{"gene":"ERLEC1","run_date":"2026-06-09T23:54:43","timeline":{"discoveries":[{"year":2008,"finding":"XTP3-B/ERLEC1 is an ER-resident glycoprotein that binds to ERAD substrates and, through the SEL1L adaptor, to the ER-membrane-embedded ubiquitin ligase Hrd1. Its MRH domain is required for interaction with SEL1L but not with substrate. XTP3-B and OS-9 form components of distinct, partially redundant quality control surveillance pathways coordinating protein folding with membrane dislocation and ubiquitin conjugation.","method":"Co-immunoprecipitation, siRNA knockdown, pulse-chase degradation assays","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP with functional knockdown validation, replicated across multiple labs in subsequent studies","pmids":["18264092"],"is_preprint":false},{"year":2008,"finding":"The long isoform of human XTP3-B (hXTP3-B) associates with the HRD1-SEL1L membrane-anchored ubiquitin ligase complex and BiP, forming a ~27S ER quality control scaffold complex. The short isoform is excluded from scaffold formation. hOS-9 is also incorporated into this large complex. hXTP3-B long isoform inhibits ERAD of NHK (null Hong Kong alpha1-antitrypsin variant), including a non-glycosylated version (NHK-QQQ), while the short isoform has almost no effect.","method":"Immunoprecipitation, sucrose density gradient centrifugation fractionation, siRNA knockdown, pulse-chase degradation assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP plus orthogonal sucrose gradient fractionation, functional siRNA validation, replicated in subsequent studies","pmids":["18502753"],"is_preprint":false},{"year":2009,"finding":"XTP3-B binds to the ERAD substrate alpha1-antitrypsin variant NHK (but not wild-type AT) specifically via its C-terminal MRH domain in a glycan-dependent manner. Mutation of Arg428 or Tyr457 in the C-terminal MRH domain abolishes glycan binding. The N-terminal MRH domain is dispensable for substrate binding.","method":"Recombinant Fc-fusion protein binding assays to Lec1 cells, EndoH treatment, competitive inhibition with mannose oligosaccharides, alanine mutagenesis, co-immunoprecipitation","journal":"Glycobiology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro binding assay with mutagenesis and multiple orthogonal methods in one study","pmids":["19917667"],"is_preprint":false},{"year":2010,"finding":"Disposal of soluble ERAD-LS substrates (nontransmembrane polypeptides with luminal lesions) is strictly dependent on XTP3-B (and OS-9) acting as interchangeable ERAD lectins along with HRD1 and SEL1L. These ERAD factors become dispensable when the same polypeptides are membrane-tethered (ERAD-LM substrates), revealing a mammalian-specific distinction from yeast.","method":"siRNA knockdown, pulse-chase degradation assays, genetic epistasis with defined substrate variants","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — systematic siRNA knockdown epistasis with multiple substrates, replicated finding across multiple ERAD components","pmids":["20100910"],"is_preprint":false},{"year":2010,"finding":"Mannose trimming is required for substrate association with XTP3-B and with E3 ubiquitin ligases HRD1 and SCF(Fbs2). Inhibition of mannose trimming (kifunensine or ERManI knockdown) prevents substrate colocalization with HRD1 and Fbs2 at the ERQC but not with EDEM1. Substrate association with XTP3-B remained dependent on mannose trimming even upon SEL1L knockdown, suggesting XTP3-B recognizes mannose-trimmed glycans for late ERAD steps.","method":"Co-immunoprecipitation, mannosidase inhibitor (kifunensine) treatment, siRNA knockdown of ERManI and SEL1L, confocal colocalization","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (Co-IP, colocalization, chemical inhibition, siRNA) in single lab study","pmids":["21062743"],"is_preprint":false},{"year":2012,"finding":"XTP3-B interacts with unassembled core-glycosylated CD147 (an endogenous ERAD substrate), and this interaction is inhibited by mutations to conserved residues in the XTP3-B lectin domain. XTP3-B participates along with OS-9 in the OS-9/SEL1L/Hrd1 ERAD pathway for an endogenous constitutive substrate.","method":"Mass spectrometry identification, Co-immunoprecipitation, lectin domain mutagenesis, siRNA depletion, proteasome inhibitor assays","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MS-based substrate identification plus mutagenesis validation and functional epistasis in single study","pmids":["23097496"],"is_preprint":false},{"year":2013,"finding":"The C-terminal MRH domain of XTP3-B specifically recognizes Man9GlcNAc2 (M9) glycans in vitro and on the ERAD substrate NHK in vivo. Endogenous XTP3-B is a component of the HRD1-SEL1L complex via direct interaction with SEL1L. Lectin activity is required for NHK binding but not for SEL1L association. Unlike OS-9, XTP3-B inhibits ERAD of NHK bearing M9 oligosaccharides, acting as a negative regulator of ERAD and protecting newly synthesized immature polypeptides from premature degradation.","method":"Frontal affinity chromatography (FAC), co-immunoprecipitation, siRNA knockdown, pulse-chase degradation assays, lectin-domain mutagenesis","journal":"The FEBS journal","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro FAC biochemical assay plus mutagenesis plus functional degradation assays in single study with multiple orthogonal methods","pmids":["23356641"],"is_preprint":false},{"year":2012,"finding":"Nonglycosylated BiP substrates (NS-1κ light chain and truncated Igγ heavy chain) interact with XTP3-B and OS-9, and require EDEM1 for degradation, revealing that XTP3-B can engage non-glycosylated ERAD substrates through protein-protein interactions, sharing the ERAD pathway with glycoproteins.","method":"Co-immunoprecipitation, siRNA knockdown, pulse-chase degradation assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP plus siRNA epistasis in single lab study","pmids":["23233672"],"is_preprint":false},{"year":2006,"finding":"Erlectin (XTP3-B/ERLEC1) is an ER luminal resident protein with two MRH domains. It interacts with the Wnt co-receptor Kremen2 (Krm2) via one MRH domain in a glycan-dependent manner (interaction abolished by Krm2 