.1038/s41467-024-45633-0). SYVN1
  functions as part of the HRD1 complex (with SEL1L, FAM8A1, HERPUD1, OS9,
  DERL1/2, and UBE2J1) in the quality control of ER proteins. Beyond classical ERAD
  substrates (TCR-alpha, CD3-delta, Pael-R, MHC class I heavy chains, APOB), SYVN1
  also ubiquitinates regulatory substrates including p53/TP53, IRE1alpha, SIRT2,
  GSDMD, GLUD1, and HMGB1 (DOI:10.1186/s40659-023-00478-7, DOI:10.1002/iid3.880,
  DOI:10.1093/jmcb/mjae014). Hypomorphic variants in SYVN1 have been associated
  with neurodevelopmental disorders (developmental delay, intellectual disability,
  microcephaly) in humans, establishing the essential role of HRD1-mediated ERAD in
  brain development (DOI:10.1172/jci170054). The HRD1 inhibitor LS-102 has been
  shown to block ERAD function in both mammalian and insect cells
  (DOI:10.1073/pnas.2317978121). It protects cells from ER stress-induced
  apoptosis and is upregulated in rheumatoid arthritis synovial tissue.
alternative_products:
- name: 1 (b, long)
  id: Q86TM6-1
- name: '2'
  id: Q86TM6-2
  sequence_note: VSP_023777, VSP_023778
- name: 3 (a, short)
  id: Q86TM6-3
  sequence_note: VSP_023778
existing_annotations:
# ============================================================
# IBA annotations (phylogenetic inference)
# ============================================================
- term:
    id: GO:0012505
    label: endomembrane system
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    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.
    action: ACCEPT
    reason: >-
      Phylogenetically inferred CC term consistent with the well-established
      ER localization of SYVN1/HRD1. Broad but correct.
    supported_by:
      - reference_id: PMID:14593114
        supporting_text: >-
          We show that human HRD1 is a non-glycosylated, stable ER protein
          with a cytosolic RING-H2 finger domain.
- term:
    id: GO:0036503
    label: ERAD pathway
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    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).
    action: ACCEPT
    reason: >-
      ERAD pathway is the core biological process of SYVN1/HRD1. Strongly
      supported by phylogenetic conservation and extensive experimental
      evidence.
    supported_by:
      - reference_id: PMID:14593114
        supporting_text: >-
          Human HRD1 is an E3 ubiquitin ligase involved in degradation of
          proteins from the endoplasmic reticulum.
- term:
    id: GO:0043161
    label: proteasome-mediated ubiquitin-dependent protein catabolic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    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.
    action: ACCEPT
    reason: >-
      Core function. HRD1-mediated ubiquitination leads to proteasomal
      degradation of substrates; K48-linked chains are the hallmark of
      proteasomal targeting.
    supported_by:
      - reference_id: PMID:14593114
        supporting_text: >-
          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
- term:
    id: GO:0044322
    label: endoplasmic reticulum quality control compartment
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    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.
    action: ACCEPT
    reason: >-
      Phylogenetically supported and consistent with multiple IDA studies
      showing HRD1 recruitment to the ERQC.
    supported_by:
      - reference_id: PMID:24478453
        supporting_text: >-
          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.
- term:
    id: GO:0061630
    label: ubiquitin protein ligase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    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).
    action: ACCEPT
    reason: >-
      Core molecular function. SYVN1 is a RING-type E3 ubiquitin ligase, its
      most fundamental catalytic activity.
    supported_by:
      - reference_id: PMID:14593114
        supporting_text: >-
          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
# ============================================================
# IEA annotations (electronic)
# ============================================================
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    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).
    action: ACCEPT
    reason: >-
      Correct electronic annotation consistent with extensive experimental
      evidence of ER membrane localization.
    supported_by:
      - reference_id: PMID:14593114
        supporting_text: >-
          We show that human HRD1 is a non-glycosylated, stable ER protein
          with a cytosolic RING-H2 finger domain.
- term:
    id: GO:0008270
    label: zinc ion binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    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.
    action: ACCEPT
    reason: >-
      Correct. The RING-H2 zinc finger domain of SYVN1 binds two zinc ions,
      structurally verified by NMR (PMID:30345569).
    supported_by:
      - reference_id: PMID:14593114
        supporting_text: >-
          We show that human HRD1 is a non-glycosylated, stable ER protein
          with a cytosolic RING-H2 finger domain.
- term:
    id: GO:0016740
    label: transferase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    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.
    action: ACCEPT
    reason: >-
      Technically correct as a broad parent term since SYVN1 catalyzes
      ubiquitin transfer, but redundant with the more specific ubiquitin
      protein ligase activity annotations.
- term:
    id: GO:0044322
    label: endoplasmic reticulum quality control compartment
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: >-
      IEA annotation from ARBA machine learning for ERQC localization.
      Consistent with IBA and IDA annotations for the same term.
    action: ACCEPT
    reason: >-
      Correct electronic annotation, redundant with IBA and IDA evidence
      for the same term.
- term:
    id: GO:0046872
    label: metal ion binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    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.
    action: ACCEPT
    reason: >-
      Correct but very broad. Redundant with the more specific zinc ion
      binding annotation.
- term:
    id: GO:0050821
    label: protein stabilization
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    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.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
      - reference_id: PMID:21454652
        supporting_text: >-
          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.
- term:
    id: GO:0061630
    label: ubiquitin protein ligase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000003
  review:
    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.
    action: ACCEPT
    reason: >-
      Correct electronic annotation based on EC classification, consistent
      with extensive experimental evidence.
- term:
    id: GO:1902236
    label: negative regulation of endoplasmic reticulum stress-induced intrinsic apoptotic
      signaling pathway
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    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).
    action: ACCEPT
    reason: >-
      Correct electronic annotation consistent with experimental evidence
      from PMID:12459480 and PMID:17059562.
    supported_by:
      - reference_id: PMID:12459480
        supporting_text: >-
          293 cells stably expressing wild-type HRD1, but not the C329S mutant,
          afforded resistance to ER stress-induced apoptosis.
# ============================================================
# protein binding (IPI) annotations
# ============================================================
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:17170702
  review:
    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.
    action: REMOVE
    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.
    supported_by:
      - reference_id: PMID:17170702
        supporting_text: >-
