ERLEC1

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0005788 endoplasmic reticulum lumen	IBA GO_REF:0000033	ACCEPT	Summary: IBA annotation placing ERLEC1 in the ER lumen, inferred from phylogenetic analysis. This is strongly supported by multiple independent experimental studies. Cruciat et al. (PMID:16531414) showed that Erlectin is a luminal resident protein of the endoplasmic reticulum. Hosokawa et al. (PMID:18502753) confirmed ER lumen localization. Christianson et al. (PMID:18264092) also demonstrated ER lumen localization. UniProt annotates subcellular location as ER lumen with experimental evidence. ERLEC1 has a signal peptide (aa 1-33) and lacks a transmembrane domain, consistent with a soluble ER lumen protein retained by the quality control machinery. Reason: ER lumen localization is a core feature of ERLEC1 function as an ERAD cargo receptor. The IBA annotation is fully consistent with multiple experimental (IDA) demonstrations of ER lumen localization. Supporting Evidence: PMID:16531414 Like other members of the MRH family, Erlectin is a luminal resident protein of the endoplasmic reticulum PMID:18502753 hXTP3-B long isoform associates with the HRD1-SEL1L membrane-anchored ubiquitin ligase complex and BiP, forming a 27 S ER quality control scaffold complex
GO:0030970 retrograde protein transport, ER to cytosol	IBA GO_REF:0000033	ACCEPT	Summary: IBA annotation for involvement in retrograde protein transport, ER to cytosol, inferred from phylogenetic analysis including yeast Yos9p. ERLEC1/XTP3-B is a key component of the ERAD pathway that delivers misfolded glycoproteins to the HRD1-SEL1L ubiquitin ligase complex for retrotranslocation and proteasomal degradation (PMID:18264092, PMID:18502753). Hosokawa et al. (PMID:18502753) showed that ERLEC1 forms a scaffold complex that provides a platform for recognition and sorting of misfolded proteins prior to retrotranslocation into the cytoplasm. Groisman et al. (PMID:21062743) demonstrated that mannose trimming is required for substrate delivery from EDEM1 to XTP3-B and to late ERAD steps. This term is appropriate as ERLEC1 participates in the process that moves ER proteins to the cytosol for degradation. Reason: Retrograde protein transport ER to cytosol is a core process that ERLEC1 participates in as an ERAD cargo receptor. The IBA annotation is well supported by experimental evidence from multiple groups showing ERLEC1 functions in delivering misfolded substrates to the retrotranslocation machinery. Supporting Evidence: PMID:18502753 this large ER quality control scaffold complex, containing ER lectins, a chaperone, and a ubiquitin ligase, provides a platform for the recognition and sorting of misfolded glycoproteins as well as nonglycosylated proteins prior to retrotranslocation into the cytoplasm for degradation PMID:18264092 OS-9 and XTP3-B/Erlectin are ER-resident glycoproteins that bind to ERAD substrates and, through the SEL1L adaptor, to the ER-membrane-embedded ubiquitin ligase Hrd1 PMID:21062743 Our results suggest that mannose trimming enables delivery of a substrate glycoprotein from EDEM1 to late ERAD steps through association with XTP3-B
GO:0005783 endoplasmic reticulum	IEA GO_REF:0000117	ACCEPT	Summary: IEA annotation from ARBA machine learning placing ERLEC1 in the endoplasmic reticulum. This is correct but less specific than GO:0005788 (endoplasmic reticulum lumen), which is supported by IDA evidence from multiple publications (PMID:16531414, PMID:18264092) and IBA evidence. ERLEC1 is a soluble ER lumen protein, not a membrane-associated protein, so the more specific ER lumen term is more appropriate. However, as an IEA annotation, it is acceptable to retain a broader term that is not incorrect. Reason: While GO:0005783 (endoplasmic reticulum) is less specific than the experimentally supported GO:0005788 (ER lumen), it is not incorrect. The IEA annotation is a broader but valid computational inference. The more specific ER lumen localization is already captured by separate IDA and IBA annotations.
GO:0005788 endoplasmic reticulum lumen	IEA GO_REF:0000044	ACCEPT	Summary: IEA annotation mapping ERLEC1 to the ER lumen based on UniProtKB/Swiss-Prot subcellular location vocabulary. UniProt annotates ERLEC1 subcellular location as "Endoplasmic reticulum lumen" with experimental evidence from PMID:16531414 and PMID:18502753. This computational mapping is fully consistent with the experimental data. Reason: The IEA mapping from UniProt subcellular location to GO:0005788 is correct and consistent with experimental evidence. ERLEC1 ER lumen localization is well established.