deglycosylation). Erlectin overexpression inhibits transport of Krm2 to the cell surface. Morpholino knockdown in Xenopus causes head and axial defects, placing Erlectin in ER glycoprotein trafficking regulation.","method":"Proteomic interaction screen, co-immunoprecipitation, deglycosylation assay, cell surface transport assay, Xenopus morpholino knockdown","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with deglycosylation functional validation plus in vivo morpholino phenotype, single lab","pmids":["16531414"],"is_preprint":false},{"year":2010,"finding":"ERLEC1/CIM sequesters OS-9 away from the HIF-1α complex and PHD2, thereby preventing HIF-1α degradation and permitting HIF-1α accumulation under hypoxic conditions. ERLEC1 also modulates the unfolded protein response through interaction with the key ER stress protein BiP, influencing cell proliferation under ER stress.","method":"Proteomic approaches, co-immunoprecipitation, ectopic expression, hypoxia tolerance assays","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP and functional overexpression data with multiple cellular readouts, single lab","pmids":["21118962"],"is_preprint":false},{"year":2013,"finding":"ERLEC1 expression is transcriptionally upregulated by ER stress via a novel ERSE-26 element (CCAAT-N26-CCACG) in its promoter, regulated by XBP1 but not ATF6α. XBP1 overexpression increased and siRNA knockdown of XBP1 reduced ERLEC1 mRNA levels.","method":"Luciferase reporter assays, ER stressor treatment (brefeldin A, tunicamycin, thapsigargin), siRNA knockdown of XBP1, mRNA quantification","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reporter assay plus siRNA knockdown and overexpression, multiple stressors tested, single lab","pmids":["23737521"],"is_preprint":false},{"year":2021,"finding":"XTP3-B/ERLEC1 stabilizes SEL1L by inhibiting its degradation. When proteasome activity is inhibited, SEL1L generates degradation intermediates that interact with aggregation-prone proteins including polyglutamine-expanded Huntingtin (Htt-polyQ-GFP), stimulating their cytosolic aggregation.","method":"Proteasome inhibitor assays, co-immunoprecipitation, GFP-tagged aggregation reporters, siRNA knockdown of OS-9 and XTP3-B","journal":"The FEBS journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional knockdown with defined biochemical readouts in single lab study","pmids":["33576152"],"is_preprint":false},{"year":2021,"finding":"ERLEC1 is identified as a substrate for the ER translocation inhibitor cyclotriazadisulfonamide (CADA). CADA inhibits ERLEC1 protein expression in a signal peptide-dependent manner. Cell-free in vitro translation/translocation assays confirmed that ERLEC1's signal peptide is a target for CADA-mediated cotranslational translocation inhibition at the Sec61 translocon.","method":"Quantitative proteomics (SILAC-MS), Western blot, flow cytometry, cell-free in vitro translation/translocation assay","journal":"Molecular & cellular proteomics","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro translation/translocation assay plus quantitative proteomics and Western blot validation, single lab","pmids":["34481949"],"is_preprint":false},{"year":2023,"finding":"SEL1L recruits ERLEC1 (along with OS9, UBE2J1, and DERLIN) to HRD1 to form a functional HRD1 ERAD complex. Attenuation of the SEL1L-HRD1 interaction (via a SEL1L variant) impairs recruitment of ERLEC1 to HRD1, demonstrating that SEL1L-HRD1 interaction is prerequisite for ERLEC1 incorporation into the functional ERAD complex.","method":"Proteomic interactome screens of SEL1L and HRD1, co-immunoprecipitation, knockin mouse model with SEL1L variant","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — proteomic interactome plus Co-IP validation and in vivo mouse model, single lab, preprint","pmids":["37333389"],"is_preprint":true},{"year":2023,"finding":"Mutation of erlec1 in zebrafish results in further suppression of the cholesterol biosynthesis pathway in the context of misfolded Z-variant alpha1-antitrypsin (ZAAT) expression, confirming a role for this ER lectin in targeting misfolded ZAAT for ER-associated degradation (ERAD).","method":"CRISPR/Cas9 erlec1 knockout in zebrafish, transcriptomic and proteomic analysis","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo gene knockout with defined molecular pathway phenotype, single lab","pmids":["36768797"],"is_preprint":false},{"year":2011,"finding":"EDEM1 overexpression or its up-regulation by IRE1 can deliver ERAD substrates to XTP3-B and OS9 even when mannose trimming is bypassed. An EDEM1 deletion mutant lacking most of the carbohydrate-recognition domain still accelerates ERAD by delivering substrate to XTP3-B, suggesting that substrate delivery from EDEM1 to XTP3-B can occur through protein-protein interactions independent of glycan recognition.","method":"siRNA knockdown, overexpression, pulse-chase degradation assays, confocal colocalization, co-immunoprecipitation","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal genetic and biochemical approaches in single lab study","pmids":["21917589"],"is_preprint":false},{"year":2020,"finding":"Rare missense variants in ERLEC1 (including p.His413Tyr, p.Thr140Ser, p.Thr140Ile, p.Asn483Ser) co-segregate with Class III malocclusion. ERLEC1 is highly expressed in mouse jaw osteoblasts and inhibits osteoblast proliferation; the His413Tyr variant significantly enhanced this inhibitory effect on osteoblast proliferation. Proper ERLEC1 expression level is required for correct osteogenic differentiation.","method":"Exome sequencing, Sanger sequencing co-segregation, ERLEC1 expression analysis in osteoblasts, overexpression of wild-type vs. mutant ERLEC1 with cell proliferation and differentiation assays","journal":"Human mutation","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — variant co-segregation plus functional cellular assays in single lab study","pmids":["32442352"],"is_preprint":false}],"current_model":"ERLEC1 (XTP3-B/Erlectin) is an ER-luminal lectin with two MRH domains that recognizes high-mannose N-glycans (particularly Man9GlcNAc2 via its C-terminal MRH domain) on misfolded glycoproteins and, through direct interaction with the adaptor SEL1L, is recruited into the ~27S HRD1-SEL1L ubiquitin ligase scaffold complex along with BiP and OS-9 to mediate ER-associated degradation (ERAD) of soluble luminal substrates; unlike OS-9, XTP3-B acts as a negative regulator of ERAD by protecting immature polypeptides bearing M9 glycans from premature degradation, and it also participates in HIF-1α stabilization by sequestering OS-9 from the HIF-1α/PHD2 complex, is transcriptionally induced by ER stress via XBP1, and its signal peptide-dependent ER translocation is inhibitable by cyclotriazadisulfonamide (CADA)."