          Cytoplasmic destruction of p53 by the endoplasmic reticulum-resident
          ubiquitin ligase 'Synoviolin'.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:18369366
  review:
    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.
    action: REMOVE
    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.
    supported_by:
      - reference_id: PMID:18369366
        supporting_text: >-
          SYVN1 interacts with and catalyses IRE1 ubiquitination and
          consequently promotes IRE1 degradation.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:19690564
  review:
    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.
    action: REMOVE
    reason: >-
      Protein binding is uninformative. Interactions between E2 conjugating
      enzymes and E3 ligases are functional aspects of ubiquitin protein
      ligase activity, not mere binding.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21343306
  review:
    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.
    action: REMOVE
    reason: >-
      Protein binding is uninformative. The interaction is in the context
      of an E3 ligase complex for ERAD substrate degradation.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:22119785
  review:
    summary: >-
      IPI for protein binding from an integrative ERAD network mapping study.
      This large-scale study defined human ERAD interaction networks.
    action: REMOVE
    reason: >-
      Protein binding is uninformative. These interactions represent
      functional ERAD complex assembly rather than nonspecific binding.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:26551274
  review:
    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.
    action: REMOVE
    reason: >-
      Protein binding is uninformative. The interaction reflects IRE1alpha
      being an endogenous ERAD substrate of SYVN1.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:28827405
  review:
    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.
    action: REMOVE
    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.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:31477895
  review:
    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.
    action: REMOVE
    reason: >-
      Protein binding is uninformative. The interaction reflects an
      E3 ligase-substrate relationship where HRD1 ubiquitinates USP15.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  review:
    summary: >-
      IPI for protein binding from a dual proteome-scale interactome study.
      High-throughput interaction data.
    action: REMOVE
    reason: >-
      Protein binding is uninformative for a protein with well-characterized
      specific binding activities (E3 ligase activity, ERAD complex formation).
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:35271311
  review:
    summary: >-
      IPI for protein binding from the OpenCell endogenous tagging study.
      High-throughput interactome data.
    action: REMOVE
    reason: >-
      Protein binding is uninformative. More specific functional annotations
      are available.
# ============================================================
# Additional IEA annotations
# ============================================================
- term:
    id: GO:0140297
    label: DNA-binding transcription factor binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    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).
    action: MARK_AS_OVER_ANNOTATED
    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.
# ============================================================
# IDA/HPA localization annotations
# ============================================================
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  review:
    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.
    action: REMOVE
    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.
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  review:
    summary: >-
      IDA from HPA immunofluorescence data. SYVN1 localization to the ER
      is well-established (PMID:14593114, PMID:12459480).
    action: ACCEPT
    reason: >-
      Consistent with extensive experimental evidence of ER localization.
    supported_by:
      - reference_id: PMID:14593114
        supporting_text: >-
          We show that human HRD1 is a non-glycosylated, stable ER protein
          with a cytosolic RING-H2 finger domain.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  review:
    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.
    action: REMOVE
    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.
# ============================================================
# Reactome TAS - ubiquitin protein ligase activity
# ============================================================
- term:
    id: GO:0061630
    label: ubiquitin protein ligase activity
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8867288
  review:
    summary: >-
      TAS from Reactome pathway for ubiquitination of unfolded glycoproteins
      by the OS9:SEL1:ERAD E3 ligase:DERL2 complex. Consistent with core
      function.
    action: ACCEPT
    reason: >-
      Reactome pathway annotation consistent with the well-established E3
      ligase activity of SYVN1 in the context of ERAD.
# ============================================================
# More protein binding IPI annotations
# ============================================================
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:37943610
  review:
    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.
    action: REMOVE
    reason: >-
      Protein binding is uninformative. This is a functional HRD1-SEL1L
      complex interaction already captured by complex annotations.
# ============================================================
# Complex/compartment IDA annotations
# ============================================================
- term:
    id: GO:0000836
    label: Hrd1p ubiquitin ligase complex
  evidence_type: IDA
  original_reference_id: PMID:28827405
  review:
    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.
    action: ACCEPT
    reason: >-
      Core annotation. SYVN1/HRD1 is the central catalytic component of the
      Hrd1 ubiquitin ligase complex.
    supported_by:
      - reference_id: PMID:28827405
        supporting_text: >-
          Conserved cytoplasmic domains promote Hrd1 ubiquitin ligase complex
          formation for ER-associated degradation (ERAD).
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: IDA
  original_reference_id: PMID:37795761
  review:
    summary: >-
      IDA showing SYVN1 localization to the ER from a study on UFMylation
      of HRD1 (PMID:37795761). Consistent with established localization.
    action: ACCEPT
    reason: >-
      Consistent with the well-established ER localization of SYVN1.
    supported_by:
      - reference_id: PMID:37795761
        supporting_text: >-
          HRD1, a ubiquitin ligase of ER-associated protein degradation
          (ERAD), is a novel substrate of UFM1 conjugation.
# ============================================================
# IEA protein ubiquitination
# ============================================================
- term:
    id: GO:0016567
    label: protein ubiquitination
  evidence_type: IEA
  original_reference_id: GO_REF:0000041
  review:
    summary: >-
      IEA from UniPathway vocabulary mapping. Protein ubiquitination is
      a core process carried out by SYVN1's E3 ligase activity.
    action: ACCEPT
    reason: >-
      Correct electronic annotation for a fundamental process catalyzed
      by SYVN1.
# ============================================================
# Ubiquitin-dependent protein catabolic process (IDA/TAS)
# ============================================================
- term:
    id: GO:0006511
    label: ubiquitin-dependent protein catabolic process
  evidence_type: IDA
  original_reference_id: PMID:14593114
  review:
    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.