GO:0030968 endoplasmic reticulum unfolded protein response	IEA GO_REF:0000002	MODIFY	Summary: IEA annotation from InterPro (IPR045149, OS-9-like domain) mapping to the ER unfolded protein response. ERLEC1 is part of the ER quality control machinery but its primary role is in ERAD, not the canonical unfolded protein response (UPR) signaling pathway. The UPR is a transcriptional signaling response involving IRE1, PERK, and ATF6 pathways that activates gene expression to cope with ER stress. ERLEC1 does not participate in UPR signaling; rather, it functions downstream as a cargo receptor in ERAD, recognizing misfolded glycoproteins and delivering them to the HRD1-SEL1L complex for retrotranslocation (PMID:18264092, PMID:18502753). The ERAD pathway annotation (GO:0036503) is the more precise term. Reason: GO:0030968 (ER unfolded protein response) refers to the UPR signaling cascade, not to ERAD per se. ERLEC1 is not a UPR signaling component but rather an ERAD cargo receptor. The correct biological process term is GO:0036503 (ERAD pathway), which is already annotated separately. This IEA annotation likely arises from an overly broad InterPro-to-GO mapping for the OS-9-like domain family. Proposed replacements: ERAD pathway
GO:0036503 ERAD pathway	IEA GO_REF:0000002	ACCEPT	Summary: IEA annotation from InterPro (IPR045149, OS-9-like) mapping to the ERAD pathway. This is fully supported by extensive experimental evidence. ERLEC1/XTP3-B is a central component of the ERAD pathway, functioning as a lectin-based cargo receptor that recognizes misfolded glycoproteins and delivers them to the HRD1-SEL1L ubiquitin ligase complex (PMID:18264092, PMID:18502753, PMID:21062743). Groisman et al. (PMID:21062743) specifically demonstrated that mannose trimming is required for substrate delivery from EDEM1 to XTP3-B and to late ERAD steps. Christianson et al. (PMID:18264092) showed that XTP3-B binds to ERAD substrates and through SEL1L to HRD1, and is required for degradation of mutant alpha1-antitrypsin. Reason: The ERAD pathway is the core biological process in which ERLEC1 participates. The IEA annotation is correct and well supported by experimental evidence from multiple independent studies.
GO:0036503 ERAD pathway	TAS PMID:21062743 Mannose trimming is required for delivery of a glycoprotein ...	ACCEPT	Summary: TAS annotation for ERAD pathway involvement based on Groisman et al. (PMID:21062743). This paper directly demonstrates that XTP3-B functions in the ERAD pathway by showing that mannose trimming by ER mannosidase I is required for substrate delivery from EDEM1 to XTP3-B, and that inhibition of mannose trimming blocks substrate association with XTP3-B and with E3 ubiquitin ligases HRD1 and SCF(Fbs2). This establishes ERLEC1 as a lectin acting at a late step in the ERAD pathway, after mannose trimming and before ubiquitination and retrotranslocation. Reason: ERAD pathway involvement is the core function of ERLEC1. The TAS annotation is well supported by the cited reference, which directly demonstrates ERLEC1 function in delivering substrates to late ERAD steps in a mannose-trimming-dependent manner. Supporting Evidence: PMID:21062743 Our results suggest that mannose trimming enables delivery of a substrate glycoprotein from EDEM1 to late ERAD steps through association with XTP3-B PMID:21062743 substrate association with XTP3-B and with the E3 ubiquitin ligases HRD1 and SCF(Fbs2) was inhibited
GO:0051082 unfolded protein binding	IDA PMID:21062743 Mannose trimming is required for delivery of a glycoprotein ...	REMOVE	Summary: GO:0051082 (unfolded protein binding) is now formally obsolete (go-ontology#30962). The suggested replacements are holdase chaperone activity or protein folding chaperone (GO:0044183), neither of which applies to ERLEC1. ERLEC1/XTP3-B is an ER lectin that recognizes misfolded glycoproteins via their trimmed N-glycan moieties as part of the ERAD pathway (PMID:21062743, PMID:18502753). It is not a chaperone. Groisman et al. (PMID:21062743) showed that mannose trimming by ER mannosidase I is required for substrate delivery from EDEM1 to XTP3-B, establishing ERLEC1 as a lectin-based cargo receptor rather than a protein that directly binds unfolded polypeptide chains. Christianson et al. (PMID:18264092) demonstrated that the MRH domains of XTP3-B are required for interaction