},"narrative":{"mechanistic_narrative":"ERLEC1 (XTP3-B/Erlectin) is an ER-luminal lectin that functions in ER-associated degradation (ERAD), recognizing misfolded glycoproteins and coupling their surveillance to the membrane ubiquitin ligase machinery [PMID:18264092, PMID:20100910]. It is directly recruited into the HRD1-SEL1L ubiquitin ligase scaffold through interaction with the adaptor SEL1L, an association that, together with OS-9 and BiP, builds a large (~27S) ER quality control complex; SEL1L-HRD1 engagement is prerequisite for ERLEC1 incorporation, and its MRH domain is required for SEL1L binding but not for substrate recognition [PMID:18264092, PMID:18502753, PMID:37333389]. Substrate engagement is mediated by the C-terminal MRH domain, which recognizes mannose-trimmed high-mannose N-glycans, specifically Man9GlcNAc2, on misfolded glycoproteins such as the alpha1-antitrypsin variant NHK and unassembled CD147; conserved residues including Arg428 and Tyr457 are essential for this glycan-dependent binding [PMID:19917667, PMID:21062743, PMID:23097496, PMID:23356641]. ERLEC1 and OS-9 act as partially redundant, interchangeable lectins selectively required for disposal of soluble luminal (ERAD-LS) substrates but dispensable when the same lesions are membrane-tethered [PMID:20100910]. ERLEC1 can also engage non-glycosylated substrates through protein-protein interactions and receives substrates handed off from EDEM1 independently of glycan recognition [PMID:23233672, PMID:21917589]. Functionally distinct from OS-9, ERLEC1 acts as a negative regulator of ERAD, protecting immature M9-glycan-bearing polypeptides from premature degradation [PMID:23356641], and it stabilizes the adaptor SEL1L against degradation [PMID:33576152]. ERLEC1 is transcriptionally induced by ER stress through an ERSE-26 promoter element controlled by XBP1 [PMID:23737521], and its cotranslational ER translocation at the Sec61 translocon is signal-peptide-dependent and blocked by cyclotriazadisulfonamide [PMID:34481949]. Rare missense variants in ERLEC1 co-segregate with Class III malocclusion, where the protein inhibits jaw osteoblast proliferation [PMID:32442352].","teleology":[{"year":2006,"claim":"Established ERLEC1 as an ER-luminal MRH-domain lectin capable of glycan-dependent control of glycoprotein trafficking, the founding observation of its function.","evidence":"Proteomic interaction screen, Co-IP with deglycosylation, cell surface transport assay, and Xenopus morpholino knockdown","pmids":["16531414"],"confidence":"Medium","gaps":["Did not connect ERLEC1 to ERAD or to the HRD1-SEL1L machinery","Kremen2 interaction not linked to degradation"]},{"year":2008,"claim":"Defined ERLEC1's core role: an ERAD lectin that binds substrate and bridges to the Hrd1 ligase via SEL1L, working in a pathway partially redundant with OS-9.","evidence":"Reciprocal Co-IP, siRNA knockdown, pulse-chase degradation assays; orthogonal sucrose density gradient fractionation defining the ~27S scaffold and isoform requirement","pmids":["18264092","18502753"],"confidence":"High","gaps":["Glycan specificity of substrate recognition not yet defined","Mechanistic basis of redundancy with OS-9 unresolved"]},{"year":2009,"claim":"Localized substrate recognition to the C-terminal MRH domain and showed it is glycan-dependent, distinguishing substrate-binding from SEL1L-binding functions.","evidence":"Recombinant Fc-fusion binding to Lec1 cells, EndoH treatment, mannose competition, alanine mutagenesis (Arg428/Tyr457), Co-IP","pmids":["19917667"],"confidence":"High","gaps":["Precise glycan species recognized not yet determined","Role of N-terminal MRH domain unexplained"]},{"year":2010,"claim":"Defined the substrate class strictly dependent on ERLEC1 and established that mannose trimming is required for substrate handoff to the ligase.","evidence":"siRNA epistasis with defined ERAD-LS/ERAD-LM substrate variants; Co-IP, kifunensine treatment, ERManI/SEL1L knockdown, confocal colocalization","pmids":["20100910","21062743"],"confidence":"High","gaps":["Structural basis of mannose-trimmed glycan selectivity not resolved","Order of factor recruitment along the pathway not fully ordered"]},{"year":2010,"claim":"Proposed a moonlighting role in hypoxia signaling whereby ERLEC1 sequesters OS-9 to stabilize HIF-1α, linking it to BiP and the UPR.","evidence":"Proteomic approaches, Co-IP, ectopic expression, hypoxia tolerance assays","pmids":["21118962"],"confidence":"Medium","gaps":["Single-lab overexpression-based; physiological relevance of OS-9 sequestration not independently validated","Quantitative competition mechanism not established"]},{"year":2011,"claim":"Showed substrate delivery to ERLEC1 can bypass glycan recognition via EDEM1 protein-protein interactions, broadening its substrate engagement modes.","evidence":"siRNA knockdown, overexpression, pulse-chase, confocal colocalization, Co-IP with EDEM1 CRD-deletion mutant","pmids":["21917589"],"confidence":"Medium","gaps":["Direct vs. indirect nature of EDEM1-ERLEC1 transfer not resolved","Physiological frequency of glycan-independent handoff unknown"]},{"year":2012,"claim":"Extended ERLEC1 function to endogenous and non-glycosylated substrates, demonstrating engagement through both lectin and protein-protein interactions.","evidence":"MS substrate identification (CD147), Co-IP, lectin-domain mutagenesis, siRNA depletion, proteasome inhibitor assays; Co-IP/siRNA epistasis for non-glycosylated BiP substrates","pmids":["23097496","23233672"],"confidence":"Medium","gaps":["Molecular basis of non-glycosylated