{"gene":"DERL1","run_date":"2026-06-09T23:54:42","timeline":{"discoveries":[{"year":1996,"finding":"Der1 (yeast ortholog of DERL1) is a novel hydrophobic protein localized to the ER membrane that is specifically required for degradation of misfolded lumenal secretory proteins; deletion of DER1 abolishes ER-associated degradation (ERAD) of substrate proteins, which are retained in the ER by the same mechanism that retains lumenal ER residents, suggesting Der1 acts in a process that directly removes proteins from the ER folding environment.","method":"Yeast genetic screen, complementation cloning, deletion mutant analysis, substrate stability assays, ER retention assays","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean genetic deletion with defined substrate phenotype, complementation cloning, replicated across multiple substrates and complementation groups in foundational study","pmids":["8631297"],"is_preprint":false},{"year":2004,"finding":"Der1p (yeast ortholog of DERL1) contains four transmembrane domains with its N- and C-termini protruding into the cytoplasm; both termini contribute to Der1p function. A C. elegans ortholog (R151.6) can complement der1-defective phenotypes in yeast. A yeast paralog Dfm1p does not appear to be involved in ERAD.","method":"Topology mapping, complementation assays with C. elegans ortholog, deletion/mutant analysis","journal":"FEMS yeast research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — topology mapped by experimental methods, functional complementation with ortholog, single lab","pmids":["15093775"],"is_preprint":false},{"year":2013,"finding":"Der1 (yeast ortholog of DERL1) oligomerizes in an Usa1-dependent manner and its transmembrane domain mutations block passage of soluble ERAD substrates across the ER membrane. Site-specific photocrosslinking showed that ER-luminal exposed parts of Der1 are in spatial proximity to substrate receptor Hrd3, while membrane-embedded domains reside adjacent to ubiquitin ligase Hrd1; both regions form crosslinks to client proteins. Der1 initiates export of aberrant polypeptides from the ER lumen by threading them into the ER membrane and routing them to Hrd1 for ubiquitylation.","method":"Site-specific photocrosslinking, transmembrane domain mutagenesis, protein oligomerization assays, substrate retrotranslocation assays","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple orthogonal methods (photocrosslinking, mutagenesis, oligomerization assays), rigorous mechanistic dissection of retrotranslocon function in single study","pmids":["24292014"],"is_preprint":false},{"year":2013,"finding":"N-terminal acetylation of Der1 (yeast ortholog of DERL1) by the NatB N-terminal acetyltransferase is essential for Hrd1 ubiquitin-ligase activity toward ER-luminal substrates. Preventing Der1 acetylation stimulates its own proteolysis via the Hrd1 pathway, partially accounting for the ERAD defect in NatB mutants. Der1 is the only ERAD factor requiring N-terminal acetylation, as demonstrated by retargeting Der1 to an alternative acetyltransferase.","method":"NatB deletion mutant analysis, substrate stability assays, acetyltransferase retargeting experiment, epistasis analysis","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 1 / Moderate — multiple orthogonal methods (deletion mutants, retargeting acetyltransferase, epistasis), rigorous functional dissection in single study","pmids":["23363603"],"is_preprint":false},{"year":2022,"finding":"DERL1 (derlin-1) interacts with VCP (valosin-containing protein) and TMEM63A in the ER membrane; TMEM63A stabilizes DERL1 by preventing TOLLIP-mediated autophagic degradation. Knockdown of DERL1 partially abolishes the oncogenic effects of TMEM63A on triple-negative breast cancer progression both in vitro and in vivo.","method":"Co-immunoprecipitation, siRNA knockdown, xenograft tumor assays, autophagic degradation assays","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP and functional knockdown with in vivo validation, single lab, cancer-cell context","pmids":["35920704"],"is_preprint":false},{"year":2010,"finding":"Bovine DERL1 co-immunoprecipitates with class I MHC in luteal tissue but not with VIMP or p97 ATPase, suggesting DERL1 regulates the integrity of MHC