with SEL1L but not with substrate, and that XTP3-B and OS-9 are components of quality control surveillance pathways that coordinate protein folding with membrane dislocation and ubiquitin conjugation. Hosokawa et al. (PMID:18502753) showed that hXTP3-B forms a scaffold with HRD1-SEL1L and BiP, and that the long isoform retarded ERAD of both glycosylated (NHK) and non-glycosylated (NHK-QQQ) substrates. While ERLEC1 does interact with misfolded proteins, this interaction is in the context of ERAD substrate recognition and delivery to the ubiquitin ligase complex, not chaperone-like unfolded protein binding. The ERAD pathway involvement is already captured by GO:0036503. Reason: GO:0051082 is now formally obsolete. The replacement terms (holdase chaperone, foldase chaperone) do not apply to ERLEC1, which is a lectin-based ERAD cargo receptor, not a chaperone. ERLEC1 recognizes misfolded glycoproteins through their N-glycan sugar moieties (requiring mannose trimming) and delivers them to the HRD1-SEL1L ubiquitin ligase complex for degradation. This is substrate recognition for ERAD targeting, not chaperone-like binding to unfolded polypeptide chains. The relevant biological function is already captured by the ERAD pathway annotation (GO:0036503) and retrograde protein transport annotation (GO:0030970). Similar to SYVN1, ERLEC1 interacts with misfolded proteins as part of the ERAD machinery, which does not constitute unfolded protein binding in the chaperone sense. Supporting Evidence: PMID:21062743 Our results suggest that mannose trimming enables delivery of a substrate glycoprotein from EDEM1 to late ERAD steps through association with XTP3-B PMID:21062743 substrate association with XTP3-B and with the E3 ubiquitin ligases HRD1 and SCF(Fbs2) was inhibited PMID:18264092 OS-9 and XTP3-B/Erlectin are ER-resident glycoproteins that bind to ERAD substrates and, through the SEL1L adaptor, to the ER-membrane-embedded ubiquitin ligase Hrd1 PMID:18264092 Both proteins contain conserved mannose 6-phosphate receptor homology (MRH) domains, which are required for interaction with SEL1L, but not with substrate PMID:18264092 XTP3-B and OS-9 are components of distinct, partially redundant, quality control surveillance pathways that coordinate protein folding with membrane dislocation and ubiquitin conjugation in mammalian cells PMID:18502753 hXTP3-B long isoform associates with the HRD1-SEL1L membrane-anchored ubiquitin ligase complex and BiP, forming a 27 S ER quality control scaffold complex PMID:18502753 this large ER quality control scaffold complex, containing ER lectins, a chaperone, and a ubiquitin ligase, provides a platform for the recognition and sorting of misfolded glycoproteins as well as nonglycosylated proteins prior to retrotranslocation into the cytoplasm for degradation PMID:16531414 Erlectin functions in N-glycan recognition in the endoplasmic reticulum, suggesting that it may regulate glycoprotein traffic
GO:1904153 negative regulation of retrograde protein transport, ER to cytosol	IMP PMID:25660456 Identification of ERAD components essential for dislocation ...	KEEP AS NON CORE	Summary: IMP annotation for negative regulation of retrograde protein transport (ER to cytosol) based on Zhong et al. (PMID:25660456). This paper used RNAi knockdown and a dislocation-reconstituted GFP (drGFP) assay to assess the requirement of ERAD components for dislocation of NHK (null Hong Kong variant of alpha1-antitrypsin). The study found that knockdown of 7 of 21 ERAD components enhanced NHK dislocation. If ERLEC1 knockdown enhanced dislocation, this would be consistent with a negative regulatory role. This seemingly contradicts the established role of ERLEC1 as a facilitator of ERAD (delivering substrates to the ubiquitin ligase), but independent evidence indicates the inhibitory activity is genuine physiology rather than an artifact. Hosokawa et al. (PMID:18502753) showed that overexpression of the long isoform of hXTP3-B retarded ERAD of both NHK and NHK-QQQ. Fujimori et al. (DOI:10.1111/febs.12157) concluded that XTP3-B inhibits ERAD of misfolded alpha1-antitrypsin NHK carrying M9 glycans, proposing that ERLEC1 protects newly synthesized glycoproteins from premature degradation. Most decisively, the genetic deletion study of van der Goot et al. (DOI:10.1016/j.molcel.2018.03.026) showed