substrate recognition undefined","Relative contribution of ERLEC1 vs OS-9 for endogenous substrates unclear"]},{"year":2013,"claim":"Defined the precise glycan ligand (Man9GlcNAc2) and revealed that ERLEC1 acts as a negative ERAD regulator protecting immature polypeptides, distinguishing it functionally from OS-9; also identified XBP1-driven ER-stress induction.","evidence":"Frontal affinity chromatography, Co-IP, siRNA, pulse-chase, lectin mutagenesis; luciferase reporter and XBP1 knockdown/overexpression with multiple ER stressors","pmids":["23356641","23737521"],"confidence":"High","gaps":["Mechanism by which ERLEC1 protects vs. targets substrates not structurally explained","Switch between protective and degradative modes not defined"]},{"year":2021,"claim":"Identified ERLEC1 as a stabilizer of SEL1L and a determinant of cytosolic aggregation behavior, and showed its biogenesis is controlled at the Sec61 translocon.","evidence":"Proteasome inhibitor assays, Co-IP, GFP-aggregation reporters, OS-9/XTP3-B siRNA; SILAC-MS, Western blot, flow cytometry, and cell-free translation/translocation assay with CADA","pmids":["33576152","34481949"],"confidence":"Medium","gaps":["Mechanism of SEL1L stabilization not biochemically defined","Functional consequence of CADA-mediated ERLEC1 depletion in vivo unknown"]},{"year":2023,"claim":"Confirmed SEL1L-HRD1 engagement as prerequisite for ERLEC1 recruitment into the functional ERAD complex and validated ERLEC1's ERAD role for misfolded ZAAT in vivo.","evidence":"SEL1L/HRD1 interactome screens, Co-IP, knockin mouse SEL1L variant (preprint); CRISPR erlec1 zebrafish knockout with transcriptomic/proteomic analysis","pmids":["37333389","36768797"],"confidence":"Medium","gaps":["bioRxiv preprint not peer-reviewed for the recruitment hierarchy","Mechanistic link between ERAD defect and cholesterol pathway suppression unclear"]},{"year":2020,"claim":"Linked ERLEC1 to a human craniofacial phenotype, implicating it in osteoblast proliferation control.","evidence":"Exome/Sanger co-segregation of missense variants with Class III malocclusion; osteoblast expression and wild-type vs mutant proliferation/differentiation assays","pmids":["32442352"],"confidence":"Medium","gaps":["Mechanistic connection between ERAD lectin function and osteoblast proliferation undefined","Causality of variants not established beyond co-segregation"]},{"year":null,"claim":"How ERLEC1 toggles between protecting immature glycoproteins and committing substrates to degradation, and how this is structurally coordinated within the HRD1-SEL1L complex, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structure of ERLEC1 within the assembled HRD1-SEL1L complex","Molecular switch between protective and degradative modes unknown","Physiological substrate repertoire incompletely mapped"]}],"mechanism_profile":{"molecular_activity":[],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[0,8]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,3,6]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[10]}],"complexes":["HRD1-SEL1L ERAD complex"],"partners":["SEL1L","HRD1","OS-9","BIP","EDEM1","KREMEN2","DERLIN","UBE2J1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q96DZ1","full_name":"Endoplasmic reticulum lectin 1","aliases":["ER lectin","Erlectin","XTP3-transactivated gene B protein"],"length_aa":483,"mass_kda":54.9,"function":"Probable lectin that binds selectively to improperly folded lumenal proteins. May function in endoplasmic reticulum quality control and endoplasmic reticulum-associated degradation (ERAD) of both non-glycosylated proteins and glycoproteins","subcellular_location":"Endoplasmic reticulum lumen","url":"https://www.uniprot.org/uniprotkb/Q96DZ1/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ERLEC1","classification":"Not Classified","n_dependent_lines":18,"n_total_lines":1208,"dependency_fraction":0.014900662251655629},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/ERLEC1","total_profiled":1310},"omim":[{"mim_id":"611229","title":"ENDOPLASMIC RETICULUM LECTIN 1; ERLEC1","url":"https://www.omim.org/entry/611229"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/ERLEC1"},"hgnc":{"alias_symbol":["CL25084","XTP3TPB","XTP3-B","ERLECTIN"],"prev_symbol":["C2orf30"]},"alphafold":{"accession":"Q96DZ1","domains":[{"cath_id":"-","chopping":"39-85_255-282","consensus_level":"medium","plddt":83.3183,"start":39,"end":282},{"cath_id":"2.70.130.10","chopping":"99-163_176-245","consensus_level":"high","plddt":84.4706,"start":99,"end":245},{"cath_id":"2.70.130.10","chopping":"328-483","consensus_level":"medium","plddt":83.8615,"start":328,"end":483}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96DZ1","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q96DZ1-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q96DZ1-F1-predicted_aligned_error_v6.png","plddt_mean":72.94},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ERLEC1","jax_strain_url":"https://www.jax.org/strain/search?query=ERLEC1"},"sequence":{"accession":"Q96DZ1","fasta_url":"https://rest.uniprot.org/uniprotkb/Q96DZ1.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q96DZ1/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96DZ1"}},"corpus_meta":[{"pmid":"18264092","id":"PMC_18264092","title":"OS-9 and GRP94 deliver mutant alpha1-antitrypsin to the Hrd1-SEL1L ubiquitin ligase complex for ERAD.","date":"2008","source":"Nature cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/18264092","citation_count":420,"is_preprint":false},{"pmid":"19346256","id":"PMC_19346256","title":"Human OS-9, a lectin required for glycoprotein endoplasmic reticulum-associated degradation, recognizes mannose-trimmed N-glycans.","date":"2009","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/19346256","citation_count":167,"is_preprint":false},{"pmid":"18502753","id":"PMC_18502753","title":"Human XTP3-B forms an endoplasmic reticulum quality control scaffold with the HRD1-SEL1L ubiquitin ligase complex and BiP.","date":"2008","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/18502753","citation_count":161,"is_preprint":false},{"pmid":"20100910","id":"PMC_20100910","title":"Stringent requirement for