    action: ACCEPT
    reason: >-
      Core function directly demonstrated by in vitro and cell-based assays.
    supported_by:
      - reference_id: PMID:14593114
        supporting_text: >-
          Human HRD1 is an E3 ubiquitin ligase involved in degradation of
          proteins from the endoplasmic reticulum.
- term:
    id: GO:0006511
    label: ubiquitin-dependent protein catabolic process
  evidence_type: IDA
  original_reference_id: PMID:17059562
  review:
    summary: >-
      IDA showing SYVN1 promotes ubiquitylation and degradation of Pael
      receptor (GPR37), demonstrating its role in ubiquitin-dependent protein
      catabolism (PMID:17059562).
    action: ACCEPT
    reason: >-
      Core function demonstrated by showing HRD1 promotes Pael-R
      ubiquitylation and degradation.
    supported_by:
      - reference_id: PMID:17059562
        supporting_text: >-
          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.
- term:
    id: GO:0006511
    label: ubiquitin-dependent protein catabolic process
  evidence_type: TAS
  original_reference_id: PMID:23710284
  review:
    summary: >-
      TAS from a review on HRD1 role in ER stress and Parkinson's disease.
      Consistent with core function.
    action: ACCEPT
    reason: >-
      Review article supporting the well-established role of SYVN1 in
      ubiquitin-dependent protein catabolism.
# ============================================================
# ERAD pathway (IDA/TAS/IMP) annotations
# ============================================================
- term:
    id: GO:0036503
    label: ERAD pathway
  evidence_type: IDA
  original_reference_id: PMID:14593114
  review:
    summary: >-
      IDA demonstrating SYVN1 function in the ERAD pathway. PMID:14593114
      showed HRD1 mediates degradation of model ERAD substrates TCR-alpha
      and CD3-delta.
    action: ACCEPT
    reason: >-
      Core function with direct experimental demonstration.
    supported_by:
      - reference_id: PMID:14593114
        supporting_text: >-
          We show that human HRD1 is involved in the elimination of two model
          ER-associated degradation substrates, TCR-alpha and CD3-delta.
- term:
    id: GO:0036503
    label: ERAD pathway
  evidence_type: IDA
  original_reference_id: PMID:17059562
  review:
    summary: >-
      IDA demonstrating SYVN1 function in ERAD by promoting ubiquitylation
      and degradation of the Pael receptor (PMID:17059562).
    action: ACCEPT
    reason: >-
      Core function supported by direct experimental evidence.
    supported_by:
      - reference_id: PMID:17059562
        supporting_text: >-
          HRD1 promotes the degradation of Pael receptor, a substrate of
          Parkin.
- term:
    id: GO:0036503
    label: ERAD pathway
  evidence_type: TAS
  original_reference_id: PMID:22013210
  review:
    summary: >-
      TAS from a review on the unfolded protein response and IRE1alpha.
      Discusses HRD1 in context of ERAD.
    action: ACCEPT
    reason: >-
      Review article supporting the core ERAD function of SYVN1.
- term:
    id: GO:0036503
    label: ERAD pathway
  evidence_type: TAS
  original_reference_id: PMID:23710284
  review:
    summary: >-
      TAS from a review on HRD1 in ER stress and Parkinson's disease.
    action: ACCEPT
    reason: >-
      Consistent with core ERAD function.
# ============================================================
# Ubiquitin protein ligase activity (IDA) - core annotations
# ============================================================
- term:
    id: GO:0061630
    label: ubiquitin protein ligase activity
  evidence_type: IDA
  original_reference_id: PMID:14593114
  review:
    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.
    action: ACCEPT
    reason: >-
      Core molecular function demonstrated by direct in vitro assay.
    supported_by:
      - reference_id: PMID:14593114
        supporting_text: >-
          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
- term:
    id: GO:0070936
    label: protein K48-linked ubiquitination
  evidence_type: IDA
  original_reference_id: PMID:14593114
  review:
    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.
    action: ACCEPT
    reason: >-
      Core annotation with direct biochemical evidence. K48-linked
      ubiquitination is the mechanism by which SYVN1 targets substrates
      for proteasomal degradation.
    supported_by:
      - reference_id: PMID:14593114
        supporting_text: >-
          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
# ============================================================
# ER mannose trimming (Reactome TAS)
# ============================================================
- term:
    id: GO:1904380
    label: endoplasmic reticulum mannose trimming
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-901032
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    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.
    supported_by:
      - reference_id: PMID:21062743
        supporting_text: >-
          In contrast, substrate association with XTP3-B and with the E3
          ubiquitin ligases HRD1 and SCF(Fbs2) was inhibited
# ============================================================
# ERQC compartment (IDA)
# ============================================================
- term:
    id: GO:0044322
    label: endoplasmic reticulum quality control compartment
  evidence_type: IDA
  original_reference_id: PMID:23233672
  review:
    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.
    action: ACCEPT
    reason: >-
      Direct experimental evidence for ERQC localization consistent with
      SYVN1's ERAD function.
    supported_by:
      - reference_id: PMID:23233672
        supporting_text: >-
          Proteasomal inhibition induced accumulation of the nonglycosylated
          proteins and ERAD machinery in the endoplasmic reticulum-derived
          quality control compartment.
- term:
    id: GO:0044322
    label: endoplasmic reticulum quality control compartment
  evidence_type: IDA
  original_reference_id: PMID:24478453
  review:
    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.
    action: ACCEPT
    reason: >-
      Direct experimental evidence for ERQC localization.
    supported_by:
      - reference_id: PMID:24478453
        supporting_text: >-
          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.
# ============================================================
# Ubiquitin protein ligase activity (IMP)
# ============================================================
- term:
    id: GO:0061630
    label: ubiquitin protein ligase activity
  evidence_type: IMP
  original_reference_id: PMID:28842558
  review:
    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.
    action: ACCEPT
    reason: >-
      Core molecular function demonstrated by mutant phenotype analysis in
      the context of lymphoma pathogenesis.
    supported_by:
      - reference_id: PMID:28842558
        supporting_text: >-
          The degradation of lymphoma-associated mutants is accelerated by
          subversion of this pathway to Hrd1-mediated cytoplasmic
          sequestration and ubiquitination.
# ============================================================
# Immature B cell differentiation (ISS)
# ============================================================
- term:
    id: GO:0002327
    label: immature B cell differentiation
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    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).
    action: KEEP_AS_NON_CORE
    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.
# ============================================================
# ERAD-L complex (IDA/IMP)
# ============================================================
- term:
    id: GO:0000839
    label: Hrd1p ubiquitin ligase ERAD-L complex
  evidence_type: IDA
  original_reference_id: PMID:28827405
  review:
    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.
    action: ACCEPT