I molecules in the ER membrane of corpus luteum cells.","method":"Co-immunoprecipitation from bovine luteal tissue, Western blot, Northern blot","journal":"Reproductive biology and endocrinology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single co-IP from tissue, no functional follow-up, single lab","pmids":["20682045"],"is_preprint":false},{"year":2024,"finding":"DERL1 directly interacts with the E3 ubiquitin ligase TRAF6, and this interaction promotes K63 ubiquitination of AKT, leading to p-AKT activation in breast cancer cells. Mutagenesis of DERL1 residues Tyr77 (and combined Tyr77Ala/Gln81Ala/Arg85Ala/Val158Ala) disrupts the DERL1-TRAF6 interaction and significantly reduces K63-ubiquitinated p-AKT production.","method":"Co-immunoprecipitation, immunoprecipitation-mass spectrometry, site-directed mutagenesis, Zdock prediction, dual-luciferase assay","journal":"Cancer cell international","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP with MS, mutagenesis, single lab, multiple orthogonal methods","pmids":["38858669"],"is_preprint":false},{"year":2025,"finding":"Deep mutational scanning of Hrd1 identified single residue variants broadly deficient in degradation of all integral membrane (ERAD-M) substrates; competition for the retrotranslocon cavity was revealed between Der1-mediated lumenal substrate degradation and membrane substrate degradation paths, with Hrd1 complex assembly serving as the primary determinant for tuning ERAD function.","method":"Deep mutational scanning of Hrd1, in vivo ERAD substrate degradation assays, genetic epistasis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — deep mutational scanning with functional assays, single lab, mechanistic competition between Der1 and ERAD-M substrates established","pmids":["41329737"],"is_preprint":false}],"current_model":"DERL1/Der1 is an ER-resident integral membrane protein with four transmembrane domains that forms oligomers (via Usa1 in yeast) and functions as a retrotranslocon component of the Hrd1 ERAD ubiquitin ligase complex: its luminal-exposed regions contact substrate receptor Hrd3 and misfolded lumenal substrates, while its transmembrane domains thread aberrant polypeptides into the ER membrane and route them to Hrd1 for K48-linked polyubiquitylation and proteasomal degradation; N-terminal acetylation by NatB is required for Der1 stability and Hrd1 activity toward lumenal substrates; in mammalian cells, DERL1 additionally interacts with VCP/p97 and TRAF6, the latter promoting K63 ubiquitination of AKT to activate pro-survival signaling."},"narrative":{"mechanistic_narrative":"DERL1 (yeast Der1) is an ER-resident multipass membrane protein that functions as the retrotranslocation channel of the Hrd1 ER-associated degradation (ERAD) machinery, selectively removing misfolded lumenal secretory proteins from the ER for proteasomal destruction [PMID:8631297, PMID:24292014]. It contains four transmembrane domains with both termini exposed to the cytoplasm [PMID:15093775], and oligomerizes (via Usa1 in yeast) to build the functional retrotranslocon [PMID:24292014]. Within the Hrd1 complex, the ER-luminal regions of Der1 lie adjacent to the substrate receptor Hrd3 and contact misfolded clients, while its transmembrane domains, positioned next to the ubiquitin ligase Hrd1, thread aberrant polypeptides through the membrane and deliver them to Hrd1 for ubiquitylation [PMID:24292014]; the same retrotranslocon cavity is shared and competed for between this Der1-dependent lumenal route and the integral-membrane (ERAD-M) degradation path, with Hrd1 complex assembly tuning the balance [PMID:41329737]. N-terminal acetylation of Der1 by NatB stabilizes the protein and is required for Hrd1 ligase activity toward lumenal substrates, since unacetylated Der1 is itself degraded by the Hrd1 pathway [PMID:23363603]. In mammalian cells DERL1 additionally engages the AAA-ATPase VCP/p97 [PMID:35920704] and, in breast cancer, binds the E3 ligase TRAF6 to promote K63-linked ubiquitination and activation of AKT, contributing to oncogenic signaling [PMID:38858669].","teleology":[{"year":1996,"claim":"Established that an ER membrane protein is specifically required for clearing misfolded lumenal proteins, defining the first dedicated