that XTP3B strongly inhibits degradation of non-glycosylated substrates, with OS9 antagonizing this inhibition. The deep research synthesis (file:human/ERLEC1/ERLEC1-deep-research-falcon.md) reconciles these observations in a model where ERLEC1 is a context-dependent triage factor that both promotes glycoprotein ERAD and restrains degradation of certain (especially non-glycosylated) substrates. Reason: The annotation captures a real, genetically supported regulatory activity (IMP evidence, corroborated by the deletion studies in DOI:10.1016/j.molcel.2018.03.026 and by DOI:10.1111/febs.12157), not merely an overexpression artifact. However, the core function of ERLEC1 is as a cargo receptor that facilitates glycoprotein ERAD; the substrate-context-dependent inhibitory activity is a modulatory facet of its triage role and is best kept as non-core rather than elevated to a core function. Supporting Evidence: PMID:25660456 knockdown of 7 of the 21 components enhanced NHK dislocation PMID:18502753 both isoforms retard ERAD of the human alpha(1)-antitrypsin variant null Hong Kong (NHK), a terminally misfolded glycoprotein PMID:18502753 The hXTP3-B long isoform strongly inhibited ERAD of NHK-QQQ, which lacks all of the N-glycosylation sites of NHK file:human/ERLEC1/ERLEC1-deep-research-falcon.md XTP3B strongly inhibits degradation of non-glycosylated substrates, and OS9 antagonizes this inhibition
GO:0044322 endoplasmic reticulum quality control compartment	TAS Reactome:R-HSA-5362412	ACCEPT	Summary: TAS annotation from Reactome (R-HSA-5362412: SYVN1 ubiquitinates Hh C-terminal fragments) placing ERLEC1 in the ER quality control compartment (ERQC). The ERQC is a pericentriolar ER-derived compartment where ERAD machinery concentrates along with misfolded substrates. Groisman et al. (PMID:21062743) showed that XTP3-B associates with ERAD substrates and E3 ligases in a mannose-trimming-dependent manner, consistent with localization to the ERQC. The Reactome entry describes ERLEC1 as a lectin in the ERAD machinery that helps target Hedgehog C-terminal fragments for degradation. This is a reasonable localization annotation for ERLEC1 given its role in ERAD substrate recognition. Reason: ERQC localization is consistent with ERLEC1 function in ERAD. As a cargo receptor that concentrates with ERAD machinery and substrates, ERLEC1 localizes to this quality control compartment. Multiple Reactome entries reference the same biological role; this is one of many duplicate TAS annotations from different Reactome reactions. Supporting Evidence: PMID:21062743 substrate association with XTP3-B and with the E3 ubiquitin ligases HRD1 and SCF(Fbs2) was inhibited
GO:0044322 endoplasmic reticulum quality control compartment	TAS Reactome:R-HSA-5362437	ACCEPT	Summary: TAS annotation from Reactome (R-HSA-5362437: C-terminal Hh fragments are bound by lectins). This Reactome entry explicitly states that depletion of OS9 and ERLEC1 abrogates degradation of Hh-C fragments, and that they may target Hh-C to the retrotranslocation channel via interaction with SEL1. ERQC localization is appropriate for ERLEC1 given its established role as an ERAD lectin cargo receptor. Reason: Duplicate ERQC localization annotation from a different Reactome reaction. Same rationale as for R-HSA-5362412: ERLEC1 localizes to the ERQC as part of its ERAD cargo receptor function.
GO:0044322 endoplasmic reticulum quality control compartment	TAS Reactome:R-HSA-5362441	ACCEPT	Summary: TAS annotation from Reactome (R-HSA-5362441: C-terminal Hh fragments are recruited to SEL1:SYVN1 at the ER membrane). ERLEC1 participates in recruiting substrates to the SEL1L-SYVN1 complex at the ER membrane, consistent with ERQC localization. Reason: Duplicate ERQC localization annotation from a different Reactome reaction describing the same ERAD process for Hh fragments.
GO:0044322 endoplasmic reticulum quality control compartment	TAS Reactome:R-HSA-5362450	ACCEPT	Summary: TAS annotation from Reactome (R-HSA-5362450: Hh processing variants bind lectins). This entry describes how OS9 and ERLEC1 lectins are required for degradation of Hh processing-defective variants via the ERAD pathway, consistent with ERQC localization. Reason: Duplicate ERQC localization annotation from a different Reactome reaction describing ERAD of Hedgehog processing variants.