    reason: >-
      Core annotation. SYVN1/HRD1 is the central E3 ligase of both the
      Hrd1 complex and its ERAD-L subcomplex.
    supported_by:
      - reference_id: PMID:28827405
        supporting_text: >-
          Conserved cytoplasmic domains promote Hrd1 ubiquitin ligase complex
          formation for ER-associated degradation (ERAD).
- term:
    id: GO:0036503
    label: ERAD pathway
  evidence_type: IMP
  original_reference_id: PMID:28827405
  review:
    summary: >-
      IMP demonstrating SYVN1 function in ERAD. PMID:28827405 showed that
      mutation of HRD1 cytoplasmic domains impairs ERAD substrate degradation.
    action: ACCEPT
    reason: >-
      Core function demonstrated by mutant phenotype analysis.
# ============================================================
# Protein stabilization (IMP)
# ============================================================
- term:
    id: GO:0050821
    label: protein stabilization
  evidence_type: IMP
  original_reference_id: PMID:21454652
  review:
    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.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
      - reference_id: PMID:21454652
        supporting_text: >-
          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.
# ============================================================
# ERAD-L complex (IMP) - SEL1L TM domain study
# ============================================================
- term:
    id: GO:0000839
    label: Hrd1p ubiquitin ligase ERAD-L complex
  evidence_type: IMP
  original_reference_id: PMID:26471130
  review:
    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.
    action: ACCEPT
    reason: >-
      Core complex annotation supported by mutant phenotype analysis.
    supported_by:
      - reference_id: PMID:26471130
        supporting_text: >-
          Association of the SEL1L protein transmembrane domain with HRD1
          ubiquitin ligase regulates ERAD-L.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:26471130
  review:
    summary: >-
      IPI for protein binding based on interaction with SEL1L. This is a
      functional complex component interaction within the ERAD machinery.
    action: REMOVE
    reason: >-
      Protein binding is uninformative. The SEL1L interaction is a
      functional ERAD complex assembly interaction already captured by
      Hrd1p ubiquitin ligase complex annotations.
- term:
    id: GO:0036503
    label: ERAD pathway
  evidence_type: IMP
  original_reference_id: PMID:26471130
  review:
    summary: >-
      IMP demonstrating SYVN1 function in ERAD, showing SEL1L TM domain
      interaction with HRD1 is required for ERAD-L function.
    action: ACCEPT
    reason: >-
      Core function supported by mutant phenotype analysis.
# ============================================================
# ER membrane (NAS)
# ============================================================
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: NAS
  original_reference_id: PMID:14593114
  review:
    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.
    action: ACCEPT
    reason: >-
      Correct annotation well-supported by the cited reference and
      consistent with extensive experimental evidence.
    supported_by:
      - reference_id: PMID:14593114
        supporting_text: >-
          We show that human HRD1 is a non-glycosylated, stable ER protein
          with a cytosolic RING-H2 finger domain.
# ============================================================
# Hrd1 complex (TAS)
# ============================================================
- term:
    id: GO:0000836
    label: Hrd1p ubiquitin ligase complex
  evidence_type: TAS
  original_reference_id: PMID:21454652
  review:
    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.
    action: ACCEPT
    reason: >-
      Core complex annotation supported by the cited study.
    supported_by:
      - reference_id: PMID:21454652
        supporting_text: >-
          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
# ============================================================
# Derlin-1 retrotranslocation complex (IDA)
# ============================================================
- term:
    id: GO:0036513
    label: Derlin-1 retrotranslocation complex
  evidence_type: IDA
  original_reference_id: PMID:21454652
  review:
    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.
    action: ACCEPT
    reason: >-
      Well-supported by experimental evidence. SYVN1 functions together with
      Derlin-1 in the retrotranslocation channel for ERAD substrates.
    supported_by:
      - reference_id: PMID:21454652
        supporting_text: >-
          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
# ============================================================
# Protein ubiquitination (IDA) - USP25 study
# ============================================================
- term:
    id: GO:0016567
    label: protein ubiquitination
  evidence_type: IDA
  original_reference_id: PMID:22590560
  review:
    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.
    action: ACCEPT
    reason: >-
      Core function with direct experimental evidence.
    supported_by:
      - reference_id: PMID:22590560
        supporting_text: >-
          HRD1 increases ubiquitination of CD3δ in cells. The presence
          of USP25 significantly reduces levels of ubiquitinated CD3δ
- term:
    id: GO:0036503
    label: ERAD pathway
  evidence_type: IDA
  original_reference_id: PMID:22590560
  review:
    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.
    action: ACCEPT
    reason: >-
      Core function supported by experimental evidence.
- term:
    id: GO:0051117
    label: ATPase binding
  evidence_type: IPI
  original_reference_id: PMID:22590560
  review:
    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.
    action: ACCEPT
    reason: >-
      Functionally informative binding annotation. VCP/p97 interaction is
      essential for SYVN1's ERAD function, coupling ubiquitination to
      substrate extraction.
    supported_by:
      - reference_id: PMID:22590560
        supporting_text: >-
          Conversely, HRD1 interacts with USP25 and VCP/p97 (Figure 1D)
- term:
    id: GO:0061630
    label: ubiquitin protein ligase activity
  evidence_type: NAS
  original_reference_id: PMID:22590560
  review:
    summary: >-
      NAS for ubiquitin protein ligase activity from PMID:22590560.
      The paper describes HRD1 as an ER-resident ubiquitin ligase
      throughout.
    action: ACCEPT
    reason: >-
      Consistent with core molecular function.
- term:
    id: GO:1990381
    label: ubiquitin-specific protease binding
  evidence_type: IPI
  original_reference_id: PMID:22590560
  review:
    summary: >-
      IPI showing SYVN1 interacts with USP25. PMID:22590560 demonstrated
      co-immunoprecipitation of endogenous HRD1 with USP25. USP25
      counteracts HRD1 ubiquitination of ERAD substrates.
    action: ACCEPT
    reason: >-
      Functionally informative binding annotation. USP25 interaction
      represents a regulatory mechanism for HRD1's E3 ligase activity
      in ERAD.
    supported_by:
      - reference_id: PMID:22590560
        supporting_text: >-
          Importantly, HRD1 and endogenous USP25 interact in cells (Figure
          1E), but USP25 does not interact with other ubiquitin ligases
          implicated in ERAD
# ============================================================
# ERQC compartment (TAS) and ligase activity (TAS)
# ============================================================
- term:
    id: GO:0044322
    label: endoplasmic reticulum quality control compartment
  evidence_type: TAS
  original_reference_id: PMID:21062743
  review:
    summary: >-
      TAS for ERQC localization from PMID:21062743. This study showed HRD1
      association with ERAD substrates at the ERQC depends on mannose
      trimming.
    action: ACCEPT
    reason: >-
      Consistent with HRD1's established ERQC localization.
    supported_by:
