{"gene":"OS9","run_date":"2026-06-10T05:19:53","timeline":{"discoveries":[{"year":2008,"finding":"OS-9 is an ER-resident glycoprotein that binds to ERAD substrates (including mutant alpha1-antitrypsin) and, through the SEL1L adaptor, to the ER-membrane-embedded E3 ubiquitin ligase HRD1. The MRH domain of OS-9 is required for interaction with SEL1L but not with substrate. OS-9 also associates with the ER chaperone GRP94, and both HRD1 and SEL1L are required for degradation of mutant alpha1-antitrypsin.","method":"Co-immunoprecipitation, RNAi knockdown, functional ERAD degradation assays, domain mutagenesis (MRH domain)","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, RNAi functional rescue, domain mutagenesis, multiple orthogonal methods; widely replicated by subsequent studies","pmids":["18264092"],"is_preprint":false},{"year":2005,"finding":"OS-9 interacts with both HIF-1alpha and HIF-1alpha prolyl hydroxylases (PHDs). OS-9 gain-of-function promotes HIF-1alpha hydroxylation, VHL binding, proteasomal degradation of HIF-1alpha, and inhibition of HIF-1-mediated transcription. OS-9 loss-of-function via RNAi increases HIF-1alpha protein levels and HIF-1-mediated transcription under non-hypoxic conditions.","method":"Co-immunoprecipitation, RNAi knockdown, reporter assays, HIF-1alpha stability assays","journal":"Molecular cell","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — single lab, reciprocal Co-IP and functional assays, but contradicted by a later study (PMID:21559462) showing OS-9 is a luminal ER protein and cannot interact with cytoplasmic PHDs in vivo","pmids":["15721254"],"is_preprint":false},{"year":2011,"finding":"A subsequent study contradicting OS-9/PHD interaction: OS-9 is a luminal ER protein (confirmed by subcellular fractionation and glycosylation tests) while PHD2 is cytoplasmic; FRET analysis showed no significant in vivo physical interaction between PHD2 and OS-9. Neither overexpression nor lentiviral knockdown of OS-9 affected HIF regulation.","method":"Subcellular fractionation, glycosylation assay, co-immunoprecipitation, FRET, lentiviral knockdown","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (fractionation, FRET, KD), single lab, directly contradicts earlier HIF study","pmids":["21559462"],"is_preprint":false},{"year":2009,"finding":"The MRH domain of human OS-9 specifically binds N-glycans lacking the terminal mannose from the C branch (i.e., Man7 isomers with trimmed C-arm alpha1,2-mannose) as demonstrated by frontal affinity chromatography. This lectin activity is required for OS-9 to promote ERAD of the glycosylated substrate NHK in vivo.","method":"Frontal affinity chromatography with recombinant MRH domain, siRNA knockdown, overexpression of mannosidases, in vivo ERAD assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with recombinant domain, frontal affinity chromatography with defined glycan structures, validated in vivo; replicated in independent studies","pmids":["19346256"],"is_preprint":false},{"year":2010,"finding":"Crystal structure of the human OS-9 MRH domain complexed with alpha3,alpha6-mannopentaose reveals a flattened beta-barrel structure with P-type lectin fold and distinctive double tryptophan (WW) residues in the oligosaccharide-binding site that recognize Manalpha1,6Manalpha1,6Man residues on the processed C-arm of high-mannose glycans.","method":"X-ray crystallography, NMR spectroscopy, biochemical binding assays","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure with ligand, validated by NMR and biochemical assays, multiple orthogonal methods in one study","pmids":["21172656"],"is_preprint":false},{"year":2010,"finding":"Disposal of soluble ERAD-L substrates (ERAD-LS) is strictly dependent on HRD1, SEL1L, and the two interchangeable lectins OS-9 and XTP3-B. Tethering the same substrates to the membrane (ERAD-LM) renders these ERAD factors dispensable, demonstrating that OS-9/XTP3-B function is pathway-selective.","method":"RNAi knockdown, pulse-chase degradation assays, genetic epistasis using membrane-tethered vs. soluble substrates","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean RNAi epistasis with multiple substrates, rigorous controls, replicated by independent labs","pmids":["20100910"],"is_preprint":false},{"year":2008,"finding":"OS-9.1 and OS-9.2 (alternative splice variants) are transcriptionally induced by the IRE1/XBP1 ER-stress pathway. OS-9 variants selectively bind folding-defective proteins but not folding-competent ones, thereby inhibiting secretion of misfolded conformers (retention function) and promoting their ERAD (disposal function). OS-9 also transiently associates with non-glycosylated misfolded proteins but this association is unproductive for ERAD.","method":"Co-immunoprecipitation, RNAi knockdown, pulse-chase assays, secretion assays, XBP1 reporter/induction","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, functional RNAi, secretion and degradation assays, single lab","pmids":["18417469"],"is_preprint":false},{"year":2008,"finding":"OS-9 is upregulated by ER stress and is required for efficient ubiquitination of glycosylated ERAD substrates (demonstrated by RNAi). OS-9 also binds a misfolded non-glycosylated ERAD substrate but is not required for its ubiquitination or degradation, indicating that OS-9's functional requirement is N-glycan-dependent.","method":"RNAi knockdown, ubiquitination assays, co-immunoprecipitation, Western blot","journal":"Journal of molecular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean RNAi functional assay, ubiquitination readout, single lab","pmids":["19084021"],"is_preprint":false},{"year":2007,"finding":"OS-9 interacts with the cytosolic N-terminal tail of TRPV4 via co-immunoprecipitation. OS-9 preferentially binds TRPV4 monomers and immature ER-localized forms, impedes TRPV4 release from the ER, reduces TRPV4 at the plasma membrane, and attenuates polyubiquitination of TRPV4 subunits, suggesting a role as an auxiliary maturation factor protecting against premature ERAD.","method":"Co-immunoprecipitation, knockdown, cell-surface biotinylation, in vivo zebrafish expression, polyubiquitination assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, functional knockdown with surface expression readout, in vivo validation, single lab","pmids":["17932042"],"is_preprint":false},{"year":2018,"finding":"Using homozygous deletion cell lines, OS9 and XTP3B were found to redundantly promote glycoprotein degradation and stabilize the SEL1L/HRD1 dislocon complex. OS9 antagonizes XTP3B-mediated inhibition of non-glycosylated protein degradation. The relative expression ratio of OS9 and XTP3B determines the fidelity of glycoprotein triage in the ER.","method":"CRISPR/Cas9 homozygous deletions, quantitative ERAD assays, co-immunoprecipitation of SEL1L/HRD1 complex, genetic epistasis","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean genetic KO (CRISPR), multiple substrates, epistasis with double KO, complex stabilization assays","pmids":["29706535"],"is_preprint":false},{"year":2015,"finding":"OS9 interacts specifically with the immature form of the renal Na-K-2Cl co-transporter NKCC2 (identified by yeast two-hybrid and confirmed by co-IP), co-localizes with NKCC2 in the ER, and promotes proteasomal degradation of immature NKCC2. Inactivation of the OS9 MRH domain does not affect this activity, but mutation of NKCC2 N-glycosylation sites abolishes OS9-induced degradation, indicating N-glycan-dependent but MRH-independent recognition.","method":"Yeast two-hybrid, co-immunoprecipitation, immunocytochemistry, pulse-chase and cycloheximide-chase assays, siRNA knockdown, MRH domain mutagenesis, glycosylation site mutagenesis","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — yeast two-hybrid + reciprocal Co-IP + functional degradation assays + domain mutagenesis, single