GO:0044322 endoplasmic reticulum quality control compartment	TAS Reactome:R-HSA-5362459	ACCEPT	Summary: TAS annotation from Reactome (R-HSA-5362459: VCP-catalyzed ATP hydrolysis promotes the translocation of Hh-C into the cytosol). ERLEC1 is part of the ERAD machinery that operates within the ERQC. Reason: Duplicate ERQC localization annotation from a Reactome reaction describing the VCP-dependent retrotranslocation step for Hh-C fragments in which ERLEC1 participates upstream.
GO:0044322 endoplasmic reticulum quality control compartment	TAS Reactome:R-HSA-5387386	ACCEPT	Summary: TAS annotation from Reactome (R-HSA-5387386: Hh processing variants are recruited to SEL1:SYVN at the ER membrane). ERLEC1 participates in recruiting Hh processing variants to the ubiquitin ligase complex. Reason: Duplicate ERQC localization annotation from a Reactome reaction. Same biological context as other Hh ERAD entries.
GO:0044322 endoplasmic reticulum quality control compartment	TAS Reactome:R-HSA-5387389	ACCEPT	Summary: TAS annotation from Reactome (R-HSA-5387389: Hh processing variants are translocated to the cytosol in a VCP-dependent manner). Part of the Hh ERAD pathway in which ERLEC1 acts as cargo receptor. Reason: Duplicate ERQC localization annotation from a Reactome reaction in the Hh ERAD pathway.
GO:0044322 endoplasmic reticulum quality control compartment	TAS Reactome:R-HSA-5483238	ACCEPT	Summary: TAS annotation from Reactome (R-HSA-5483238: Hh processing variants are ubiquitinated). ERLEC1 functions upstream of the ubiquitination step in ERAD, within the ERQC. Reason: Duplicate ERQC localization annotation from a Reactome reaction describing Hh variant ubiquitination in which ERLEC1 participates.
GO:0044322 endoplasmic reticulum quality control compartment	TAS Reactome:R-HSA-8866542	ACCEPT	Summary: TAS annotation from Reactome (R-HSA-8866542: VCP-catalyzed ATP hydrolysis promotes the translocation of misfolded CFTR into the cytosol). ERLEC1 is part of the ERAD machinery for misfolded CFTR, consistent with ERQC localization. Reason: Duplicate ERQC localization annotation from a Reactome reaction describing CFTR ERAD in which ERLEC1 participates as cargo receptor.
GO:0044322 endoplasmic reticulum quality control compartment	TAS Reactome:R-HSA-8866546	ACCEPT	Summary: TAS annotation from Reactome (R-HSA-8866546: RNF5 and RNF185 ubiquitinate misfolded CFTR). ERLEC1 operates within the ERQC as part of the CFTR ERAD pathway. Reason: Duplicate ERQC localization annotation from a Reactome reaction in the CFTR ERAD pathway.
GO:0044322 endoplasmic reticulum quality control compartment	TAS Reactome:R-HSA-8866551	ACCEPT	Summary: TAS annotation from Reactome (R-HSA-8866551: CFTR binds components of the ERAD machinery for ubiquitination and degradation). ERLEC1 is one of the ERAD components that binds misfolded CFTR in the ERQC. Reason: Duplicate ERQC localization annotation from a Reactome reaction describing CFTR binding to ERAD components including ERLEC1.
GO:0044322 endoplasmic reticulum quality control compartment	TAS Reactome:R-HSA-8866854	ACCEPT	Summary: TAS annotation from Reactome (R-HSA-8866854: VCP-catalyzed ATP hydrolysis promotes the translocation of CFTR F508del into the cytosol). ERLEC1 participates in ERAD of the common CF-causing CFTR F508del mutation, within the ERQC. Reason: Duplicate ERQC localization annotation from a Reactome reaction in the CFTR F508del ERAD pathway.
GO:0044322 endoplasmic reticulum quality control compartment	TAS Reactome:R-HSA-8866856	ACCEPT	Summary: TAS annotation from Reactome (R-HSA-8866856: RNF5 and RNF185 ubiquitinate CFTR F508del). ERLEC1 is part of the ERAD machinery for CFTR F508del within the ERQC. Reason: Duplicate ERQC localization annotation from a Reactome reaction in the CFTR F508del ERAD pathway.