      - reference_id: PMID:21062743
        supporting_text: >-
          In contrast, substrate association with XTP3-B and with the E3
          ubiquitin ligases HRD1 and SCF(Fbs2) was inhibited
- term:
    id: GO:0061630
    label: ubiquitin protein ligase activity
  evidence_type: TAS
  original_reference_id: PMID:21062743
  review:
    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.
    action: ACCEPT
    reason: >-
      Consistent with core molecular function.
# ============================================================
# Protein binding IPI - YOD1 study
# ============================================================
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:24068323
  review:
    summary: >-
      IPI for protein binding from a study on the deubiquitinase YOD1 and
      retrotranslocation of nonubiquitinated substrates (PMID:24068323).
    action: REMOVE
    reason: >-
      Protein binding is uninformative. Already captured by more specific
      ubiquitin-specific protease binding annotations.
- term:
    id: GO:1990381
    label: ubiquitin-specific protease binding
  evidence_type: IPI
  original_reference_id: PMID:24068323
  review:
    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.
    action: ACCEPT
    reason: >-
      Functionally informative binding annotation. YOD1 is an ERAD-associated
      DUB that acts on the HRD1 complex machinery.
# ============================================================
# ER localization (IDA) - key papers
# ============================================================
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: IDA
  original_reference_id: PMID:14593114
  review:
    summary: >-
      IDA demonstrating SYVN1 localization to the ER. PMID:14593114
      showed HRD1 is a stable ER protein using immunofluorescence and
      biochemical fractionation.
    action: ACCEPT
    reason: >-
      Core localization with direct experimental evidence.
    supported_by:
      - reference_id: PMID:14593114
        supporting_text: >-
          We show that human HRD1 is a non-glycosylated, stable ER protein
          with a cytosolic RING-H2 finger domain.
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: IDA
  original_reference_id: PMID:17059562
  review:
    summary: >-
      IDA demonstrating SYVN1 localization to the ER from PMID:17059562.
      Consistent with established localization.
    action: ACCEPT
    reason: >-
      Core localization confirmed by immunofluorescence.
# ============================================================
# Unfolded protein binding (ALREADY REVIEWED - REMOVE)
# ============================================================
- term:
    id: GO:0051082
    label: unfolded protein binding
  evidence_type: IPI
  original_reference_id: PMID:17059562
  review:
    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 being obsoleted
      (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).
    action: REMOVE
    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
      being obsoleted (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.
    supported_by:
      - reference_id: PMID:17059562
        supporting_text: >-
          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.
# ============================================================
# Protein-folding chaperone binding (IPI)
# ============================================================
- term:
    id: GO:0051087
    label: protein-folding chaperone binding
  evidence_type: IPI
  original_reference_id: PMID:21636303
  review:
    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.
    action: ACCEPT
    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.
    supported_by:
      - reference_id: PMID:21636303
        supporting_text: >-
          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.
# ============================================================
# Ubiquitin protein ligase activity (IDA) - PMID:17059562
# ============================================================
- term:
    id: GO:0061630
    label: ubiquitin protein ligase activity
  evidence_type: IDA
  original_reference_id: PMID:17059562
  review:
    summary: >-
      IDA demonstrating SYVN1 E3 ligase activity. PMID:17059562 showed HRD1
      promotes ubiquitylation and degradation of Pael-R, with RING finger
      activity required.
    action: ACCEPT
    reason: >-
      Core molecular function with direct experimental evidence.
    supported_by:
      - reference_id: PMID:17059562
        supporting_text: >-
          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
# ============================================================
# Anti-apoptotic signaling (IDA) - PMID:17059562
# ============================================================
- term:
    id: GO:1902236
    label: negative regulation of endoplasmic reticulum stress-induced intrinsic apoptotic
      signaling pathway
  evidence_type: IDA
  original_reference_id: PMID:17059562
  review:
    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.
    action: ACCEPT
    reason: >-
      Well-supported annotation. HRD1 protects against ER stress-induced
      apoptosis by promoting degradation of toxic misfolded substrates.
    supported_by:
      - reference_id: PMID:17059562
        supporting_text: >-
          The disruption of endogenous HRD1 by small interfering RNA (siRNA)
          induced Pael-R accumulation and caspase-3 activation.
# ============================================================
# Retrograde protein transport (IMP)
# ============================================================
- term:
    id: GO:0030970
    label: retrograde protein transport, ER to cytosol
  evidence_type: IMP
  original_reference_id: PMID:25660456
  review:
    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.
    action: ACCEPT
    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.
# ============================================================
# Smooth ER (IDA)
# ============================================================
- term:
    id: GO:0005790
    label: smooth endoplasmic reticulum
  evidence_type: IDA
  original_reference_id: PMID:16186510
  review:
    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.
    action: ACCEPT
    reason: >-
      Experimentally supported localization consistent with retrotranslocation
      sites at the ER membrane.
# ============================================================
# ATPase binding (IPI) - PMID:16186510
# ============================================================
- term:
    id: GO:0051117
    label: ATPase binding
  evidence_type: IPI
  original_reference_id: PMID:16186510
  review:
    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.
    action: ACCEPT
    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.
    supported_by:
      - reference_id: PMID:16186510
        supporting_text: >-
          p97 interacts directly with several ubiquitin ligases and
          facilitates their recruitment to Derlin-1.
# ============================================================
# Protein ubiquitination and ligase activity (IDA) - PMID:12459480
# ============================================================
- term:
    id: GO:0016567
    label: protein ubiquitination
  evidence_type: IDA
  original_reference_id: PMID:12459480
  review:
    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.
    action: ACCEPT
    reason: >-
      Core function with direct experimental evidence including mutant
      analysis.
    supported_by:
      - reference_id: PMID:12459480
        supporting_text: >-
          Human HRD1 was localized to the ER and ubiquitinated its substrates.
- term:
    id: GO:0061630
    label: ubiquitin protein ligase activity
  evidence_type: IDA
  original_reference_id: PMID:12459480
  review:
    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.
    action: ACCEPT
    reason: >-
      Core molecular function with direct evidence including mutagenesis.
    supported_by:
      - reference_id: PMID:12459480