ERAD component for lumenal substrates.","evidence":"Yeast genetic screen, complementation cloning, and DER1 deletion with substrate stability and ER-retention assays","pmids":["8631297"],"confidence":"High","gaps":["Molecular mechanism by which Der1 acts on substrates not defined","Membrane topology and partners unknown at this stage"]},{"year":2004,"claim":"Determined the membrane architecture of Der1, showing four transmembrane domains with cytoplasmic termini both contributing to function, and demonstrated functional conservation across species.","evidence":"Topology mapping, deletion/mutant analysis, and complementation with the C. elegans ortholog R151.6 in yeast","pmids":["15093775"],"confidence":"Medium","gaps":["Does not define how the termini contribute mechanistically","Relationship to the Hrd1 ligase complex not yet established","Role of paralog Dfm1 left unresolved beyond exclusion from ERAD"]},{"year":2013,"claim":"Resolved the molecular function of Der1 as the retrotranslocon, placing it spatially between the substrate receptor Hrd3 and the ligase Hrd1 and showing it threads lumenal substrates into the membrane.","evidence":"Site-specific photocrosslinking, transmembrane-domain mutagenesis, oligomerization and retrotranslocation assays in yeast","pmids":["24292014"],"confidence":"High","gaps":["Atomic structure of the channel and the threading conduit not resolved","Stoichiometry of the Usa1-dependent oligomer undefined","Mechanism coupling threading to Hrd1 ubiquitylation not detailed"]},{"year":2013,"claim":"Identified a post-translational requirement for Der1 stability and Hrd1 activity, showing NatB N-terminal acetylation protects Der1 from self-directed degradation.","evidence":"NatB deletion analysis, substrate stability assays, acetyltransferase retargeting, and epistasis in yeast","pmids":["23363603"],"confidence":"High","gaps":["How acetylation structurally stabilizes Der1 not defined","Whether mammalian DERL1 is similarly regulated untested in this corpus"]},{"year":2010,"claim":"Provided early tissue-level evidence for a mammalian DERL1 interaction with a client class (MHC I), but without the canonical p97 partner in that context.","evidence":"Co-immunoprecipitation from bovine luteal tissue with Western and Northern blot","pmids":["20682045"],"confidence":"Low","gaps":["Single Co-IP from tissue with no functional follow-up","Absence of VIMP/p97 association unexplained","Direct role in MHC I degradation not demonstrated"]},{"year":2022,"claim":"Connected mammalian DERL1 to membrane partners regulating its own stability, linking it to tumor progression.","evidence":"Co-IP, siRNA knockdown, autophagic degradation assays, and xenograft tumor assays in triple-negative breast cancer","pmids":["35920704"],"confidence":"Medium","gaps":["Mechanism by which TMEM63A blocks TOLLIP-mediated autophagy of DERL1 not detailed","Whether ERAD activity mediates the oncogenic effect unclear","Single-lab, cancer-specific context"]},{"year":2024,"claim":"Revealed a non-canonical signaling role for DERL1, binding TRAF6 to drive K63 ubiquitination and activation of AKT in cancer cells.","evidence":"Reciprocal Co-IP, IP-mass spectrometry, site-directed mutagenesis (Tyr77 and combinatorial mutants), and dual-luciferase assays in breast cancer cells","pmids":["38858669"],"confidence":"Medium","gaps":["Relationship between this signaling role and ERAD function unclear","In vivo relevance beyond cell-based assays not established","Single-lab finding"]},{"year":2025,"claim":"Defined a competition for the shared retrotranslocon cavity between Der1-dependent lumenal and integral-membrane substrate degradation, identifying complex assembly as the tuning determinant.","evidence":"Deep mutational scanning of Hrd1 with in vivo ERAD substrate degradation assays and genetic epistasis","pmids":["41329737"],"confidence":"Medium","gaps":["Structural basis of the competing substrate paths not resolved","How assembly state is regulated in cells unknown"]},{"year":null,"claim":"How the yeast retrotranslocon mechanism and the mammalian non-ERAD signaling roles of DERL1 are reconciled, and whether they operate in the same or distinct cellular contexts, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of