lab","pmids":["26721884"],"is_preprint":false},{"year":2014,"finding":"OS-9 facilitates turnover of hyperglycosylated (nonnative) GRP94 via a lysosomal-like, ERAD-independent mechanism. OS-9 binds preferentially to a subpopulation of GRP94 that is hyperglycosylated on cryptic N-linked acceptor sites, and these GRP94 forms have nonnative conformations and are less active. GRP94 is not required for OS-9 folding and does not collaborate with OS-9 in ERAD of misfolded substrates.","method":"Co-immunoprecipitation, pulse-chase assays, glycosylation analysis, lysosome inhibitor experiments, RNAi","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, pulse-chase, inhibitor studies, single lab, multiple orthogonal approaches","pmids":["24899641"],"is_preprint":false},{"year":2014,"finding":"The C-terminal domain of mammalian OS-9 contains mammalian-specific inserts that are intrinsically disordered and specifically recognized by the middle and C-terminal domains of GRP94. Glycosylation of full-length GRP94 is essential for OS-9 binding, but this requirement is relieved by deletion of the GRP94 N-terminal domain, indicating an allosteric rather than direct glycan-mediated interaction.","method":"Domain mapping by co-immunoprecipitation, deletion mutagenesis, biochemical binding assays","journal":"Journal of molecular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — deletion mapping + Co-IP + mutagenesis, single lab","pmids":["25193139"],"is_preprint":false},{"year":2014,"finding":"OS-9 (but not XTP3-B) is required for ERAD of mutant neuroserpin in familial encephalopathy with neuroserpin inclusion bodies. OS-9 binds mutant neuroserpin via glycan recognition; removal of glycosylation sites increases neuroserpin protein load, while OS-9 overexpression decreases it. This was validated in both cell culture and a murine FENIB model.","method":"Co-immunoprecipitation, RNAi, overexpression, glycosylation site mutagenesis, mouse model analysis","journal":"Neurobiology of aging","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional Co-IP, mutagenesis, in vivo mouse model validation, single lab","pmids":["24795221"],"is_preprint":false},{"year":2014,"finding":"OS-9 is required for ERAD of both glycosylated and non-glycosylated sonic hedgehog (SHH). OS-9 robustly interacts with a non-glycosylated SHH variant (N278A), indicating that the misfolded polypeptide backbone rather than a glycan signature can serve as the predominant recognition signal for OS-9 in certain substrates.","method":"RNAi knockdown, co-immunoprecipitation, pulse-chase ERAD assays, glycosylation mutant analysis","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus functional RNAi ERAD assays with multiple substrates, single lab","pmids":["24910992"],"is_preprint":false},{"year":2002,"finding":"OS-9 interacts specifically with the cytoplasmic intracellular region of the membrane proteinase meprin beta. OS-9 is associated with ER membranes and exposed to the cytoplasm. OS-9 associates transiently with meprin beta coinciding with ER-to-Golgi transport of meprin beta. Only the non-spliced form of OS-9 binds meprin beta, implicating the alternatively spliced segment in binding specificity.","method":"Yeast two-hybrid, co-immunoprecipitation, subcellular fractionation, deletion mutagenesis, pulse-chase assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — yeast two-hybrid + reciprocal Co-IP + fractionation + functional transport analysis, single lab","pmids":["12093806"],"is_preprint":false},{"year":2009,"finding":"The OS-9 MRH domain binds N-glycans containing terminal alpha1,6-linked mannose in the Manalpha1,6(Manalpha1,3)Manalpha1,6(Manalpha1,3)Man structure (Ka ~10^4 M^-1), as determined by frontal affinity chromatography with 92 oligosaccharides. Trimming of either an alpha1,6-linked mannose from the C-arm or an alpha1,3-linked mannose from the B-arm abolishes OS-9 MRH binding. The alpha1-antitrypsin NHK variant (but not wild-type) interacts with OS-9 in cells in a sugar-dependent manner.","method":"Frontal affinity chromatography (92 glycan panel), tetramer binding assay, site-directed mutagenesis of MRH residues, co-immunoprecipitation","journal":"Glycobiology","confidence":"High","confidence_rationale":"Tier 1 / Strong — systematic in vitro glycan-binding assay with recombinant domain + mutagenesis + in-cell co-IP validation, large glycan panel","pmids":["19914915"],"is_preprint":false},{"year":2008,"finding":"OS9 physically interacts with DC-STAMP and both proteins co-localize in the ER. Upon TLR-induced DC maturation, DC-STAMP translocates from the ER to the Golgi while OS9 localization is unchanged. The DC-STAMP/OS9 interaction is involved in this ER-to-Golgi translocation process.","method":"Yeast two-hybrid, co-immunoprecipitation, confocal co-localization, TLR stimulation experiments in CHO cells and dendritic cells","journal":"Molecular immunology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — yeast two-hybrid + single Co-IP + localization, mechanistic link to translocation inferred rather than directly demonstrated, single lab","pmids":["18952287"],"is_preprint":false},{"year":1999,"finding":"OS-9 interacts with N-copine (a two-C2-domain protein) via the second C2 domain of N-copine and the carboxy-terminal region of OS-9. This interaction is Ca2+-dependent as shown by in vitro binding assays and co-immunoprecipitation.","method":"Yeast two-hybrid, co-immunoprecipitation, in vitro Ca2+-dependent binding assay","journal":"FEBS letters","confidence":"Low","confidence_rationale":"Tier 3 / Weak — yeast two-hybrid + single Co-IP + in vitro binding, single lab, no functional consequence established","pmids":["10403379"],"is_preprint":false},{"year":2016,"finding":"Meprin beta (but not meprin A) cleaves OS-9 in vitro and in vivo during ischemia/reperfusion-induced renal injury. Fragmentation of OS-9 by meprin beta was observed in WT mice subjected to IR but not in meprin αβKO mice. Transfection with meprin beta cDNA prevented accumulation of OS-9 under hypoxia mimic conditions.","method":"In vitro protease assay with purified proteins, meprin knockout mouse model, IR injury model, Western blot, cell transfection","journal":"International journal of nephrology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro cleavage assay + knockout mouse model validation, single lab","pmids":["27478637"],"is_preprint":false},{"year":2017,"finding":"OS-9 interacts with the immature form of the calcium-sensing receptor (CaSR) in the ER (identified by yeast two-hybrid and co-IP). OS-9 binding to CaSR requires the MRH domain. Two distinct binding interactions were identified: one involving both C-terminal domains and another involving both N-terminal domains of OS-9 and CaSR. However, OS-9 knockdown or overexpression did not significantly affect CaSR cell surface expression or CaSR-mediated ERK1/2 phosphorylation (negative functional result).","method":"Yeast two-hybrid, co-immunoprecipitation, confocal co-localization, MRH domain mutagenesis, siRNA knockdown, ERK phosphorylation assay","journal":"Journal of cellular physiology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — yeast two-hybrid + Co-IP + domain mutagenesis, but functional consequence of OS-9/CaSR interaction was negative, single lab","pmids":["28419469"],"is_preprint":false},{"year":2025,"finding":"Cryo-EM structure of the core mammalian ERAD complex comprising OS9, SEL1L, and HRD1 reveals a dimeric assembly where SEL1L and OS9 form a claw-like configuration in the ER lumen for substrate engagement while HRD1 dimerizes in the membrane for substrate translocation. Pathogenic SEL1L mutations at the SEL1L-OS9 interface (Gly585Asp) disrupt complex formation and impair ERAD activity, validated by mutagenesis and crosslinking assays.","method":"Cryo-EM structure determination, site-directed mutagenesis, crosslinking assays, ERAD functional assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — cryo-EM structure validated by mutagenesis and crosslinking, functional ERAD assays, published in peer-reviewed journal","pmids":["41593065","40661598"],"is_preprint":false}],"current_model":"OS9 is an ER-resident lectin that recognizes mannose-trimmed N-glycans (specifically Manalpha1,6Man structures on the processed C-arm of high-mannose glycans) via its MRH domain, and together with SEL1L forms a claw-like luminal complex that delivers misfolded glycoproteins to the HRD1 E3 ubiquitin ligase for ERAD; OS9 is required for ubiquitination of glycosylated substrates and functions redundantly with XTP3B for glycoprotein triage while antagonizing XTP3B-mediated inhibition of non-glycosylated substrate degradation."