HRD1, SEL1L, and OS-9/XTP3-B for disposal of ERAD-LS substrates.","date":"2010","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/20100910","citation_count":148,"is_preprint":false},{"pmid":"23097496","id":"PMC_23097496","title":"Unassembled CD147 is an endogenous endoplasmic reticulum-associated degradation substrate.","date":"2012","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/23097496","citation_count":78,"is_preprint":false},{"pmid":"21172656","id":"PMC_21172656","title":"Structural basis for oligosaccharide recognition of misfolded glycoproteins by OS-9 in ER-associated degradation.","date":"2010","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/21172656","citation_count":67,"is_preprint":false},{"pmid":"20118070","id":"PMC_20118070","title":"The role of MRH domain-containing lectins in ERAD.","date":"2010","source":"Glycobiology","url":"https://pubmed.ncbi.nlm.nih.gov/20118070","citation_count":53,"is_preprint":false},{"pmid":"21917589","id":"PMC_21917589","title":"Bypass of glycan-dependent glycoprotein delivery to ERAD by up-regulated EDEM1.","date":"2011","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/21917589","citation_count":52,"is_preprint":false},{"pmid":"21062743","id":"PMC_21062743","title":"Mannose trimming is required for delivery of a glycoprotein from EDEM1 to XTP3-B and to late endoplasmic reticulum-associated degradation steps.","date":"2010","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/21062743","citation_count":50,"is_preprint":false},{"pmid":"23233672","id":"PMC_23233672","title":"A shared endoplasmic reticulum-associated degradation pathway involving the EDEM1 protein for glycosylated and nonglycosylated proteins.","date":"2012","source":"The Journal of biological 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Its MRH domain is required for interaction with SEL1L but not with substrate. XTP3-B and OS-9 form components of distinct, partially redundant quality control surveillance pathways coordinating protein folding with membrane dislocation and ubiquitin conjugation.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, pulse-chase degradation assays\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP with functional knockdown validation, replicated across multiple labs in subsequent studies\",\n      \"pmids\": [\"18264092\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"The long isoform of human XTP3-B (hXTP3-B) associates with the HRD1-SEL1L membrane-anchored ubiquitin ligase complex and BiP, forming a ~27S ER quality control scaffold complex. The short isoform is excluded from scaffold formation. hOS-9 is also incorporated into this large complex. hXTP3-B long isoform inhibits ERAD of NHK (null Hong Kong alpha1-antitrypsin variant), including a non-glycosylated version (NHK-QQQ), while the short isoform has almost no effect.\",\n      \"method\": \"Immunoprecipitation, sucrose density gradient centrifugation fractionation, siRNA knockdown, pulse-chase degradation assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP plus orthogonal sucrose gradient fractionation, functional siRNA validation, replicated in subsequent studies\",\n      \"pmids\": [\"18502753\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"XTP3-B binds to the ERAD substrate alpha1-antitrypsin variant NHK (but not wild-type AT) specifically via its C-terminal MRH domain in a glycan-dependent manner. Mutation of Arg428 or Tyr457 in the C-terminal MRH domain abolishes glycan binding. The N-terminal MRH domain is dispensable for substrate binding.\",\n      \"method\": \"Recombinant Fc-fusion protein binding assays to Lec1 cells, EndoH treatment, competitive inhibition with mannose oligosaccharides, alanine mutagenesis, co-immunoprecipitation\",\n      \"journal\": \"Glycobiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro binding assay with mutagenesis and multiple orthogonal methods in one study\",\n      \"pmids\": [\"19917667\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Disposal of soluble ERAD-LS substrates (nontransmembrane polypeptides with luminal lesions) is strictly dependent on XTP3-B (and OS-9) acting as interchangeable ERAD lectins along with HRD1 and SEL1L. These ERAD factors become dispensable when the same polypeptides are membrane-tethered (ERAD-LM substrates), revealing a mammalian-specific distinction from yeast.\",\n      \"method\": \"siRNA knockdown, pulse-chase degradation assays, genetic epistasis with defined substrate variants\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — systematic siRNA knockdown epistasis with multiple substrates, replicated finding across multiple ERAD components\",\n      \"pmids\": [\"20100910\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Mannose trimming is required for substrate association with XTP3-B and with E3 ubiquitin ligases HRD1 and SCF(Fbs2). Inhibition of mannose trimming (kifunensine or ERManI knockdown) prevents substrate colocalization with HRD1 and Fbs2 at the ERQC but not with EDEM1. Substrate association with XTP3-B remained dependent on mannose trimming even upon SEL1L knockdown, suggesting XTP3-B recognizes mannose-trimmed glycans for late ERAD steps.\",\n      \"method\": \"Co-immunoprecipitation, mannosidase inhibitor (kifunensine) treatment, siRNA knockdown of ERManI and SEL1L, confocal colocalization\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (Co-IP, colocalization, chemical inhibition, siRNA) in single lab study\",\n      \"pmids\": [\"21062743\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"XTP3-B interacts with unassembled core-glycosylated CD147 (an endogenous ERAD substrate), and this interaction is inhibited by mutations to conserved residues in the XTP3-B lectin domain. XTP3-B participates along with OS-9 in the OS-9/SEL1L/Hrd1 ERAD pathway for an endogenous constitutive substrate.