the human DERL1-containing retrotranslocon","ERAD substrate spectrum of mammalian DERL1 not mapped in this corpus","Mechanistic link between retrotranslocation and AKT/TRAF6 signaling undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[2,6]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[2]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[0,1,2,4]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,2,3]}],"complexes":["Hrd1 ERAD complex"],"partners":["HRD1","HRD3","USA1","VCP","TMEM63A","TRAF6"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9BUN8","full_name":"Derlin-1","aliases":["Degradation in endoplasmic reticulum protein 1","DERtrin-1","Der1-like protein 1"],"length_aa":251,"mass_kda":28.8,"function":"Functional component of endoplasmic reticulum-associated degradation (ERAD) for misfolded lumenal proteins (PubMed:15215856, PubMed:33658201). Forms homotetramers which encircle a large channel traversing the endoplasmic reticulum (ER) membrane (PubMed:33658201). This allows the retrotranslocation of misfolded proteins from the ER into the cytosol where they are ubiquitinated and degraded by the proteasome (PubMed:33658201). The channel has a lateral gate within the membrane which provides direct access to membrane proteins with no need to reenter the ER lumen first (PubMed:33658201). May mediate the interaction between VCP and the misfolded protein (PubMed:15215856). Also involved in endoplasmic reticulum stress-induced pre-emptive quality control, a mechanism that selectively attenuates the translocation of newly synthesized proteins into the endoplasmic reticulum and reroutes them to the cytosol for proteasomal degradation (PubMed:26565908). By controlling the steady-state expression of the IGF1R receptor, indirectly regulates the insulin-like growth factor receptor signaling pathway (PubMed:26692333) (Microbial infection) In case of infection by cytomegaloviruses, it plays a central role in the export from the ER and subsequent degradation of MHC class I heavy chains via its interaction with US11 viral protein, which recognizes and associates with MHC class I heavy chains. Also participates in the degradation process of misfolded cytomegalovirus US2 protein","subcellular_location":"Endoplasmic reticulum membrane","url":"https://www.uniprot.org/uniprotkb/Q9BUN8/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/DERL1","classification":"Not Classified","n_dependent_lines":89,"n_total_lines":1208,"dependency_fraction":0.07367549668874172},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CCDC47","stoichiometry":4.0},{"gene":"NCLN","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/DERL1","total_profiled":1310},"omim":[{"mim_id":"620965","title":"SMALL VCP-INTERACTING PROTEIN; SVIP","url":"https://www.omim.org/entry/620965"},{"mim_id":"620529","title":"RING FINGER PROTEIN 121; RNF121","url":"https://www.omim.org/entry/620529"},{"mim_id":"616175","title":"UBIQUITIN-CONJUGATING ENZYME E2 J1; UBE2J1","url":"https://www.omim.org/entry/616175"},{"mim_id":"615975","title":"TRANSMEMBRANE PROTEIN 129; TMEM129","url":"https://www.omim.org/entry/615975"},{"mim_id":"610305","title":"DER1-LIKE DOMAIN FAMILY, MEMBER 3; DERL3","url":"https://www.omim.org/entry/610305"}],"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/DERL1"},"hgnc":{"alias_symbol":["MGC3067","PRO2577","FLJ13784","DER1","DER-1","derlin-1"],"prev_symbol":[]},"alphafold":{"accession":"Q9BUN8","domains":[{"cath_id":"1.20.1540.10","chopping":"2-208","consensus_level":"medium","plddt":85.8237,"start":2,"end":208}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9BUN8","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9BUN8-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9BUN8-F1-predicted_aligned_error_v6.png","plddt_mean":80.0},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=DERL1","jax_strain_url":"https://www.jax.org/strain/search?query=DERL1"},"sequence":{"accession":"Q9BUN8","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9BUN8.