},"narrative":{"mechanistic_narrative":"OS9 is an ER-luminal lectin that triages misfolded glycoproteins for endoplasmic-reticulum-associated degradation (ERAD) by recognizing mannose-trimmed N-glycans and delivering substrates to the membrane ubiquitin ligase machinery [PMID:18264092, PMID:19346256]. Its mannose-6-phosphate-receptor-homology (MRH) domain binds high-mannose glycans bearing terminal alpha1,6-linked mannose on the trimmed C-arm (Man7 isomers), and this lectin activity is required for OS9 to promote degradation of glycosylated substrates such as the alpha1-antitrypsin NHK variant [PMID:19346256, PMID:19914915]; crystallography defined a P-type lectin fold with a distinctive double-tryptophan site recognizing Manalpha1,6Manalpha1,6Man residues [PMID:21172656]. OS9 bridges captured substrates to the HRD1 E3 ligase through the SEL1L adaptor, with the MRH domain required for SEL1L binding [PMID:18264092], and cryo-EM of the OS9-SEL1L-HRD1 core complex shows SEL1L and OS9 forming a claw-like luminal substrate-engagement module above a membrane HRD1 dimer that translocates substrate [PMID:41593065, PMID:40661598]. Degradation of soluble ERAD-L substrates strictly requires HRD1, SEL1L, and the interchangeable lectins OS9 and XTP3B, whereas membrane-tethered substrates bypass this requirement, defining OS9 as a pathway-selective luminal recognition factor [PMID:20100910]; OS9 and XTP3B act redundantly to promote glycoprotein degradation and stabilize the SEL1L/HRD1 dislocon, and their expression ratio tunes triage fidelity, with OS9 antagonizing XTP3B-mediated inhibition of non-glycosylated substrate degradation [PMID:29706535]. OS9 is induced by ER stress through the IRE1/XBP1 pathway and selectively retains and disposes of folding-defective conformers [PMID:18417469], and is required for ubiquitination of glycosylated ERAD substrates [PMID:19084021]. Beyond canonical glycan-dependent ERAD, OS9 also recognizes certain misfolded substrates through the polypeptide backbone in an MRH-independent manner, as shown for NKCC2 and sonic hedgehog [PMID:26721884, PMID:24910992]. OS9 is required for ERAD of mutant neuroserpin in a cell and mouse model of familial encephalopathy with neuroserpin inclusion bodies (FENIB) [PMID:24795221].","teleology":[{"year":2002,"claim":"Established OS-9 as an ER-membrane-associated protein that transiently engages a client (meprin beta) during early secretory transport, providing the first localization and interaction context.","evidence":"Yeast two-hybrid, co-IP, subcellular fractionation, and pulse-chase in mammalian cells","pmids":["12093806"],"confidence":"Medium","gaps":["Topology assigned as cytoplasm-exposed, later revised to luminal","No link to ERAD machinery yet"]},{"year":2005,"claim":"Proposed a cytoplasmic role linking OS-9 to HIF-1alpha hydroxylation and degradation, raising the question of whether OS-9 acts outside the ER lumen.","evidence":"Co-IP, RNAi, reporter and HIF stability assays","pmids":["15721254"],"confidence":"Medium","gaps":["Topologically incompatible with later luminal localization data","Directly contradicted by subsequent study"]},{"year":2008,"claim":"Defined OS-9 as the core ERAD lectin-adaptor by showing it binds misfolded substrates and bridges them, via SEL1L, to the HRD1 E3 ligase, with the MRH domain required for SEL1L (but not substrate) binding.","evidence":"Reciprocal Co-IP, RNAi functional ERAD assays, MRH domain mutagenesis","pmids":["18264092"],"confidence":"High","gaps":["Glycan ligand of MRH domain not yet defined","Structural basis of complex assembly unknown"]},{"year":2008,"claim":"Connected OS-9 to the unfolded protein response and partitioned its function into retention of misfolded conformers and promotion of their disposal, while flagging an unproductive association with non-glycosylated clients.","evidence":"Co-IP, RNAi, pulse-chase, secretion assays, XBP1 induction","pmids":["18417469"],"confidence":"Medium","gaps":["Mechanistic basis for productive vs unproductive binding unresolved","Single lab"]},{"year":2008,"claim":"Showed OS-9 is required for ubiquitination specifically of glycosylated ERAD substrates, localizing its functional requirement to the N-glycan signal.","evidence":"RNAi, ubiquitination assays, Co-IP","pmids":["19084021"],"confidence":"Medium","gaps":["Did not define which glycan species are recognized","Single lab"]},{"year":2009,"claim":"Resolved the molecular recognition signal by demonstrating the MRH domain binds trimmed-C-arm Man7 glycans (terminal alpha1,6-mannose), and that this lectin activity is required for ERAD of glycosylated substrates in vivo.","evidence":"Frontal affinity chromatography with defined glycan panels, MRH mutagenesis, in-cell Co-IP, in vivo ERAD assays","pmids":["19346256","19914915"],"confidence":"High","gaps":["Atomic basis of glycan selectivity not yet structurally defined"]},{"year":2010,"claim":"Defined the structural basis of glycan recognition, revealing a P-type lectin fold with a double-tryptophan binding site engaging Manalpha1,6Manalpha1,6Man on the trimmed C-arm.","evidence":"X-ray crystallography with mannopentaose, NMR, biochemical binding","pmids":["21172656"],"confidence":"High","gaps":["Did not show how MRH-bound substrate is handed to SEL1L/HRD1"]},{"year":2010,"claim":"Established pathway selectivity by showing OS-9/XTP3-B (with HRD1 and SEL1L) are strictly required only for soluble ERAD-L substrates and dispensable when substrates are membrane-tethered.","evidence":"RNAi epistasis with soluble vs membrane-tethered substrates, pulse-chase","pmids":["20100910"],"confidence":"High","gaps":["Functional division between OS-9 and XTP3-B not yet defined"]},{"year":2011,"claim":"Refuted the cytoplasmic HIF model by establishing OS-9 as a luminal ER protein incapable of in vivo interaction with cytoplasmic PHD2, consolidating its role within the ER lumen.","evidence":"Subcellular fractionation, glycosylation assays, FRET, lentiviral knockdown","pmids":["21559462"],"confidence":"Medium","gaps":["Cannot exclude indirect effects on HIF in some contexts","Single lab"]},{"year":2014,"claim":"Broadened OS-9's substrate repertoire and showed glycan-independent recognition modes, including disease-mutant neuroserpin (FENIB) ERAD and backbone-based recognition of sonic hedgehog and a GRP94-specific lysosomal turnover route.","evidence":"Co-IP, RNAi, glycosylation-site mutagenesis, pulse-chase, mouse FENIB model, lysosome inhibitor studies","pmids":["24795221","24910992","24899641","25193139"],"confidence":"Medium","gaps":["How OS-9 discriminates glycan vs polypeptide signals unresolved","GRP94 lysosomal route mechanism unclear"]},{"year":2015,"claim":"Demonstrated MRH-independent, N-glycan-dependent recognition of immature NKCC2, showing OS-9 can target substrates through glycan signals not read by its MRH domain.","evidence":"Yeast two-hybrid, Co-IP, immunocytochemistry, chase assays, MRH and glycosylation-site mutagenesis","pmids":["26721884"],"confidence":"Medium","gaps":["The