        supporting_text: >-
          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.
# ============================================================
# Anti-apoptotic signaling (IDA) - PMID:12459480
# ============================================================
- term:
    id: GO:1902236
    label: negative regulation of endoplasmic reticulum stress-induced intrinsic apoptotic
      signaling pathway
  evidence_type: IDA
  original_reference_id: PMID:12459480
  review:
    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.
    action: ACCEPT
    reason: >-
      Well-supported annotation from the foundational paper on HRD1's
      anti-apoptotic function. Requires E3 ligase activity (RING finger).
    supported_by:
      - reference_id: PMID:12459480
        supporting_text: >-
          293 cells stably expressing wild-type HRD1, but not the C329S
          mutant, afforded resistance to ER stress-induced apoptosis.
# ============================================================
# Hrd1 complex (TAS) - PMID:23710284
# ============================================================
- term:
    id: GO:0000836
    label: Hrd1p ubiquitin ligase complex
  evidence_type: TAS
  original_reference_id: PMID:23710284
  review:
    summary: >-
      TAS for Hrd1 ubiquitin ligase complex from a review on HRD1 in ER
      stress and Parkinson's disease.
    action: ACCEPT
    reason: >-
      Consistent with core complex annotation.
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: TAS
  original_reference_id: PMID:23710284
  review:
    summary: >-
      TAS for ER localization from a review on HRD1 in Parkinson's disease.
    action: ACCEPT
    reason: >-
      Consistent with established ER localization.
- term:
    id: GO:0016567
    label: protein ubiquitination
  evidence_type: TAS
  original_reference_id: PMID:23710284
  review:
    summary: >-
      TAS for protein ubiquitination from a review discussing HRD1's
      E3 ligase function.
    action: ACCEPT
    reason: >-
      Consistent with core function.
- term:
    id: GO:0061630
    label: ubiquitin protein ligase activity
  evidence_type: TAS
  original_reference_id: PMID:23710284
  review:
    summary: >-
      TAS for ubiquitin protein ligase activity from a review on HRD1.
    action: ACCEPT
    reason: >-
      Consistent with core molecular function.
- term:
    id: GO:1902236
    label: negative regulation of endoplasmic reticulum stress-induced intrinsic apoptotic
      signaling pathway
  evidence_type: TAS
  original_reference_id: PMID:23710284
  review:
    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.
    action: ACCEPT
    reason: >-
      Consistent with HRD1's established anti-apoptotic function.
# ============================================================
# Protein binding IPI - IRE1alpha/USP14
# ============================================================
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:19135427
  review:
    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.
    action: REMOVE
    reason: >-
      Protein binding is uninformative. The interaction reflects ERAD
      regulatory mechanisms already captured by ERAD pathway and complex
      annotations.
# ============================================================
# ERAD pathway and ligase activity (IMP) - MHC class I
# ============================================================
- term:
    id: GO:0036503
    label: ERAD pathway
  evidence_type: IMP
  original_reference_id: PMID:21245296
  review:
    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.
    action: ACCEPT
    reason: >-
      Core function demonstrated by loss-of-function analysis in a
      physiologically important ERAD substrate pathway.
    supported_by:
      - reference_id: PMID:21245296
        supporting_text: >-
          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.
- term:
    id: GO:0061630
    label: ubiquitin protein ligase activity
  evidence_type: IMP
  original_reference_id: PMID:21245296
  review:
    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.
    action: ACCEPT
    reason: >-
      Core molecular function demonstrated by loss-of-function analysis.
    supported_by:
      - reference_id: PMID:21245296
        supporting_text: >-
          HRD1 is also required for the ubiquitination and degradation of the
          naturally occurring hemochromatosis-associated HFE-C282Y mutant,
          which is unable to bind β2m
# ============================================================
# Ubiquitin protein ligase activity (IDA) - CYP3A4 study
# ============================================================
- term:
    id: GO:0061630
    label: ubiquitin protein ligase activity
  evidence_type: IDA
  original_reference_id: PMID:19103148
  review:
    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.
    action: UNDECIDED
    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.
# ============================================================
# Membrane (HDA)
# ============================================================
- term:
    id: GO:0016020
    label: membrane
  evidence_type: HDA
  original_reference_id: PMID:19946888
  review:
    summary: >-
      HDA annotation from a proteomics study defining the membrane proteome
      of NK cells. SYVN1 is indeed a multi-pass transmembrane protein.
    action: ACCEPT
    reason: >-
      Correct but very broad. SYVN1 is a multi-pass transmembrane protein.
      More specific ER membrane annotations are already present.
# ============================================================
# Protein binding IPI - UBXD6 study
# ============================================================
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21949850
  review:
    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.
    action: REMOVE
    reason: >-
      Protein binding is uninformative. The interaction is within the ERAD
      machinery context already captured by more specific annotations.
# ============================================================
# ER membrane (TAS) - multiple Reactome references
# ============================================================
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-1791084
  review:
    summary: >-
      TAS from Reactome for expression of SYVN1 at the ER membrane.
    action: ACCEPT
    reason: >-
      Correct annotation consistent with ER membrane localization.
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5362412
  review:
    summary: >-
      TAS from Reactome for SYVN1 ubiquitination of Hedgehog C-terminal
      fragments at the ER membrane.
    action: ACCEPT
    reason: >-
      Correct annotation in context of Hedgehog processing ERAD pathway.
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5362441
  review:
    summary: >-
      TAS from Reactome for recruitment of Hedgehog fragments to SEL1:SYVN1
      at the ER membrane.
    action: ACCEPT
    reason: >-
      Correct annotation.
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5362459
  review:
    summary: >-
      TAS from Reactome for VCP-catalyzed translocation of Hedgehog-C
      at the ER membrane.
    action: ACCEPT
    reason: >-
      Correct annotation.
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5387386
  review:
    summary: >-
      TAS from Reactome for recruitment of Hedgehog processing variants
      to SEL1:SYVN at the ER membrane.
    action: ACCEPT
    reason: >-
      Correct annotation.
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5387389
  review:
    summary: >-
      TAS from Reactome for VCP-dependent translocation of Hedgehog
      processing variants at the ER membrane.
    action: ACCEPT
    reason: >-
      Correct annotation.
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5483238
  review:
    summary: >-
      TAS from Reactome for ubiquitination of Hedgehog processing variants
      at the ER membrane.
    action: ACCEPT
    reason: >-
      Correct annotation.