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9BUN8/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9BUN8"}},"corpus_meta":[{"pmid":"8631297","id":"PMC_8631297","title":"Der1, 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and evolution","url":"https://pubmed.ncbi.nlm.nih.gov/17244602","citation_count":115,"is_preprint":false},{"pmid":"15093775","id":"PMC_15093775","title":"Der1p, a protein required for degradation of malfolded soluble proteins of the endoplasmic reticulum: topology and Der1-like proteins.","date":"2004","source":"FEMS yeast research","url":"https://pubmed.ncbi.nlm.nih.gov/15093775","citation_count":66,"is_preprint":false},{"pmid":"7688559","id":"PMC_7688559","title":"Two-color FISH characterization of i(1q) and der(1;16) in human breast cancer cells.","date":"1993","source":"Genes, chromosomes & cancer","url":"https://pubmed.ncbi.nlm.nih.gov/7688559","citation_count":59,"is_preprint":false},{"pmid":"14579147","id":"PMC_14579147","title":"Translocation breakpoint mapping and sequence analysis in three monosomy 1p36 subjects with der(1)t(1;1)(p36;q44) suggest mechanisms for telomere capture in stabilizing de novo terminal rearrangements.","date":"2003","source":"Human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/14579147","citation_count":49,"is_preprint":false},{"pmid":"35920704","id":"PMC_35920704","title":"TOLLIP-mediated autophagic degradation pathway links the VCP-TMEM63A-DERL1 signaling axis to triple-negative breast cancer progression.","date":"2022","source":"Autophagy","url":"https://pubmed.ncbi.nlm.nih.gov/35920704","citation_count":47,"is_preprint":false},{"pmid":"20375427","id":"PMC_20375427","title":"The combined expression pattern of BMP2, LTBP4, and DERL1 discriminates malignant from benign canine mammary tumors.","date":"2010","source":"Veterinary pathology","url":"https://pubmed.ncbi.nlm.nih.gov/20375427","citation_count":38,"is_preprint":false},{"pmid":"23363603","id":"PMC_23363603","title":"N-terminal acetylation of the yeast Derlin Der1 is essential for Hrd1 ubiquitin-ligase activity toward luminal ER substrates.","date":"2013","source":"Molecular biology of the 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Part A","url":"https://pubmed.ncbi.nlm.nih.gov/18958851","citation_count":3,"is_preprint":false},{"pmid":"20682045","id":"PMC_20682045","title":"Molecular characterization and expression of DERL1 in bovine ovarian follicles and corpora lutea.","date":"2010","source":"Reproductive biology and endocrinology : RB&E","url":"https://pubmed.ncbi.nlm.nih.gov/20682045","citation_count":2,"is_preprint":false},{"pmid":"36819182","id":"PMC_36819182","title":"Outcomes after allogeneic hematopoietic stem cell transplantation in acute myeloid leukemia patients with der(1;7)(q10;p10).","date":"2022","source":"EJHaem","url":"https://pubmed.ncbi.nlm.nih.gov/36819182","citation_count":2,"is_preprint":false},{"pmid":"16080298","id":"PMC_16080298","title":"A dysmorphic newborn with 45,X,der(1)inv(1)(p13;qter)t(Y;1)(pter-->q11;p13),-Y de novo karyotype.","date":"2005","source":"Genetic counseling (Geneva, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/16080298","citation_count":2,"is_preprint":false},{"pmid":"17656259","id":"PMC_17656259","title":"Molecular cytogenetic analysis of complex karyotypes with derivative chromosome der(1)t(1;5) found in two patients with myeloid leukemia.","date":"2007","source":"Cancer genetics and cytogenetics","url":"https://pubmed.ncbi.nlm.nih.gov/17656259","citation_count":2,"is_preprint":false},{"pmid":"38164059","id":"PMC_38164059","title":"The der(1;7)(q10;p10) defining a distinct profile from -7/del(7q) in myelodysplastic syndromes: A systematic review and meta-analysis.","date":"2024","source":"Cancer medicine","url":"https://pubmed.ncbi.nlm.nih.gov/38164059","citation_count":1,"is_preprint":false},{"pmid":"37544721","id":"PMC_37544721","title":"[Myelodysplastic syndrome with der (1;7)(q10;p10) complicated with eosinophilia and organizing pneumonia].","date":"2023","source":"[Rinsho ketsueki] The Japanese journal of clinical hematology","url":"https://pubmed.ncbi.nlm.nih.gov/37544721","citation_count":1,"is_preprint":false},{"pmid":"41329737","id":"PMC_41329737","title":"Competition between Der1 and ERAD-M substrates controls Hrd1 complex function.","date":"2025","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/41329737","citation_count":0,"is_preprint":false},{"pmid":"38220152","id":"PMC_38220152","title":"[Characteristics of myelodysplastic