GO:0044322 endoplasmic reticulum quality control compartment	TAS Reactome:R-HSA-8866857	ACCEPT	Summary: TAS annotation from Reactome (R-HSA-8866857: CFTR F508del binds components of the ERAD machinery for ubiquitination and degradation). ERLEC1 is an ERAD component that binds misfolded CFTR F508del. Reason: Duplicate ERQC localization annotation from a Reactome reaction describing CFTR F508del ERAD.
GO:0044322 endoplasmic reticulum quality control compartment	TAS Reactome:R-HSA-9931264	ACCEPT	Summary: TAS annotation from Reactome (R-HSA-9931264: Active transport of ubiquitinated CD274 from ER to cytosol). ERLEC1 participates in ERAD of CD274 (PD-L1) within the ERQC. Reason: Duplicate ERQC localization annotation from a Reactome reaction describing CD274 ERAD.
GO:0044322 endoplasmic reticulum quality control compartment	TAS Reactome:R-HSA-9931298	ACCEPT	Summary: TAS annotation from Reactome (R-HSA-9931298: Ubiquitination of CD274 by ERAD complex). ERLEC1 is part of the ERAD complex that ubiquitinates CD274. Reason: Duplicate ERQC localization annotation from a Reactome reaction describing CD274 ubiquitination by ERAD.
GO:0044322 endoplasmic reticulum quality control compartment	TAS Reactome:R-HSA-9931313	ACCEPT	Summary: TAS annotation from Reactome (R-HSA-9931313: p-S195-CD274 binds ERAD complex). ERLEC1 is part of the ERAD complex that binds phosphorylated CD274 for degradation. Reason: Duplicate ERQC localization annotation from a Reactome reaction describing CD274 ERAD. Last of the 16 duplicate Reactome TAS annotations for ERQC localization, all consistent with ERLEC1 role in ERAD.
GO:0005515 protein binding	IPI PMID:18502753 Human XTP3-B forms an endoplasmic reticulum quality control ...	MODIFY	Summary: IPI annotation for protein binding based on Hosokawa et al. (PMID:18502753), with UniProtKB:Q13438 (OS-9/OS9) as the interacting partner. This paper showed that hXTP3-B forms an ER quality control scaffold complex with OS-9, HRD1-SEL1L, and BiP. The interaction between ERLEC1 and OS-9 is in the context of the ERAD scaffold complex. While the interaction is real, GO:0005515 (protein binding) is uninformative. A more specific term such as GO:0051787 (misfolded protein binding) would capture the functional context, though the direct interaction with OS-9 is more of a scaffold co-complex interaction. The term could be modified to misfolded protein binding to reflect ERLEC1 function, but since the with/from is OS-9 (a co-complex partner, not a misfolded substrate), the annotation as stated is simply documenting a physical interaction. Reason: GO:0005515 (protein binding) is uninformative per curation guidelines. ERLEC1 binds misfolded glycoproteins as a cargo receptor. The more informative term is GO:0051787 (misfolded protein binding), which captures ERLEC1 core molecular function of recognizing misfolded glycoprotein substrates for ERAD. Proposed replacements: misfolded protein binding Supporting Evidence: PMID:18502753 this large ER quality control scaffold complex, containing ER lectins, a chaperone, and a ubiquitin ligase, provides a platform for the recognition and sorting of misfolded glycoproteins as well as nonglycosylated proteins prior to retrotranslocation into the cytoplasm for degradation
GO:0005515 protein binding	IDA PMID:16531414 The MRH protein Erlectin is a member of the endoplasmic reti...	MODIFY	Summary: IDA annotation for protein binding based on Cruciat et al. (PMID:16531414). This paper identified Erlectin as a protein that interacts with Kremen2 (KREMEN2), a coreceptor for Dickkopf1 in Wnt signaling. The interaction with Kremen2 is glycosylation-dependent (abolished by Kremen2 deglycosylation) and requires the second MRH domain of Erlectin (G379S mutation abolishes binding). Overexpression of Erlectin inhibited transport of Krm2 to the cell surface. This interaction reflects ERLEC1 lectin activity in glycoprotein quality control. GO:0005515 is uninformative; the functional activity is better captured by misfolded protein binding or N-glycan recognition. Reason: GO:0005515 (protein binding) is uninformative per curation guidelines. The interaction with Kremen2 via N-glycan recognition represents ERLEC1 lectin function in the ER. The more informative term is GO:0051787 (misfolded protein binding), reflecting ERLEC1 role in recognizing glycoproteins for ER quality control. Proposed replacements: misfolded protein binding Supporting Evidence: PMID:16531414 Erlectin functions in N-glycan recognition in the endoplasmic reticulum, suggesting that it may regulate glycoprotein traffic PMID:16531414 It contains two MRH domains, of which one is essential for Krm2 binding, and this interaction is abolished by Krm2 deglycosylation