\",\n      \"method\": \"Mass spectrometry identification, Co-immunoprecipitation, lectin domain mutagenesis, siRNA depletion, proteasome inhibitor assays\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MS-based substrate identification plus mutagenesis validation and functional epistasis in single study\",\n      \"pmids\": [\"23097496\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"The C-terminal MRH domain of XTP3-B specifically recognizes Man9GlcNAc2 (M9) glycans in vitro and on the ERAD substrate NHK in vivo. Endogenous XTP3-B is a component of the HRD1-SEL1L complex via direct interaction with SEL1L. Lectin activity is required for NHK binding but not for SEL1L association. Unlike OS-9, XTP3-B inhibits ERAD of NHK bearing M9 oligosaccharides, acting as a negative regulator of ERAD and protecting newly synthesized immature polypeptides from premature degradation.\",\n      \"method\": \"Frontal affinity chromatography (FAC), co-immunoprecipitation, siRNA knockdown, pulse-chase degradation assays, lectin-domain mutagenesis\",\n      \"journal\": \"The FEBS journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro FAC biochemical assay plus mutagenesis plus functional degradation assays in single study with multiple orthogonal methods\",\n      \"pmids\": [\"23356641\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Nonglycosylated BiP substrates (NS-1κ light chain and truncated Igγ heavy chain) interact with XTP3-B and OS-9, and require EDEM1 for degradation, revealing that XTP3-B can engage non-glycosylated ERAD substrates through protein-protein interactions, sharing the ERAD pathway with glycoproteins.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, pulse-chase degradation assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP plus siRNA epistasis in single lab study\",\n      \"pmids\": [\"23233672\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Erlectin (XTP3-B/ERLEC1) is an ER luminal resident protein with two MRH domains. It interacts with the Wnt co-receptor Kremen2 (Krm2) via one MRH domain in a glycan-dependent manner (interaction abolished by Krm2 deglycosylation). Erlectin overexpression inhibits transport of Krm2 to the cell surface. Morpholino knockdown in Xenopus causes head and axial defects, placing Erlectin in ER glycoprotein trafficking regulation.\",\n      \"method\": \"Proteomic interaction screen, co-immunoprecipitation, deglycosylation assay, cell surface transport assay, Xenopus morpholino knockdown\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with deglycosylation functional validation plus in vivo morpholino phenotype, single lab\",\n      \"pmids\": [\"16531414\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"ERLEC1/CIM sequesters OS-9 away from the HIF-1α complex and PHD2, thereby preventing HIF-1α degradation and permitting HIF-1α accumulation under hypoxic conditions. ERLEC1 also modulates the unfolded protein response through interaction with the key ER stress protein BiP, influencing cell proliferation under ER stress.\",\n      \"method\": \"Proteomic approaches, co-immunoprecipitation, ectopic expression, hypoxia tolerance assays\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP and functional overexpression data with multiple cellular readouts, single lab\",\n      \"pmids\": [\"21118962\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"ERLEC1 expression is transcriptionally upregulated by ER stress via a novel ERSE-26 element (CCAAT-N26-CCACG) in its promoter, regulated by XBP1 but not ATF6α. XBP1 overexpression increased and siRNA knockdown of XBP1 reduced ERLEC1 mRNA levels.\",\n      \"method\": \"Luciferase reporter assays, ER stressor treatment (brefeldin A, tunicamycin, thapsigargin), siRNA knockdown of XBP1, mRNA quantification\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reporter assay plus siRNA knockdown and overexpression, multiple stressors tested, single lab\",\n      \"pmids\": [\"23737521\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"XTP3-B/ERLEC1 stabilizes SEL1L by inhibiting its degradation. When proteasome activity is inhibited, SEL1L generates degradation intermediates that interact with aggregation-prone proteins including polyglutamine-expanded Huntingtin (Htt-polyQ-GFP), stimulating their cytosolic aggregation.\",\n      \"method\": \"Proteasome inhibitor assays, co-immunoprecipitation, GFP-tagged aggregation reporters, siRNA knockdown of OS-9 and XTP3-B\",\n      \"journal\": \"The FEBS journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional knockdown with defined biochemical readouts in single lab study\",\n      \"pmids\": [\"33576152\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ERLEC1 is identified as a substrate for the ER translocation inhibitor cyclotriazadisulfonamide (CADA). CADA inhibits ERLEC1 protein expression in a signal peptide-dependent manner. Cell-free in vitro translation/translocation assays confirmed that ERLEC1's signal peptide is a target for CADA-mediated cotranslational translocation inhibition at the Sec61 translocon.\",\n      \"method\": \"Quantitative proteomics (SILAC-MS), Western blot, flow cytometry, cell-free in vitro translation/translocation assay\",\n      \"journal\": \"Molecular & cellular proteomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro translation/translocation assay plus quantitative proteomics and Western blot validation, single lab\",\n      \"pmids\": [\"34481949\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"SEL1L recruits ERLEC1 (along with OS9, UBE2J1, and DERLIN) to HRD1 to form a functional HRD1 ERAD complex. Attenuation of the SEL1L-HRD1 interaction (via a SEL1L variant) impairs recruitment of ERLEC1 to HRD1, demonstrating that SEL1L-HRD1 interaction is prerequisite for ERLEC1 incorporation into the functional ERAD complex.\",\n      \"method\": \"Proteomic interactome screens of SEL1L and HRD1, co-immunoprecipitation, knockin mouse model with SEL1L variant\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — proteomic interactome plus Co-IP validation and in vivo mouse model, single lab, preprint\",\n      \"pmids\": [\"37333389\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Mutation of erlec1 in zebrafish results in further suppression of the cholesterol biosynthesis pathway in the context of misfolded Z-variant alpha1-antitrypsin (ZAAT) expression, confirming a role for this ER lectin in targeting misfolded ZAAT for ER-associated degradation (ERAD).