syndromes with der(1;7)(q10;p10)].","date":"2023","source":"[Rinsho ketsueki] The Japanese journal of clinical hematology","url":"https://pubmed.ncbi.nlm.nih.gov/38220152","citation_count":0,"is_preprint":false},{"pmid":"39482002","id":"PMC_39482002","title":"First-trimester application of expanded non-invasive prenatal testing in the genetic investigation of fetal 1p36 deletion syndrome associated with a familial unbalanced reciprocal translocation of 46,XX,der(1)t(1;2) (p36.2;q37.3)dmat.","date":"2024","source":"Taiwanese journal of obstetrics & gynecology","url":"https://pubmed.ncbi.nlm.nih.gov/39482002","citation_count":0,"is_preprint":false},{"pmid":"31245275","id":"PMC_31245275","title":"A rare case of acute myeloid leukemia with der(1)t(1;19)(p13;p13.1).","date":"2019","source":"Leukemia research reports","url":"https://pubmed.ncbi.nlm.nih.gov/31245275","citation_count":0,"is_preprint":false},{"pmid":"27664585","id":"PMC_27664585","title":"Characterization of a novel acquired der(1)del(1)(p13p31)t(1;15)(q42;q15) in a high risk t(12;21)-positive acute lymphoblastic leukemia.","date":"2016","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/27664585","citation_count":0,"is_preprint":false},{"pmid":"30498621","id":"PMC_30498621","title":"An isolated der(1;21)(q10;q10) translocation in a patient with myelodysplastic syndrome: a case report.","date":"2018","source":"American journal of blood research","url":"https://pubmed.ncbi.nlm.nih.gov/30498621","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":22002,"output_tokens":2250,"usd":0.049878,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":9280,"output_tokens":2892,"usd":0.05935,"stage2_stop_reason":"end_turn"},"total_usd":0.109228,"stage1_batch_id":"msgbatch_01AsR7g8dGTEiEw9U83bJeWn","stage2_batch_id":"msgbatch_01YV5ZyxtFNUZEjxRcpd9jzb","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1996,\n      \"finding\": \"Der1 (yeast ortholog of DERL1) is a novel hydrophobic protein localized to the ER membrane that is specifically required for degradation of misfolded lumenal secretory proteins; deletion of DER1 abolishes ER-associated degradation (ERAD) of substrate proteins, which are retained in the ER by the same mechanism that retains lumenal ER residents, suggesting Der1 acts in a process that directly removes proteins from the ER folding environment.\",\n      \"method\": \"Yeast genetic screen, complementation cloning, deletion mutant analysis, substrate stability assays, ER retention assays\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean genetic deletion with defined substrate phenotype, complementation cloning, replicated across multiple substrates and complementation groups in foundational study\",\n      \"pmids\": [\"8631297\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Der1p (yeast ortholog of DERL1) contains four transmembrane domains with its N- and C-termini protruding into the cytoplasm; both termini contribute to Der1p function. A C. elegans ortholog (R151.6) can complement der1-defective phenotypes in yeast. A yeast paralog Dfm1p does not appear to be involved in ERAD.\",\n      \"method\": \"Topology mapping, complementation assays with C. elegans ortholog, deletion/mutant analysis\",\n      \"journal\": \"FEMS yeast research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — topology mapped by experimental methods, functional complementation with ortholog, single lab\",\n      \"pmids\": [\"15093775\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Der1 (yeast ortholog of DERL1) oligomerizes in an Usa1-dependent manner and its transmembrane domain mutations block passage of soluble ERAD substrates across the ER membrane. Site-specific photocrosslinking showed that ER-luminal exposed parts of Der1 are in spatial proximity to substrate receptor Hrd3, while membrane-embedded domains reside adjacent to ubiquitin ligase Hrd1; both regions form crosslinks to client proteins. Der1 initiates export of aberrant polypeptides from the ER lumen by threading them into the ER membrane and routing them to Hrd1 for ubiquitylation.