GO:0005515 protein binding	IPI PMID:18264092 OS-9 and GRP94 deliver mutant alpha1-antitrypsin to the Hrd1...	MODIFY	Summary: IPI annotation for protein binding based on Christianson et al. (PMID:18264092), with multiple interacting partners (UniProtKB:P11021 HSPA5/BiP, UniProtKB:Q86TM6 SYVN1/HRD1, UniProtKB:Q9UBV2 SEL1L). This paper showed that XTP3-B binds to ERAD substrates and through SEL1L to HRD1. The MRH domains are required for interaction with SEL1L but not with substrate. XTP3-B and OS-9 are components of distinct, partially redundant quality control surveillance pathways. GO:0005515 is uninformative; ERLEC1 interactions with SEL1L and HRD1 reflect its role as a substrate adaptor for the ERAD ubiquitin ligase complex. Reason: GO:0005515 (protein binding) is uninformative per curation guidelines. The interactions documented here are functionally significant: ERLEC1 binding to SEL1L and HRD1 via its MRH domains reflects its role as a substrate adaptor that bridges misfolded glycoproteins to the E3 ubiquitin ligase complex. The most informative molecular function term would be GO:0051787 (misfolded protein binding), capturing ERLEC1 core activity of recognizing misfolded substrates. Proposed replacements: misfolded protein binding Supporting Evidence: PMID:18264092 OS-9 and XTP3-B/Erlectin are ER-resident glycoproteins that bind to ERAD substrates and, through the SEL1L adaptor, to the ER-membrane-embedded ubiquitin ligase Hrd1 PMID:18264092 Both proteins contain conserved mannose 6-phosphate receptor homology (MRH) domains, which are required for interaction with SEL1L, but not with substrate
GO:0005788 endoplasmic reticulum lumen	IDA PMID:16531414 The MRH protein Erlectin is a member of the endoplasmic reti...	ACCEPT	Summary: IDA annotation for ER lumen localization based on Cruciat et al. (PMID:16531414). This paper demonstrated by immunofluorescence and mass spectrometry that Erlectin is a luminal resident protein of the endoplasmic reticulum. ERLEC1 has a signal peptide (aa 1-33) and lacks a transmembrane domain, consistent with a soluble ER lumen protein. Reason: ER lumen localization is a well-established core feature of ERLEC1, directly demonstrated by Cruciat et al. The IDA evidence is strong and consistent with the protein sequence (signal peptide, no TM domain) and with other experimental studies. Supporting Evidence: PMID:16531414 Like other members of the MRH family, Erlectin is a luminal resident protein of the endoplasmic reticulum
GO:0005788 endoplasmic reticulum lumen	IDA PMID:18264092 OS-9 and GRP94 deliver mutant alpha1-antitrypsin to the Hrd1...	ACCEPT	Summary: IDA annotation for ER lumen localization based on Christianson et al. (PMID:18264092). This paper confirmed that XTP3-B/Erlectin is an ER-resident glycoprotein, consistent with ER lumen localization established by Cruciat et al. (PMID:16531414) and Hosokawa et al. (PMID:18502753). Reason: Independent experimental confirmation of ER lumen localization by a second research group. Consistent with all other evidence. Supporting Evidence: PMID:18264092 OS-9 and XTP3-B/Erlectin are ER-resident glycoproteins that bind to ERAD substrates and, through the SEL1L adaptor, to the ER-membrane-embedded ubiquitin ligase Hrd1