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8867288
  review:
    summary: >-
      TAS from Reactome for OS9:SEL1:ERAD E3 ligase:DERL2 ubiquitination
      of unfolded glycoproteins at the ER membrane.
    action: ACCEPT
    reason: >-
      Correct annotation.
# ============================================================
# ERAD pathway (IMP) - STT3B study
# ============================================================
- term:
    id: GO:0036503
    label: ERAD pathway
  evidence_type: IMP
  original_reference_id: PMID:22607976
  review:
    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.
    action: ACCEPT
    reason: >-
      Core function demonstrated in the context of glycosylation-dependent
      ERAD quality control.
# ============================================================
# Protein binding IPI - OS-9/ERLEC1/SEL1L complex studies
# ============================================================
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:18502753
  review:
    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).
    action: REMOVE
    reason: >-
      Protein binding is uninformative. The interaction is a functional
      ERAD complex assembly already captured by Hrd1 complex and ERQC
      annotations.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:18264092
  review:
    summary: >-
      IPI for protein binding from a study on OS-9 and GRP94 delivering
      mutant alpha1-antitrypsin to the Hrd1-SEL1L complex (PMID:18264092).
    action: REMOVE
    reason: >-
      Protein binding is uninformative. The interaction is functional ERAD
      substrate delivery to the HRD1 complex.
# ============================================================
# ER localization (IDA) and ERAD pathway (IDA) - PMID:12459480
# ============================================================
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: IDA
  original_reference_id: PMID:12459480
  review:
    summary: >-
      IDA demonstrating SYVN1 localization to the ER. PMID:12459480
      showed HRD1 was localized to the ER by immunofluorescence.
    action: ACCEPT
    reason: >-
      Core localization with direct experimental evidence.
    supported_by:
      - reference_id: PMID:12459480
        supporting_text: >-
          Human HRD1 was localized to the ER and ubiquitinated its substrates.
- term:
    id: GO:0036503
    label: ERAD pathway
  evidence_type: IDA
  original_reference_id: PMID:12459480
  review:
    summary: >-
      IDA demonstrating SYVN1 function in the ERAD pathway. PMID:12459480
      showed HRD1 protects against ER stress through ER-associated
      degradation.
    action: ACCEPT
    reason: >-
      Core function from the foundational paper on human HRD1.
    supported_by:
      - reference_id: PMID:12459480
        supporting_text: >-
          Human HRD1 protects against ER stress-induced apoptosis through
          ER-associated degradation.
core_functions:
- description: >-
    SYVN1/HRD1 is the central E3 ubiquitin-protein ligase of the ERAD pathway,
    representing the most conserved branch of mammalian ERAD. Its RING-H2 zinc
    finger domain catalyzes K48-linked polyubiquitination of misfolded ER
    substrates (including TCR-alpha, CD3-delta, Pael-R, MHC class I heavy chains,
    IRE1alpha, and APOB), targeting them for VCP/p97-dependent retrotranslocation
    and proteasomal degradation. Physical SEL1L-HRD1 interaction is required for
    recruitment of the E2 enzyme UBE2J1 and DERLIN proteins to form a functional
    ERAD complex (DOI:10.1038/s41467-024-45633-0). SYVN1 also forms the
    retrotranslocation channel and protects cells from ER stress-induced
    apoptosis. Hypomorphic SYVN1 variants cause impaired ERAD substrate clearance
    and are associated with neurodevelopmental disorders in humans
    (DOI:10.1172/jci170054). Beyond ERAD, SYVN1 ubiquitinates regulatory
    substrates including SIRT2 (modulating ER stress/EMT in airway remodeling),
    GSDMD (modulating inflammasome/pyroptosis), and HMGB1
    (DOI:10.1186/s40659-023-00478-7, DOI:10.1002/iid3.880).
  molecular_function:
    id: GO:0061630
    label: ubiquitin protein ligase activity
  directly_involved_in:
    - id: GO:0036503
      label: ERAD pathway
    - id: GO:0070936
      label: protein K48-linked ubiquitination
    - id: GO:0030970
      label: retrograde protein transport, ER to cytosol
    - id: GO:1902236
      label: negative regulation of endoplasmic reticulum stress-induced intrinsic
        apoptotic signaling pathway
  locations:
    - id: GO:0005789
      label: endoplasmic reticulum membrane
    - id: GO:0044322
      label: endoplasmic reticulum quality control compartment
  in_complex:
    id: GO:0000836
    label: Hrd1p ubiquitin ligase complex
  supported_by:
    - reference_id: PMID:14593114
      supporting_text: >-
        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
    - reference_id: PMID:12459480
      supporting_text: >-
        293 cells stably expressing wild-type HRD1, but not the C329S mutant,
        afforded resistance to ER stress-induced apoptosis.
    - reference_id: PMID:17059562
      supporting_text: >-
        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
references:
- id: GO_REF:0000003
  title: Gene Ontology annotation based on Enzyme Commission mapping
  findings: []
- id: GO_REF:0000024
  title: Manual transfer of experimentally-verified manual GO annotation data to orthologs
    by curator judgment of sequence similarity
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000041
  title: Gene Ontology annotation based on UniPathway vocabulary mapping
  findings: []
- id: GO_REF:0000043
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location
    vocabulary mapping, accompanied by conservative changes to GO terms applied by
    UniProt
  findings: []
- id: GO_REF:0000052
  title: Gene Ontology annotation based on curation of immunofluorescence data
  findings: []
- id: GO_REF:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data to
    orthologs using Ensembl Compara
  findings: []
- id: GO_REF:0000117
  title: Electronic Gene Ontology annotations created by ARBA machine learning models
  findings: []
- id: PMID:12459480
  title: Human HRD1 protects against ER stress-induced apoptosis through ER-associated
    degradation.
  findings: []
- id: PMID:14593114
  title: Human HRD1 is an E3 ubiquitin ligase involved in degradation of proteins
    from the endoplasmic reticulum.
  findings: []
- id: PMID:16186510
  title: Recruitment of the p97 ATPase and ubiquitin ligases to the site of retrotranslocation
    at the endoplasmic reticulum membrane.
  findings: []
- id: PMID:17059562
  title: A ubiquitin ligase HRD1 promotes the degradation of Pael receptor, a substrate
    of Parkin.
  findings: []
- id: PMID:17170702
  title: Cytoplasmic destruction of p53 by the endoplasmic reticulum-resident ubiquitin
    ligase 'Synoviolin'.
  findings: []
- id: PMID:18264092
  title: OS-9 and GRP94 deliver mutant alpha1-antitrypsin to the Hrd1-SEL1L ubiquitin
    ligase complex for ERAD.
  findings: []
- id: PMID:18369366
  title: Synoviolin promotes IRE1 ubiquitination and degradation in synovial fibroblasts
    from mice with collagen-induced arthritis.
  findings: []
- id: PMID:18502753
  title: Human XTP3-B forms an endoplasmic reticulum quality control scaffold with
    the HRD1-SEL1L ubiquitin ligase complex and BiP.
  findings: []
- id: PMID:19103148
  title: CYP3A4 ubiquitination by gp78 (the tumor autocrine motility factor receptor,
    AMFR) and CHIP E3 ligases.
  findings: []
- id: PMID:19135427
  title: USP14 inhibits ER-associated degradation via interaction with IRE1alpha.
  findings: []
- id: PMID:19690564
  title: A comprehensive framework of E2-RING E3 interactions of the human ubiquitin-proteasome
    system.
  findings: []
- id: PMID:19946888
  title: Defining the membrane proteome of NK cells.
  findings: []
- id: PMID:21062743
  title: Mannose trimming is required for delivery of a glycoprotein from EDEM1 to