\",\n      \"method\": \"CRISPR/Cas9 erlec1 knockout in zebrafish, transcriptomic and proteomic analysis\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo gene knockout with defined molecular pathway phenotype, single lab\",\n      \"pmids\": [\"36768797\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"EDEM1 overexpression or its up-regulation by IRE1 can deliver ERAD substrates to XTP3-B and OS9 even when mannose trimming is bypassed. An EDEM1 deletion mutant lacking most of the carbohydrate-recognition domain still accelerates ERAD by delivering substrate to XTP3-B, suggesting that substrate delivery from EDEM1 to XTP3-B can occur through protein-protein interactions independent of glycan recognition.\",\n      \"method\": \"siRNA knockdown, overexpression, pulse-chase degradation assays, confocal colocalization, co-immunoprecipitation\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal genetic and biochemical approaches in single lab study\",\n      \"pmids\": [\"21917589\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Rare missense variants in ERLEC1 (including p.His413Tyr, p.Thr140Ser, p.Thr140Ile, p.Asn483Ser) co-segregate with Class III malocclusion. ERLEC1 is highly expressed in mouse jaw osteoblasts and inhibits osteoblast proliferation; the His413Tyr variant significantly enhanced this inhibitory effect on osteoblast proliferation. Proper ERLEC1 expression level is required for correct osteogenic differentiation.\",\n      \"method\": \"Exome sequencing, Sanger sequencing co-segregation, ERLEC1 expression analysis in osteoblasts, overexpression of wild-type vs. mutant ERLEC1 with cell proliferation and differentiation assays\",\n      \"journal\": \"Human mutation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — variant co-segregation plus functional cellular assays in single lab study\",\n      \"pmids\": [\"32442352\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ERLEC1 (XTP3-B/Erlectin) is an ER-luminal lectin with two MRH domains that recognizes high-mannose N-glycans (particularly Man9GlcNAc2 via its C-terminal MRH domain) on misfolded glycoproteins and, through direct interaction with the adaptor SEL1L, is recruited into the ~27S HRD1-SEL1L ubiquitin ligase scaffold complex along with BiP and OS-9 to mediate ER-associated degradation (ERAD) of soluble luminal substrates; unlike OS-9, XTP3-B acts as a negative regulator of ERAD by protecting immature polypeptides bearing M9 glycans from premature degradation, and it also participates in HIF-1α stabilization by sequestering OS-9 from the HIF-1α/PHD2 complex, is transcriptionally induced by ER stress via XBP1, and its signal peptide-dependent ER translocation is inhibitable by cyclotriazadisulfonamide (CADA).\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ERLEC1 (XTP3-B/Erlectin) is an ER-luminal lectin that functions in ER-associated degradation (ERAD), recognizing misfolded glycoproteins and coupling their surveillance to the membrane ubiquitin ligase machinery [#0, #3]. It is directly recruited into the HRD1-SEL1L ubiquitin ligase scaffold through interaction with the adaptor SEL1L, an association that, together with OS-9 and BiP, builds a large (~27S) ER quality control complex; SEL1L-HRD1 engagement is prerequisite for ERLEC1 incorporation, and its MRH domain is required for SEL1L binding but not for substrate recognition [#0, #1, #13]. Substrate engagement is mediated by the C-terminal MRH domain, which recognizes mannose-trimmed high-mannose N-glycans, specifically Man9GlcNAc2, on misfolded glycoproteins such as the alpha1-antitrypsin variant NHK and unassembled CD147; conserved residues including Arg428 and Tyr457 are essential for this glycan-dependent binding [#2, #4, #5, #6]. ERLEC1 and OS-9 act as partially redundant, interchangeable lectins selectively required for disposal of soluble luminal (ERAD-LS) substrates but dispensable when the same lesions are membrane-tethered [#3]. ERLEC1 can also engage non-glycosylated substrates through protein-protein interactions and receives substrates handed off from EDEM1 independently of glycan recognition [#7, #15]. Functionally distinct from OS-9, ERLEC1 acts as a negative regulator of ERAD, protecting immature M9-glycan-bearing polypeptides from premature degradation [#6], and it stabilizes the adaptor SEL1L against degradation [#11]. ERLEC1 is transcriptionally induced by ER stress through an ERSE-26 promoter element controlled by XBP1 [#10], and its cotranslational ER translocation at the Sec61 translocon is signal-peptide-dependent and blocked by cyclotriazadisulfonamide [#12]. Rare missense variants in ERLEC1 co-segregate with Class III malocclusion, where the protein inhibits jaw osteoblast proliferation [#16].\",\n  \"teleology\": [\n    {\n      \"year\": 2006,\n      \"claim\": \"Established ERLEC1 as an ER-luminal MRH-domain lectin capable of glycan-dependent control of glycoprotein trafficking, the founding observation of its function.\",\n      \"evidence\": \"Proteomic interaction screen, Co-IP with deglycosylation, cell surface transport assay, and Xenopus morpholino knockdown\",\n      \"pmids\": [\"16531414\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not connect ERLEC1 to ERAD or to the HRD1-SEL1L machinery\", \"Kremen2 interaction not linked to degradation\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Defined ERLEC1's core role: an ERAD lectin that binds substrate and bridges to the Hrd1 ligase via SEL1L, working in a pathway partially redundant with OS-9.\",\n      \"evidence\": \"Reciprocal Co-IP, siRNA knockdown, pulse-chase degradation assays; orthogonal sucrose density gradient fractionation defining the ~27S scaffold and isoform requirement\",\n      \"pmids\": [\"18264092\", \"18502753\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Glycan specificity of substrate recognition not yet defined\", \"Mechanistic basis of redundancy with OS-9 unresolved\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Localized substrate recognition to the C-terminal MRH domain and showed it is glycan-dependent, distinguishing substrate-binding from SEL1L-binding functions.