MRH-independent recognition determinant not identified","Single lab"]},{"year":2018,"claim":"Defined the functional relationship between the two lectins, showing OS9 and XTP3B redundantly promote glycoprotein degradation, stabilize the SEL1L/HRD1 dislocon, and that their expression ratio tunes triage fidelity with OS9 antagonizing XTP3B repression of non-glycosylated substrate disposal.","evidence":"CRISPR homozygous deletions, quantitative ERAD assays, SEL1L/HRD1 complex Co-IP, double-KO epistasis","pmids":["29706535"],"confidence":"High","gaps":["Structural basis of dislocon stabilization not resolved here","Physiological substrates governed by the ratio not enumerated"]},{"year":2025,"claim":"Provided the architectural basis of ERAD by resolving the OS9-SEL1L-HRD1 core complex, showing a luminal claw-like SEL1L-OS9 substrate-engagement module over a membrane HRD1 dimer, and validating a pathogenic SEL1L-OS9 interface mutation that impairs ERAD.","evidence":"Cryo-EM, site-directed mutagenesis, crosslinking, ERAD functional assays","pmids":["41593065","40661598"],"confidence":"High","gaps":["Dynamics of substrate handoff from MRH to HRD1 not captured","How non-glycosylated substrates are accommodated structurally unknown"]},{"year":null,"claim":"How OS9 mechanistically reconciles glycan-dependent (MRH-mediated) and glycan-independent/polypeptide-based substrate recognition, and how the OS9:XTP3B ratio is physiologically regulated, remain open.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model of dual recognition modes","Regulation of lectin expression ratio in tissues unknown","Structural account of backbone-based recognition lacking"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[3,4,16]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,21]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[0,2,6,10]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,5,9]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[6]}],"complexes":["HRD1-SEL1L ERAD dislocon complex"],"partners":["SEL1L","HRD1","XTP3B","GRP94","TRPV4","NKCC2","CASR","MEPRIN BETA"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q13438","full_name":"Protein OS-9","aliases":["Amplified in osteosarcoma 9"],"length_aa":667,"mass_kda":75.6,"function":"Lectin component of the HRD1 complex, which functions in endoplasmic reticulum (ER) quality control and ER-associated degradation (ERAD) (PubMed:18264092, PubMed:18417469, PubMed:19084021, PubMed:19346256, PubMed:21172656, PubMed:24899641). Specifically recognizes and binds improperly folded glycoproteins as well as hyperglycosylated proteins, retain them in the ER, and transfers them to the ubiquitination machinery and promote their degradation (PubMed:18264092, PubMed:18417469, PubMed:19084021, PubMed:19346256, PubMed:21172656, PubMed:24899641). Possible targets include TRPV4 as well as hyperglycosylated HSP90B1 (PubMed:17932042)","subcellular_location":"Endoplasmic reticulum lumen","url":"https://www.uniprot.org/uniprotkb/Q13438/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/OS9","classification":"Not Classified","n_dependent_lines":57,"n_total_lines":1208,"dependency_fraction":0.04718543046357616},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CANX","stoichiometry":0.2},{"gene":"SYVN1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/OS9","total_profiled":1310},"omim":[{"mim_id":"616175","title":"UBIQUITIN-CONJUGATING ENZYME E2 J1; UBE2J1","url":"https://www.omim.org/entry/616175"},{"mim_id":"613777","title":"FAD-DEPENDENT OXIDOREDUCTASE DOMAIN-CONTAINING PROTEIN 2; FOXRED2","url":"https://www.omim.org/entry/613777"},{"mim_id":"610304","title":"DER1-LIKE DOMAIN FAMILY, MEMBER 2; DERL2","url":"https://www.omim.org/entry/610304"},{"mim_id":"609677","title":"OS9 ENDOPLASMIC RETICULUM LECTIN; OS9","url":"https://www.omim.org/entry/609677"},{"mim_id":"608046","title":"SYNOVIAL APOPTOSIS INHIBITOR 1; SYVN1","url":"https://www.omim.org/entry/608046"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Endoplasmic reticulum","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/OS9"},"hgnc":{"alias_symbol":["OS-9","ERLEC2"],"prev_symbol":[]},"alphafold":{"accession":"Q13438","domains":[{"cath_id":"-","chopping":"39-94_243-274","consensus_level":"medium","plddt":80.055,"start":39,"end":274},{"cath_id":"2.70.130.10","chopping":"99-225","consensus_level":"high","plddt":89.2735,"start":99,"end":225},{"cath_id":"-","chopping":"540-628","consensus_level":"high","plddt":72.1101,"start":540,"end":628}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q13438","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q13438-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q13438-F1-predicted_aligned_error_v6.png","plddt_mean":64.06},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=OS9","jax_strain_url":"https://www.jax.org/strain/search?query=OS9"},"sequence":{"accession":"Q13438","fasta_url":"https://rest.uniprot.org/uniprotkb/Q13438.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q13438/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q13438"}},"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":"15721254","id":"PMC_15721254","title":"OS-9 interacts with hypoxia-inducible factor 1alpha and prolyl hydroxylases to promote oxygen-dependent degradation of HIF-1alpha.","date":"2005","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/15721254","citation_count":193,"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":"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":"18417469","id":"PMC_18417469","title":"A dual task for the Xbp1-responsive OS-9 variants in the mammalian endoplasmic reticulum: inhibiting secretion of misfolded protein conformers and enhancing their disposal.","date":"2008","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/18417469","citation_count":102,"is_preprint":false},{"pmid":"25314054","id":"PMC_25314054","title":"A novel long non-coding RNA ENST00000480739 suppresses tumour cell invasion by regulating OS-9 and HIF-1α in pancreatic ductal adenocarcinoma.","date":"2014","source":"British journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/25314054","citation_count":96,"is_preprint":false},{"pmid":"21172656","id":"PMC_21172656","title":"Structural basis for oligosaccharide recognition of misfolded glycoproteins by 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cell","url":"https://pubmed.ncbi.nlm.nih.gov/29706535","citation_count":45,"is_preprint":false},{"pmid":"12093806","id":"PMC_12093806","title":"A selective interaction between OS-9 and the carboxyl-terminal tail of meprin beta.","date":"2002","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/12093806","citation_count":38,"is_preprint":false},{"pmid":"9562620","id":"PMC_9562620","title":"Cloning and characterization of three isoforms of OS-9 cDNA and expression of the OS-9 gene in various human tumor cell lines.","date":"1998","source":"Journal of biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/9562620","citation_count":36,"is_preprint":false},{"pmid":"26721884","id":"PMC_26721884","title":"OS9 Protein Interacts with Na-K-2Cl Co-transporter (NKCC2) and Targets Its Immature Form for the Endoplasmic Reticulum-associated Degradation Pathway.","date":"2015","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/26721884","citation_count":30,"is_preprint":false},{"pmid":"24899641","id":"PMC_24899641","title":"OS-9 facilitates turnover of nonnative GRP94 marked by hyperglycosylation.","date":"2014","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/24899641","citation_count":30,"is_preprint":false},{"pmid":"10403379","id":"PMC_10403379","title":"Ca2(+)-dependent interaction of N-copine, a member of the two C2 domain protein family, with OS-9, the product of a gene frequently amplified in