\",\n      \"method\": \"Site-specific photocrosslinking, transmembrane domain mutagenesis, protein oligomerization assays, substrate retrotranslocation assays\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple orthogonal methods (photocrosslinking, mutagenesis, oligomerization assays), rigorous mechanistic dissection of retrotranslocon function in single study\",\n      \"pmids\": [\"24292014\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"N-terminal acetylation of Der1 (yeast ortholog of DERL1) by the NatB N-terminal acetyltransferase is essential for Hrd1 ubiquitin-ligase activity toward ER-luminal substrates. Preventing Der1 acetylation stimulates its own proteolysis via the Hrd1 pathway, partially accounting for the ERAD defect in NatB mutants. Der1 is the only ERAD factor requiring N-terminal acetylation, as demonstrated by retargeting Der1 to an alternative acetyltransferase.\",\n      \"method\": \"NatB deletion mutant analysis, substrate stability assays, acetyltransferase retargeting experiment, epistasis analysis\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — multiple orthogonal methods (deletion mutants, retargeting acetyltransferase, epistasis), rigorous functional dissection in single study\",\n      \"pmids\": [\"23363603\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"DERL1 (derlin-1) interacts with VCP (valosin-containing protein) and TMEM63A in the ER membrane; TMEM63A stabilizes DERL1 by preventing TOLLIP-mediated autophagic degradation. Knockdown of DERL1 partially abolishes the oncogenic effects of TMEM63A on triple-negative breast cancer progression both in vitro and in vivo.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, xenograft tumor assays, autophagic degradation assays\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP and functional knockdown with in vivo validation, single lab, cancer-cell context\",\n      \"pmids\": [\"35920704\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Bovine DERL1 co-immunoprecipitates with class I MHC in luteal tissue but not with VIMP or p97 ATPase, suggesting DERL1 regulates the integrity of MHC I molecules in the ER membrane of corpus luteum cells.\",\n      \"method\": \"Co-immunoprecipitation from bovine luteal tissue, Western blot, Northern blot\",\n      \"journal\": \"Reproductive biology and endocrinology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single co-IP from tissue, no functional follow-up, single lab\",\n      \"pmids\": [\"20682045\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"DERL1 directly interacts with the E3 ubiquitin ligase TRAF6, and this interaction promotes K63 ubiquitination of AKT, leading to p-AKT activation in breast cancer cells. Mutagenesis of DERL1 residues Tyr77 (and combined Tyr77Ala/Gln81Ala/Arg85Ala/Val158Ala) disrupts the DERL1-TRAF6 interaction and significantly reduces K63-ubiquitinated p-AKT production.\",\n      \"method\": \"Co-immunoprecipitation, immunoprecipitation-mass spectrometry, site-directed mutagenesis, Zdock prediction, dual-luciferase assay\",\n      \"journal\": \"Cancer cell international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP with MS, mutagenesis, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"38858669\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Deep mutational scanning of Hrd1 identified single residue variants broadly deficient in degradation of all integral membrane (ERAD-M) substrates; competition for the retrotranslocon cavity was revealed between Der1-mediated lumenal substrate degradation and membrane substrate degradation paths, with Hrd1 complex assembly serving as the primary determinant for tuning ERAD function.\",\n      \"method\": \"Deep mutational scanning of Hrd1, in vivo ERAD substrate degradation assays, genetic epistasis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — deep mutational scanning with functional assays, single lab, mechanistic competition between Der1 and ERAD-M substrates established\",\n      \"pmids\": [\"41329737\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"DERL1/Der1 is an ER-resident integral membrane protein with four transmembrane domains that forms oligomers (via Usa1 in yeast) and functions as a retrotranslocon component of the Hrd1 ERAD ubiquitin ligase complex: its luminal-exposed regions contact substrate receptor Hrd3 and misfolded lumenal substrates, while its transmembrane domains thread aberrant polypeptides into the ER membrane and route them to Hrd1 for K48-linked polyubiquitylation and proteasomal degradation; N-terminal acetylation by NatB is required for Der1 stability and Hrd1 activity toward lumenal substrates; in mammalian cells, DERL1 additionally interacts with VCP/p97 and TRAF6, the latter promoting K63 ubiquitination of AKT to activate pro-survival signaling.