\",\n      \"evidence\": \"Recombinant Fc-fusion binding to Lec1 cells, EndoH treatment, mannose competition, alanine mutagenesis (Arg428/Tyr457), Co-IP\",\n      \"pmids\": [\"19917667\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Precise glycan species recognized not yet determined\", \"Role of N-terminal MRH domain unexplained\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Defined the substrate class strictly dependent on ERLEC1 and established that mannose trimming is required for substrate handoff to the ligase.\",\n      \"evidence\": \"siRNA epistasis with defined ERAD-LS/ERAD-LM substrate variants; Co-IP, kifunensine treatment, ERManI/SEL1L knockdown, confocal colocalization\",\n      \"pmids\": [\"20100910\", \"21062743\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of mannose-trimmed glycan selectivity not resolved\", \"Order of factor recruitment along the pathway not fully ordered\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Proposed a moonlighting role in hypoxia signaling whereby ERLEC1 sequesters OS-9 to stabilize HIF-1\\u03b1, linking it to BiP and the UPR.\",\n      \"evidence\": \"Proteomic approaches, Co-IP, ectopic expression, hypoxia tolerance assays\",\n      \"pmids\": [\"21118962\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab overexpression-based; physiological relevance of OS-9 sequestration not independently validated\", \"Quantitative competition mechanism not established\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Showed substrate delivery to ERLEC1 can bypass glycan recognition via EDEM1 protein-protein interactions, broadening its substrate engagement modes.\",\n      \"evidence\": \"siRNA knockdown, overexpression, pulse-chase, confocal colocalization, Co-IP with EDEM1 CRD-deletion mutant\",\n      \"pmids\": [\"21917589\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs. indirect nature of EDEM1-ERLEC1 transfer not resolved\", \"Physiological frequency of glycan-independent handoff unknown\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Extended ERLEC1 function to endogenous and non-glycosylated substrates, demonstrating engagement through both lectin and protein-protein interactions.\",\n      \"evidence\": \"MS substrate identification (CD147), Co-IP, lectin-domain mutagenesis, siRNA depletion, proteasome inhibitor assays; Co-IP/siRNA epistasis for non-glycosylated BiP substrates\",\n      \"pmids\": [\"23097496\", \"23233672\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular basis of non-glycosylated substrate recognition undefined\", \"Relative contribution of ERLEC1 vs OS-9 for endogenous substrates unclear\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Defined the precise glycan ligand (Man9GlcNAc2) and revealed that ERLEC1 acts as a negative ERAD regulator protecting immature polypeptides, distinguishing it functionally from OS-9; also identified XBP1-driven ER-stress induction.\",\n      \"evidence\": \"Frontal affinity chromatography, Co-IP, siRNA, pulse-chase, lectin mutagenesis; luciferase reporter and XBP1 knockdown/overexpression with multiple ER stressors\",\n      \"pmids\": [\"23356641\", \"23737521\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which ERLEC1 protects vs. targets substrates not structurally explained\", \"Switch between protective and degradative modes not defined\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identified ERLEC1 as a stabilizer of SEL1L and a determinant of cytosolic aggregation behavior, and showed its biogenesis is controlled at the Sec61 translocon.\",\n      \"evidence\": \"Proteasome inhibitor assays, Co-IP, GFP-aggregation reporters, OS-9/XTP3-B siRNA; SILAC-MS, Western blot, flow cytometry, and cell-free translation/translocation assay with CADA\",\n      \"pmids\": [\"33576152\", \"34481949\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of SEL1L stabilization not biochemically defined\", \"Functional consequence of CADA-mediated ERLEC1 depletion in vivo unknown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Confirmed SEL1L-HRD1 engagement as prerequisite for ERLEC1 recruitment into the functional ERAD complex and validated ERLEC1's ERAD role for misfolded ZAAT in vivo.\",\n      \"evidence\": \"SEL1L/HRD1 interactome screens, Co-IP, knockin mouse SEL1L variant (preprint); CRISPR erlec1 zebrafish knockout with transcriptomic/proteomic analysis\",\n      \"pmids\": [\"37333389\", \"36768797\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"bioRxiv preprint not peer-reviewed for the recruitment hierarchy\", \"Mechanistic link between ERAD defect and cholesterol pathway suppression unclear\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Linked ERLEC1 to a human craniofacial phenotype, implicating it in osteoblast proliferation control.\",\n      \"evidence\": \"Exome/Sanger co-segregation of missense variants with Class III malocclusion; osteoblast expression and wild-type vs mutant proliferation/differentiation assays\",\n      \"pmids\": [\"32442352\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanistic connection between ERAD lectin function and osteoblast proliferation undefined\", \"Causality of variants not established beyond co-segregation\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How ERLEC1 toggles between protecting immature glycoproteins and committing substrates to degradation, and how this is structurally coordinated within the HRD1-SEL1L complex, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structure of ERLEC1 within the assembled HRD1-SEL1L complex\", \"Molecular switch between protective and degradative modes unknown\", \"Physiological substrate repertoire incompletely mapped\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0030246\", \"supporting_discovery_ids\": [2, 6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [0, 8]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 3, 6]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [10]}\n    ],\n    \"complexes\": [\n      \"HRD1-SEL1L ERAD complex\"\n    ],\n    \"partners\": [\n      \"SEL1L\",\n      \"HRD1\",\n      \"OS-9\",\n      \"BiP\",\n      \"EDEM1\",\n      \"Kremen2\",\n      \"DERLIN\",\n      \"UBE2J1\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}