osteosarcoma.","date":"1999","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/10403379","citation_count":24,"is_preprint":false},{"pmid":"24910992","id":"PMC_24910992","title":"EDEM2 and OS-9 are required for ER-associated degradation of non-glycosylated sonic hedgehog.","date":"2014","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/24910992","citation_count":23,"is_preprint":false},{"pmid":"18952287","id":"PMC_18952287","title":"OS9 interacts with DC-STAMP and modulates its intracellular localization in response to TLR ligation.","date":"2008","source":"Molecular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/18952287","citation_count":22,"is_preprint":false},{"pmid":"24795221","id":"PMC_24795221","title":"Lectin OS-9 delivers mutant neuroserpin to endoplasmic reticulum associated degradation in familial encephalopathy with neuroserpin inclusion bodies.","date":"2014","source":"Neurobiology of aging","url":"https://pubmed.ncbi.nlm.nih.gov/24795221","citation_count":21,"is_preprint":false},{"pmid":"8021646","id":"PMC_8021646","title":"OS9: a novel olfactory gene of Drosophila expressed in two olfactory organs.","date":"1994","source":"Journal of neurobiology","url":"https://pubmed.ncbi.nlm.nih.gov/8021646","citation_count":17,"is_preprint":false},{"pmid":"25010283","id":"PMC_25010283","title":"Interaction of structural core protein of classical swine fever virus with endoplasmic reticulum-associated degradation pathway protein OS9.","date":"2014","source":"Virology","url":"https://pubmed.ncbi.nlm.nih.gov/25010283","citation_count":16,"is_preprint":false},{"pmid":"25193139","id":"PMC_25193139","title":"Characterization of the Grp94/OS-9 chaperone-lectin complex.","date":"2014","source":"Journal of molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/25193139","citation_count":13,"is_preprint":false},{"pmid":"9498564","id":"PMC_9498564","title":"Genomic organization of the OS-9 gene amplified in human sarcomas.","date":"1997","source":"Journal of biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/9498564","citation_count":12,"is_preprint":false},{"pmid":"25999789","id":"PMC_25999789","title":"A Novel Role of OS-9 in the Maintenance of Intestinal Barrier Function from Hypoxia-induced Injury via p38-dependent Pathway.","date":"2015","source":"International journal of biological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/25999789","citation_count":12,"is_preprint":false},{"pmid":"21559462","id":"PMC_21559462","title":"The function of hypoxia-inducible factor (HIF) is independent of the endoplasmic reticulum protein OS-9.","date":"2011","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/21559462","citation_count":10,"is_preprint":false},{"pmid":"15721249","id":"PMC_15721249","title":"OS-9: another piece in the HIF complex story.","date":"2005","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/15721249","citation_count":7,"is_preprint":false},{"pmid":"28419469","id":"PMC_28419469","title":"The endoplasmic reticulum-associated protein, OS-9, behaves as a lectin in targeting the immature calcium-sensing receptor.","date":"2017","source":"Journal of cellular 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communications","url":"https://pubmed.ncbi.nlm.nih.gov/41593065","citation_count":2,"is_preprint":false},{"pmid":"21186601","id":"PMC_21186601","title":"[The cooperation of OS-9 and PHDs in hypoxia-induced pulmonary hypertension of rats].","date":"2009","source":"Zhongguo ying yong sheng li xue za zhi = Zhongguo yingyong shenglixue zazhi = Chinese journal of applied physiology","url":"https://pubmed.ncbi.nlm.nih.gov/21186601","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2024.12.26.629558","title":"Target deconvolution of an insulin hypersecretion-inducer acting through VDAC1 with a distinct transcriptomic signature in beta-cells","date":"2024-12-26","source":"bioRxiv","url":"https://doi.org/10.1101/2024.12.26.629558","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":18113,"output_tokens":5836,"usd":0.07094,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":14268,"output_tokens":4254,"usd":0.088845,"stage2_stop_reason":"end_turn"},"total_usd":0.159785,"stage1_batch_id":"msgbatch_013a8chtv3AWyTqv4z4sEF4C","stage2_batch_id":"msgbatch_01AHsuW63vinsvuTgzmQ3n62","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2008,\n      \"finding\": \"OS-9 is an ER-resident glycoprotein that binds to ERAD substrates (including mutant alpha1-antitrypsin) and, through the SEL1L adaptor, to the ER-membrane-embedded E3 ubiquitin ligase HRD1. The MRH domain of OS-9 is required for interaction with SEL1L but not with substrate. OS-9 also associates with the ER chaperone GRP94, and both HRD1 and SEL1L are required for degradation of mutant alpha1-antitrypsin.\",\n      \"method\": \"Co-immunoprecipitation, RNAi knockdown, functional ERAD degradation assays, domain mutagenesis (MRH domain)\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, RNAi functional rescue, domain mutagenesis, multiple orthogonal methods; widely replicated by subsequent studies\",\n      \"pmids\": [\"18264092\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"OS-9 interacts with both HIF-1alpha and HIF-1alpha prolyl hydroxylases (PHDs). OS-9 gain-of-function promotes HIF-1alpha hydroxylation, VHL binding, proteasomal degradation of HIF-1alpha, and inhibition of HIF-1-mediated transcription. OS-9 loss-of-function via RNAi increases HIF-1alpha protein levels and HIF-1-mediated transcription under non-hypoxic conditions.\",\n      \"method\": \"Co-immunoprecipitation, RNAi knockdown, reporter assays, HIF-1alpha stability assays\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — single lab, reciprocal Co-IP and functional assays, but contradicted by a later study (PMID:21559462) showing OS-9 is a luminal ER protein and cannot interact with cytoplasmic PHDs in vivo\",\n      \"pmids\": [\"15721254\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"A subsequent study contradicting OS-9/PHD interaction: OS-9 is a luminal ER protein (confirmed by subcellular fractionation and glycosylation tests) while PHD2 is cytoplasmic; FRET analysis showed no significant in vivo physical interaction between PHD2 and OS-9. Neither overexpression nor lentiviral knockdown of OS-9 affected HIF regulation.\",\n      \"method\": \"Subcellular fractionation, glycosylation assay, co-immunoprecipitation, FRET, lentiviral knockdown\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (fractionation, FRET, KD), single lab, directly contradicts earlier HIF study\",\n      \"pmids\": [\"21559462\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"The MRH domain of human OS-9 specifically binds N-glycans lacking the terminal mannose from the C branch (i.e., Man7 isomers with trimmed C-arm alpha1,2-mannose) as demonstrated by frontal affinity chromatography. This lectin activity is required for OS-9 to promote ERAD of the glycosylated substrate NHK in vivo.\",\n      \"method\": \"Frontal affinity chromatography with recombinant MRH domain, siRNA knockdown, overexpression of mannosidases, in vivo ERAD assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with recombinant domain, frontal affinity chromatography with defined glycan structures, validated in vivo; replicated in independent studies\",\n      \"pmids\": [\"19346256\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Crystal structure of the human OS-9 MRH domain complexed with alpha3,alpha6-mannopentaose reveals a flattened beta-barrel structure with P-type lectin fold and distinctive double tryptophan (WW) residues in the oligosaccharide-binding site that recognize Manalpha1,6Manalpha1,6Man residues on the processed C-arm of high-mannose glycans.