GO:0005515 protein binding	IPI PMID:16531414 The MRH protein Erlectin is a member of the endoplasmic reti...	MODIFY	Summary: IPI annotation for protein binding based on Cruciat et al. (PMID:16531414), with UniProtKB:Q8K1S7 (mouse Kremen2) as the interacting partner. This paper identified Erlectin in a proteomic approach as a protein that interacts with Kremen2. The interaction is glycosylation-dependent and requires the MRH domain of Erlectin. GO:0005515 is uninformative; this interaction reflects ERLEC1 lectin activity in N-glycan recognition and glycoprotein quality control. Reason: GO:0005515 (protein binding) is uninformative per curation guidelines. The interaction with glycosylated Kremen2 via the MRH domain reflects ERLEC1 lectin function. The more informative term is GO:0051787 (misfolded protein binding), as ERLEC1 recognizes glycoproteins in the context of ER quality control. Proposed replacements: misfolded protein binding Supporting Evidence: PMID:16531414 It contains two MRH domains, of which one is essential for Krm2 binding, and this interaction is abolished by Krm2 deglycosylation PMID:16531414 The overexpression of Erlectin inhibits transport of Krm2 to the cell surface
GO:0051787 misfolded protein binding	IDA PMID:18264092 OS-9 and GRP94 deliver mutant alpha1-antitrypsin to the Hrd1...	NEW	Summary: NEW annotation proposed for GO:0051787 (misfolded protein binding). Multiple studies demonstrate that ERLEC1/XTP3-B binds to misfolded glycoproteins in the ER. Christianson et al. (PMID:18264092) showed that XTP3-B binds to ERAD substrates (mutant alpha1-antitrypsin NHK). Hosokawa et al. (PMID:18502753) showed that hXTP3-B forms a scaffold complex for recognition and sorting of misfolded glycoproteins and nonglycosylated proteins. Groisman et al. (PMID:21062743) demonstrated that substrate association with XTP3-B depends on mannose trimming. This term is more informative than the generic GO:0005515 (protein binding) annotations currently present and accurately captures ERLEC1 core molecular function as a lectin that recognizes misfolded glycoprotein substrates for ERAD. Reason: GO:0051787 (misfolded protein binding) is the most informative molecular function term for ERLEC1. It replaces the uninformative GO:0005515 (protein binding) annotations and provides the correct replacement for the obsolescent GO:0051082 (unfolded protein binding). ERLEC1 specifically binds misfolded glycoproteins (not simply unfolded polypeptides) as a cargo receptor for ERAD. Supporting Evidence: PMID:18264092 OS-9 and XTP3-B/Erlectin are ER-resident glycoproteins that bind to ERAD substrates and, through the SEL1L adaptor, to the ER-membrane-embedded ubiquitin ligase Hrd1 PMID:18502753 this large ER quality control scaffold complex, containing ER lectins, a chaperone, and a ubiquitin ligase, provides a platform for the recognition and sorting of misfolded glycoproteins as well as nonglycosylated proteins prior to retrotranslocation into the cytoplasm for degradation PMID:21062743 substrate association with XTP3-B and with the E3 ubiquitin ligases HRD1 and SCF(Fbs2) was inhibited
GO:0097466 ubiquitin-dependent glycoprotein ERAD pathway	TAS PMID:21062743 Mannose trimming is required for delivery of a glycoprotein ...	NEW	Summary: NEW annotation proposed for GO:0097466 (ubiquitin-dependent glycoprotein ERAD pathway). This term is more specific than GO:0036503 (ERAD pathway) and captures the fact that ERLEC1 specifically functions in the glycoprotein-specific branch of ERAD. Groisman et al. (PMID:21062743) showed that mannose trimming of N-glycans is required for substrate delivery from EDEM1 to XTP3-B, establishing ERLEC1 as a lectin that acts specifically in glycoprotein ERAD. The broader GO:0036503 (ERAD pathway) annotation should be retained as well, since Hosokawa et al. (PMID:18502753) showed that the long isoform also affects ERAD of the non-glycosylated NHK-QQQ substrate. Reason: GO:0097466 is a more specific child term of GO:0036503 that precisely captures ERLEC1 role in the glycoprotein-specific branch of ERAD, where it recognizes trimmed N-glycans on misfolded substrates. This provides higher annotation specificity while the broader ERAD pathway term is retained for the non-glycoprotein ERAD role. Supporting Evidence: PMID:21062743 Our results suggest that mannose trimming enables delivery of a substrate glycoprotein from EDEM1 to late ERAD steps through association with XTP3-B PMID:21062743 the mannosidase inhibitor kifunensine or ERManI knockdown do not affect binding of an ERAD substrate glycoprotein to EDEM1. In contrast, substrate association with XTP3-B and with the E3 ubiquitin ligases HRD1 and SCF(Fbs2) was inhibited

Gene Description

Existing Annotations Review

Core Functions

References

Deep Research

Falcon

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