    XTP3-B and to late endoplasmic reticulum-associated degradation steps.
  findings: []
- id: PMID:21245296
  title: HRD1 and UBE2J1 target misfolded MHC class I heavy chains for endoplasmic
    reticulum-associated degradation.
  findings: []
- id: PMID:21343306
  title: Membrane-associated ubiquitin ligase complex containing gp78 mediates sterol-accelerated
    degradation of 3-hydroxy-3-methylglutaryl-coenzyme A reductase.
  findings: []
- id: PMID:21454652
  title: SEL1L protein critically determines the stability of the HRD1-SEL1L endoplasmic
    reticulum-associated degradation (ERAD) complex to optimize the degradation kinetics
    of ERAD substrates.
  findings: []
- id: PMID:21636303
  title: A ubiquitin ligase-associated chaperone holdase maintains polypeptides in
    soluble states for proteasome degradation.
  findings: []
- id: PMID:21949850
  title: The tissue-specific Rep8/UBXD6 tethers p97 to the endoplasmic reticulum membrane
    for degradation of misfolded proteins.
  findings: []
- id: PMID:22013210
  title: 'The unfolded protein response: integrating stress signals through the stress
    sensor IRE1α.'
  findings: []
- id: PMID:22119785
  title: Defining human ERAD networks through an integrative mapping strategy.
  findings: []
- id: PMID:22590560
  title: Ubiquitin-specific protease 25 functions in Endoplasmic Reticulum-associated
    degradation.
  findings: []
- id: PMID:22607976
  title: STT3B-dependent posttranslational N-glycosylation as a surveillance system
    for secretory protein.
  findings: []
- id: PMID:23233672
  title: A shared endoplasmic reticulum-associated degradation pathway involving the
    EDEM1 protein for glycosylated and nonglycosylated proteins.
  findings: []
- id: PMID:23710284
  title: 'Endoplasmic reticulum stress and Parkinson''s disease: the role of HRD1
    in averting apoptosis in neurodegenerative disease.'
  findings: []
- id: PMID:24068323
  title: A deubiquitinase negatively regulates retro-translocation of nonubiquitinated
    substrates.
  findings: []
- id: PMID:24478453
  title: Herp coordinates compartmentalization and recruitment of HRD1 and misfolded
    proteins for ERAD.
  findings: []
- id: PMID:25660456
  title: Identification of ERAD components essential for dislocation of the null Hong
    Kong variant of α-1-antitrypsin (NHK).
  findings: []
- id: PMID:26471130
  title: Association of the SEL1L protein transmembrane domain with HRD1 ubiquitin
    ligase regulates ERAD-L.
  findings: []
- id: PMID:26551274
  title: IRE1α is an endogenous substrate of endoplasmic-reticulum-associated degradation.
  findings: []
- id: PMID:28827405
  title: Conserved cytoplasmic domains promote Hrd1 ubiquitin ligase complex formation
    for ER-associated degradation (ERAD).
  findings: []
- id: PMID:28842558
  title: HSP70-Hrd1 axis precludes the oncorepressor potential of N-terminal misfolded
    Blimp-1s in lymphoma cells.
  findings: []
- id: PMID:31477895
  title: ER-localized Hrd1 ubiquitinates and inactivates Usp15 to promote TLR4-induced
    inflammation during bacterial infection.
  findings: []
- id: PMID:33961781
  title: Dual proteome-scale networks reveal cell-specific remodeling of the human
    interactome.
  findings: []
- id: PMID:35271311
  title: 'OpenCell: Endogenous tagging for the cartography of human cellular organization.'
  findings: []
- id: PMID:37795761
  title: UFMylation of HRD1 regulates endoplasmic reticulum homeostasis.
  findings: []
- id: PMID:37943610
  title: Hypomorphic variants of SEL1L-HRD1 ER-associated degradation are associated
    with neurodevelopmental disorders.
  findings: []
- id: Reactome:R-HSA-1791084
  title: Expression of SYVN1 (HRD1)
  findings: []
- id: Reactome:R-HSA-5362412
  title: SYVN1 ubiquitinates Hh C-terminal fragments
  findings: []
- id: Reactome:R-HSA-5362441
  title: C-terminal Hh fragments are recruited to SEL1:SYVN1 at the ER membrane
  findings: []
- id: Reactome:R-HSA-5362459
  title: VCP-catalyzed ATP hydrolysis promotes the translocation of Hh-C into the
    cytosol
  findings: []
- id: Reactome:R-HSA-5387386
  title: Hh processing variants are recruited to SEL1:SYVN at the ER membrane
  findings: []
- id: Reactome:R-HSA-5387389
  title: Hh processing variants are translocated to the cytosol in a VCP-dependent
    manner
  findings: []
- id: Reactome:R-HSA-5483238
  title: Hh processing variants are ubiquitinated
  findings: []
- id: Reactome:R-HSA-8867288
  title: OS9:SEL1:ERAD E3 ligase:DERL2 ubiquitinates unfolded protein:(GlcNAc)2 (Man)9-5
  findings: []
- id: Reactome:R-HSA-901032
  title: ER Quality Control Compartment (ERQC)
  findings: []
- id: DOI:10.1038/s41467-024-45633-0
  title: SEL1L-HRD1 interaction is required to form a functional HRD1 ERAD complex.
  findings:
  - statement: >-
      SEL1L-HRD1 physical interaction is a prerequisite for recruitment of E2
      UBE2J1 and DERLIN proteins to HRD1, assembling a functional ERAD complex
  - statement: >-
      SEL1L hypomorphic variant S658P weakens SEL1L-HRD1 interaction (~5-fold)
      and causes partial embryonic lethality and cerebellar ataxia in mice
- id: DOI:10.1172/jci170054
  title: Hypomorphic variants of SEL1L-HRD1 ER-associated degradation are associated
    with neurodevelopmental disorders.
  findings:
  - statement: >-
      Autosomal-recessive hypomorphic variants in HRD1/SYVN1 (including
      p.Pro398Leu) cause neurodevelopmental disorders with developmental delay,
      intellectual disability, and microcephaly in humans
  - statement: >-
      ERAD substrates IRE1alpha, OS9, and CD147 accumulate in knock-in cells
      with pathogenic HRD1 variants, confirming impaired ERAD function
- id: DOI:10.1186/s40659-023-00478-7
  title: Role of SYVN1 in the control of airway remodeling in asthma by promoting
    SIRT2 ubiquitination and degradation.
  findings:
  - statement: >-
      SYVN1 binds SIRT2 and promotes its ubiquitination and
      proteasome-dependent degradation in bronchial epithelial cells
  - statement: >-
      SYVN1 activity suppresses ER stress markers GRP78 and CHOP and
      epithelial-mesenchymal transition phenotypes through SIRT2 degradation
- id: DOI:10.1002/iid3.880
  title: Synoviolin alleviates GSDMD-mediated periodontitis by suppressing its stability.
  findings:
  - statement: >-
      Synoviolin/SYVN1 interacts with GSDMD and promotes its ubiquitination,
      modulating inflammasome-driven cytokine release
  - statement: >-
      Myeloid-specific Synoviolin conditional KO mice show greater bone loss
      in a periodontitis model
- id: DOI:10.1073/pnas.2317978121
  title: An evolutionarily conserved ubiquitin ligase drives infection and transmission
    of flaviviruses.
  findings:
  - statement: >-
      HRD1 inhibitor LS-102 blocks HRD1 E3 activity in both mammalian and
      mosquito cells with EC50 values of 1.391 uM (A549) and 2.757 uM (C6/36)
  - statement: >-
      LS-102 treatment at 15 mg/kg in mice reduces dengue viremia and tissue
      viral burden ~10-fold with improved survival
- id: DOI:10.1093/cvr/cvae121
  title: A suite of genome-engineered hepatic cells provides novel insights into the
    spatiotemporal metabolism of apolipoprotein B.
  findings:
  - statement: >-
      SYVN1 identified as the E3 ligase responsible for degradation of poorly
      lipidated APOB in HepG2 cells via a targeted ERAD E3 sgRNA screen

SYVN1

Gene Description

Existing Annotations Review

Core Functions

References

📚 Additional Documentation

Deep Research Falcon

Question

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

Target Gene/Protein Identity (from UniProt):

MANDATORY VERIFICATION STEPS:

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

Research Target:

Output

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

Target Gene/Protein Identity (from UniProt):

MANDATORY VERIFICATION STEPS:

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

Research Target:

Citations

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