\",\n      \"method\": \"X-ray crystallography, NMR spectroscopy, biochemical binding assays\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure with ligand, validated by NMR and biochemical assays, multiple orthogonal methods in one study\",\n      \"pmids\": [\"21172656\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Disposal of soluble ERAD-L substrates (ERAD-LS) is strictly dependent on HRD1, SEL1L, and the two interchangeable lectins OS-9 and XTP3-B. Tethering the same substrates to the membrane (ERAD-LM) renders these ERAD factors dispensable, demonstrating that OS-9/XTP3-B function is pathway-selective.\",\n      \"method\": \"RNAi knockdown, pulse-chase degradation assays, genetic epistasis using membrane-tethered vs. soluble substrates\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean RNAi epistasis with multiple substrates, rigorous controls, replicated by independent labs\",\n      \"pmids\": [\"20100910\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"OS-9.1 and OS-9.2 (alternative splice variants) are transcriptionally induced by the IRE1/XBP1 ER-stress pathway. OS-9 variants selectively bind folding-defective proteins but not folding-competent ones, thereby inhibiting secretion of misfolded conformers (retention function) and promoting their ERAD (disposal function). OS-9 also transiently associates with non-glycosylated misfolded proteins but this association is unproductive for ERAD.\",\n      \"method\": \"Co-immunoprecipitation, RNAi knockdown, pulse-chase assays, secretion assays, XBP1 reporter/induction\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, functional RNAi, secretion and degradation assays, single lab\",\n      \"pmids\": [\"18417469\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"OS-9 is upregulated by ER stress and is required for efficient ubiquitination of glycosylated ERAD substrates (demonstrated by RNAi). OS-9 also binds a misfolded non-glycosylated ERAD substrate but is not required for its ubiquitination or degradation, indicating that OS-9's functional requirement is N-glycan-dependent.\",\n      \"method\": \"RNAi knockdown, ubiquitination assays, co-immunoprecipitation, Western blot\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean RNAi functional assay, ubiquitination readout, single lab\",\n      \"pmids\": [\"19084021\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"OS-9 interacts with the cytosolic N-terminal tail of TRPV4 via co-immunoprecipitation. OS-9 preferentially binds TRPV4 monomers and immature ER-localized forms, impedes TRPV4 release from the ER, reduces TRPV4 at the plasma membrane, and attenuates polyubiquitination of TRPV4 subunits, suggesting a role as an auxiliary maturation factor protecting against premature ERAD.\",\n      \"method\": \"Co-immunoprecipitation, knockdown, cell-surface biotinylation, in vivo zebrafish expression, polyubiquitination assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, functional knockdown with surface expression readout, in vivo validation, single lab\",\n      \"pmids\": [\"17932042\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Using homozygous deletion cell lines, OS9 and XTP3B were found to redundantly promote glycoprotein degradation and stabilize the SEL1L/HRD1 dislocon complex. OS9 antagonizes XTP3B-mediated inhibition of non-glycosylated protein degradation. The relative expression ratio of OS9 and XTP3B determines the fidelity of glycoprotein triage in the ER.\",\n      \"method\": \"CRISPR/Cas9 homozygous deletions, quantitative ERAD assays, co-immunoprecipitation of SEL1L/HRD1 complex, genetic epistasis\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean genetic KO (CRISPR), multiple substrates, epistasis with double KO, complex stabilization assays\",\n      \"pmids\": [\"29706535\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"OS9 interacts specifically with the immature form of the renal Na-K-2Cl co-transporter NKCC2 (identified by yeast two-hybrid and confirmed by co-IP), co-localizes with NKCC2 in the ER, and promotes proteasomal degradation of immature NKCC2. Inactivation of the OS9 MRH domain does not affect this activity, but mutation of NKCC2 N-glycosylation sites abolishes OS9-induced degradation, indicating N-glycan-dependent but MRH-independent recognition.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, immunocytochemistry, pulse-chase and cycloheximide-chase assays, siRNA knockdown, MRH domain mutagenesis, glycosylation site mutagenesis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast two-hybrid + reciprocal Co-IP + functional degradation assays + domain mutagenesis, single lab\",\n      \"pmids\": [\"26721884\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"OS-9 facilitates turnover of hyperglycosylated (nonnative) GRP94 via a lysosomal-like, ERAD-independent mechanism. OS-9 binds preferentially to a subpopulation of GRP94 that is hyperglycosylated on cryptic N-linked acceptor sites, and these GRP94 forms have nonnative conformations and are less active. GRP94 is not required for OS-9 folding and does not collaborate with OS-9 in ERAD of misfolded substrates.\",\n      \"method\": \"Co-immunoprecipitation, pulse-chase assays, glycosylation analysis, lysosome inhibitor experiments, RNAi\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, pulse-chase, inhibitor studies, single lab, multiple orthogonal approaches\",\n      \"pmids\": [\"24899641\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"The C-terminal domain of mammalian OS-9 contains mammalian-specific inserts that are intrinsically disordered and specifically recognized by the middle and C-terminal domains of GRP94. Glycosylation of full-length GRP94 is essential for OS-9 binding, but this requirement is relieved by deletion of the GRP94 N-terminal domain, indicating an allosteric rather than direct glycan-mediated interaction.\",\n      \"method\": \"Domain mapping by co-immunoprecipitation, deletion mutagenesis, biochemical binding assays\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — deletion mapping + Co-IP + mutagenesis, single lab\",\n      \"pmids\": [\"25193139\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"OS-9 (but not XTP3-B) is required for ERAD of mutant neuroserpin in familial encephalopathy with neuroserpin inclusion bodies. OS-9 binds mutant neuroserpin via glycan recognition; removal of glycosylation sites increases neuroserpin protein load, while OS-9 overexpression decreases it. This was validated in both cell culture and a murine FENIB model.\",\n      \"method\": \"Co-immunoprecipitation, RNAi, overexpression, glycosylation site mutagenesis, mouse model analysis\",\n      \"journal\": \"Neurobiology of aging\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional Co-IP, mutagenesis, in vivo mouse model validation, single lab\",\n      \"pmids\": [\"24795221\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"OS-9 is required for ERAD of both glycosylated and non-glycosylated sonic hedgehog (SHH). OS-9 robustly interacts with a non-glycosylated SHH variant (N278A), indicating that the misfolded polypeptide backbone rather than a glycan signature can serve as the predominant recognition signal for OS-9 in certain substrates.\",\n      \"method\": \"RNAi knockdown, co-immunoprecipitation, pulse-chase ERAD assays, glycosylation mutant analysis\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus functional RNAi ERAD assays with multiple substrates, single lab\",\n      \"pmids\": [\"24910992\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"OS-9 interacts specifically with the cytoplasmic intracellular region of the membrane proteinase meprin beta. OS-9 is associated with ER membranes and exposed to the cytoplasm. OS-9 associates transiently with meprin beta coinciding with ER-to-Golgi transport of meprin beta. Only the non-spliced form of OS-9 binds meprin beta, implicating the alternatively spliced segment in binding specificity.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, subcellular fractionation, deletion mutagenesis, pulse-chase assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast two-hybrid + reciprocal Co-IP + fractionation + functional transport analysis, single lab\",\n      \"pmids\": [\"12093806\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"The OS-9 MRH domain binds N-glycans containing terminal alpha1,6-linked mannose in the Manalpha1,6(Manalpha1,3)Manalpha1,6(Manalpha1,3)Man structure (Ka ~10^4 M^-1), as determined by frontal affinity chromatography with 92 oligosaccharides. Trimming of either an alpha1,6-linked mannose from the C-arm or an alpha1,3-linked mannose from the B-arm abolishes OS-9 MRH binding. The alpha1-antitrypsin NHK variant (but not wild-type) interacts with OS-9 in cells in a sugar-dependent manner.\",\n      \"method\": \"Frontal affinity chromatography (92 glycan panel), tetramer binding assay, site-directed mutagenesis of MRH residues, co-immunoprecipitation\",\n      \"journal\": \"Glycobiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — systematic in vitro glycan-binding assay with recombinant domain + mutagenesis + in-cell co-IP validation, large glycan panel\",\n      \"pmids\": [\"19914915\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"OS9 physically interacts with DC-STAMP and both proteins co-localize in the ER. Upon TLR-induced DC maturation, DC-STAMP translocates from the ER to the Golgi while OS9 localization is unchanged. The DC-STAMP/OS9 interaction is involved in this ER-to-Golgi translocation process.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, confocal co-localization, TLR stimulation experiments in CHO cells and dendritic cells\",\n      \"journal\": \"Molecular immunology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — yeast two-hybrid + single Co-IP + localization, mechanistic link to translocation inferred rather than directly demonstrated, single lab\",\n      \"pmids\": [\"18952287\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"OS-9 interacts with N-copine (a two-C2-domain protein) via the second C2 domain of N-copine and the carboxy-terminal region of OS-9. This interaction is Ca2+-dependent as shown by in vitro binding assays and co-immunoprecipitation.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, in vitro Ca2+-dependent binding assay\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — yeast two-hybrid + single Co-IP + in vitro binding, single lab, no functional consequence established\",\n      \"pmids\": [\"10403379\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Meprin beta (but not meprin A) cleaves OS-9 in vitro and in vivo during ischemia/reperfusion-induced renal injury. Fragmentation of OS-9 by meprin beta was observed in WT mice subjected to IR but not in meprin αβKO mice. Transfection with meprin beta cDNA prevented accumulation of OS-9 under hypoxia mimic conditions.\",\n      \"method\": \"In vitro protease assay with purified proteins, meprin knockout mouse model, IR injury model, Western blot, cell transfection\",\n      \"journal\": \"International journal of nephrology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro cleavage assay + knockout mouse model validation, single lab\",\n      \"pmids\": [\"27478637\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"OS-9 interacts with the immature form of the calcium-sensing receptor (CaSR) in the ER (identified by yeast two-hybrid and co-IP). OS-9 binding to CaSR requires the MRH domain. Two distinct binding interactions were identified: one involving both C-terminal domains and another involving both N-terminal domains of OS-9 and CaSR. However, OS-9 knockdown or overexpression did not significantly affect CaSR cell surface expression or CaSR-mediated ERK1/2 phosphorylation (negative functional result).\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, confocal co-localization, MRH domain mutagenesis, siRNA knockdown, ERK phosphorylation assay\",\n      \"journal\": \"Journal of cellular physiology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — yeast two-hybrid + Co-IP + domain mutagenesis, but functional consequence of OS-9/CaSR interaction was negative, single lab\",\n      \"pmids\": [\"28419469\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Cryo-EM structure of the core mammalian ERAD complex comprising OS9, SEL1L, and HRD1 reveals a dimeric assembly where SEL1L and OS9 form a claw-like configuration in the ER lumen for substrate engagement while HRD1 dimerizes in the membrane for substrate translocation. Pathogenic SEL1L mutations at the SEL1L-OS9 interface (Gly585Asp) disrupt complex formation and impair ERAD activity, validated by mutagenesis and crosslinking assays.\",\n      \"method\": \"Cryo-EM structure determination, site-directed mutagenesis, crosslinking assays, ERAD functional assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cryo-EM structure validated by mutagenesis and crosslinking, functional ERAD assays, published in peer-reviewed journal\",\n      \"pmids\": [\"41593065\", \"40661598\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"OS9 is an ER-resident lectin that recognizes mannose-trimmed N-glycans (specifically Manalpha1,6Man structures on the processed C-arm of high-mannose glycans) via its MRH domain, and together with SEL1L forms a claw-like luminal complex that delivers misfolded glycoproteins to the HRD1 E3 ubiquitin ligase for ERAD; OS9 is required for ubiquitination of glycosylated substrates and functions redundantly with XTP3B for glycoprotein triage while antagonizing XTP3B-mediated inhibition of non-glycosylated substrate degradation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"OS9 is an ER-luminal lectin that triages misfolded glycoproteins for endoplasmic-reticulum-associated degradation (ERAD) by recognizing mannose-trimmed N-glycans and delivering substrates to the membrane ubiquitin ligase machinery [#0, #3]. Its mannose-6-phosphate-receptor-homology (MRH) domain binds high-mannose glycans bearing terminal alpha1,6-linked mannose on the trimmed C-arm (Man7 isomers), and this lectin activity is required for OS9 to promote degradation of glycosylated substrates such as the alpha1-antitrypsin NHK variant [#3, #16]; crystallography defined a P-type lectin fold with a distinctive double-tryptophan site recognizing Manalpha1,6Manalpha1,6Man residues [#4]. OS9 bridges captured substrates to the HRD1 E3 ligase through the SEL1L adaptor, with the MRH domain required for SEL1L binding [#0], and cryo-EM of the OS9-SEL1L-HRD1 core complex shows SEL1L and OS9 forming a claw-like luminal substrate-engagement module above a membrane HRD1 dimer that translocates substrate [#21]. Degradation of soluble ERAD-L substrates strictly requires HRD1, SEL1L, and the interchangeable lectins OS9 and XTP3B, whereas membrane-tethered substrates bypass this requirement, defining OS9 as a pathway-selective luminal recognition factor [#5]; OS9 and XTP3B act redundantly to promote glycoprotein degradation and stabilize the SEL1L/HRD1 dislocon, and their expression ratio tunes triage fidelity, with OS9 antagonizing XTP3B-mediated inhibition of non-glycosylated substrate degradation [#9]. OS9 is induced by ER stress through the IRE1/XBP1 pathway and selectively retains and disposes of folding-defective conformers [#6], and is required for ubiquitination of glycosylated ERAD substrates [#7]. Beyond canonical glycan-dependent ERAD, OS9 also recognizes certain misfolded substrates through the polypeptide backbone in an MRH-independent manner, as shown for NKCC2 and sonic hedgehog [#10, #14]. OS9 is required for ERAD of mutant neuroserpin in a cell and mouse model of familial encephalopathy with neuroserpin inclusion bodies (FENIB) [#13].\",\n  \"teleology\": [\n    {\n      \"year\": 2002,\n      \"claim\": \"Established OS-9 as an ER-membrane-associated protein that transiently engages a client (meprin beta) during early secretory transport, providing the first localization and interaction context.\",\n      \"evidence\": \"Yeast two-hybrid, co-IP, subcellular fractionation, and pulse-chase in mammalian cells\",\n      \"pmids\": [\"12093806\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Topology assigned as cytoplasm-exposed, later revised to luminal\", \"No link to ERAD machinery yet\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Proposed a cytoplasmic role linking OS-9 to HIF-1alpha hydroxylation and degradation, raising the question of whether OS-9 acts outside the ER lumen.\",\n      \"evidence\": \"Co-IP, RNAi, reporter and HIF stability assays\",\n      \"pmids\": [\"15721254\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Topologically incompatible with later luminal localization data\", \"Directly contradicted by subsequent study\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Defined OS-9 as the core ERAD lectin-adaptor by showing it binds misfolded substrates and bridges them, via SEL1L, to the HRD1 E3 ligase, with the MRH domain required for SEL1L (but not substrate) binding.\",\n      \"evidence\": \"Reciprocal Co-IP, RNAi functional ERAD assays, MRH domain mutagenesis\",\n      \"pmids\": [\"18264092\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Glycan ligand of MRH domain not yet defined\", \"Structural basis of complex assembly unknown\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Connected OS-9 to the unfolded protein response and partitioned its function into retention of misfolded conformers and promotion of their disposal, while flagging an unproductive association with non-glycosylated clients.\",\n      \"evidence\": \"Co-IP, RNAi, pulse-chase, secretion assays, XBP1 induction\",\n      \"pmids\": [\"18417469\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanistic basis for productive vs unproductive binding unresolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Showed OS-9 is required for ubiquitination specifically of glycosylated ERAD substrates, localizing its functional requirement to the N-glycan signal.\",\n      \"evidence\": \"RNAi, ubiquitination assays, Co-IP\",\n      \"pmids\": [\"19084021\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not define which glycan species are recognized\", \"Single lab\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Resolved the molecular recognition signal by demonstrating the MRH domain binds trimmed-C-arm Man7 glycans (terminal alpha1,6-mannose), and that this lectin activity is required for ERAD of glycosylated substrates in vivo.\",\n      \"evidence\": \"Frontal affinity chromatography with defined glycan panels, MRH mutagenesis, in-cell Co-IP, in vivo ERAD assays\",\n      \"pmids\": [\"19346256\", \"19914915\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Atomic basis of glycan selectivity not yet structurally defined\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Defined the structural basis of glycan recognition, revealing a P-type lectin fold with a double-tryptophan binding site engaging Manalpha1,6Manalpha1,6Man on the trimmed C-arm.\",\n      \"evidence\": \"X-ray crystallography with mannopentaose, NMR, biochemical binding\",\n      \"pmids\": [\"21172656\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not show how MRH-bound substrate is handed to SEL1L/HRD1\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Established pathway selectivity by showing OS-9/XTP3-B (with HRD1 and SEL1L) are strictly required only for soluble ERAD-L substrates and dispensable when substrates are membrane-tethered.\",\n      \"evidence\": \"RNAi epistasis with soluble vs membrane-tethered substrates, pulse-chase\",\n      \"pmids\": [\"20100910\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional division between OS-9 and XTP3-B not yet defined\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Refuted the cytoplasmic HIF model by establishing OS-9 as a luminal ER protein incapable of in vivo interaction with cytoplasmic PHD2, consolidating its role within the ER lumen.\",\n      \"evidence\": \"Subcellular fractionation, glycosylation assays, FRET, lentiviral knockdown\",\n      \"pmids\": [\"21559462\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cannot exclude indirect effects on HIF in some contexts\", \"Single lab\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Broadened OS-9's substrate repertoire and showed glycan-independent recognition modes, including disease-mutant neuroserpin (FENIB) ERAD and backbone-based recognition of sonic hedgehog and a GRP94-specific lysosomal turnover route.\",\n      \"evidence\": \"Co-IP, RNAi, glycosylation-site mutagenesis, pulse-chase, mouse FENIB model, lysosome inhibitor studies\",\n      \"pmids\": [\"24795221\", \"24910992\", \"24899641\", \"25193139\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How OS-9 discriminates glycan vs polypeptide signals unresolved\", \"GRP94 lysosomal route mechanism unclear\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Demonstrated MRH-independent, N-glycan-dependent recognition of immature NKCC2, showing OS-9 can target substrates through glycan signals not read by its MRH domain.\",\n      \"evidence\": \"Yeast two-hybrid, Co-IP, immunocytochemistry, chase assays, MRH and glycosylation-site mutagenesis\",\n      \"pmids\": [\"26721884\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"The MRH-independent recognition determinant not identified\", \"Single lab\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Defined the functional relationship between the two lectins, showing OS9 and XTP3B redundantly promote glycoprotein degradation, stabilize the SEL1L/HRD1 dislocon, and that their expression ratio tunes triage fidelity with OS9 antagonizing XTP3B repression of non-glycosylated substrate disposal.\",\n      \"evidence\": \"CRISPR homozygous deletions, quantitative ERAD assays, SEL1L/HRD1 complex Co-IP, double-KO epistasis\",\n      \"pmids\": [\"29706535\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of dislocon stabilization not resolved here\", \"Physiological substrates governed by the ratio not enumerated\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Provided the architectural basis of ERAD by resolving the OS9-SEL1L-HRD1 core complex, showing a luminal claw-like SEL1L-OS9 substrate-engagement module over a membrane HRD1 dimer, and validating a pathogenic SEL1L-OS9 interface mutation that impairs ERAD.\",\n      \"evidence\": \"Cryo-EM, site-directed mutagenesis, crosslinking, ERAD functional assays\",\n      \"pmids\": [\"41593065\", \"40661598\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Dynamics of substrate handoff from MRH to HRD1 not captured\", \"How non-glycosylated substrates are accommodated structurally unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How OS9 mechanistically reconciles glycan-dependent (MRH-mediated) and glycan-independent/polypeptide-based substrate recognition, and how the OS9:XTP3B ratio is physiologically regulated, remain open.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model of dual recognition modes\", \"Regulation of lectin expression ratio in tissues unknown\", \"Structural account of backbone-based recognition lacking\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [3, 4, 16]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 21]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [0, 2, 6, 10]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 5, 9]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [6]}\n    ],\n    \"complexes\": [\n      \"HRD1-SEL1L ERAD dislocon complex\"\n    ],\n    \"partners\": [\n      \"SEL1L\",\n      \"HRD1\",\n      \"XTP3B\",\n      \"GRP94\",\n      \"TRPV4\",\n      \"NKCC2\",\n      \"CaSR\",\n      \"meprin beta\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}