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"DERL1 (yeast Der1) is an ER-resident multipass membrane protein that functions as the retrotranslocation channel of the Hrd1 ER-associated degradation (ERAD) machinery, selectively removing misfolded lumenal secretory proteins from the ER for proteasomal destruction [#0, #2]. It contains four transmembrane domains with both termini exposed to the cytoplasm [#1], and oligomerizes (via Usa1 in yeast) to build the functional retrotranslocon [#2]. Within the Hrd1 complex, the ER-luminal regions of Der1 lie adjacent to the substrate receptor Hrd3 and contact misfolded clients, while its transmembrane domains, positioned next to the ubiquitin ligase Hrd1, thread aberrant polypeptides through the membrane and deliver them to Hrd1 for ubiquitylation [#2]; the same retrotranslocon cavity is shared and competed for between this Der1-dependent lumenal route and the integral-membrane (ERAD-M) degradation path, with Hrd1 complex assembly tuning the balance [#7]. N-terminal acetylation of Der1 by NatB stabilizes the protein and is required for Hrd1 ligase activity toward lumenal substrates, since unacetylated Der1 is itself degraded by the Hrd1 pathway [#3]. In mammalian cells DERL1 additionally engages the AAA-ATPase VCP/p97 [#4] and, in breast cancer, binds the E3 ligase TRAF6 to promote K63-linked ubiquitination and activation of AKT, contributing to oncogenic signaling [#6].\",\n  \"teleology\": [\n    {\n      \"year\": 1996,\n      \"claim\": \"Established that an ER membrane protein is specifically required for clearing misfolded lumenal proteins, defining the first dedicated ERAD component for lumenal substrates.\",\n      \"evidence\": \"Yeast genetic screen, complementation cloning, and DER1 deletion with substrate stability and ER-retention assays\",\n      \"pmids\": [\"8631297\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism by which Der1 acts on substrates not defined\", \"Membrane topology and partners unknown at this stage\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Determined the membrane architecture of Der1, showing four transmembrane domains with cytoplasmic termini both contributing to function, and demonstrated functional conservation across species.\",\n      \"evidence\": \"Topology mapping, deletion/mutant analysis, and complementation with the C. elegans ortholog R151.6 in yeast\",\n      \"pmids\": [\"15093775\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not define how the termini contribute mechanistically\", \"Relationship to the Hrd1 ligase complex not yet established\", \"Role of paralog Dfm1 left unresolved beyond exclusion from ERAD\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Resolved the molecular function of Der1 as the retrotranslocon, placing it spatially between the substrate receptor Hrd3 and the ligase Hrd1 and showing it threads lumenal substrates into the membrane.\",\n      \"evidence\": \"Site-specific photocrosslinking, transmembrane-domain mutagenesis, oligomerization and retrotranslocation assays in yeast\",\n      \"pmids\": [\"24292014\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Atomic structure of the channel and the threading conduit not resolved\", \"Stoichiometry of the Usa1-dependent oligomer undefined\", \"Mechanism coupling threading to Hrd1 ubiquitylation not detailed\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identified a post-translational requirement for Der1 stability and Hrd1 activity, showing NatB N-terminal acetylation protects Der1 from self-directed degradation.\",\n      \"evidence\": \"NatB deletion analysis, substrate stability assays, acetyltransferase retargeting, and epistasis in yeast\",\n      \"pmids\": [\"23363603\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How acetylation structurally stabilizes Der1 not defined\", \"Whether mammalian DERL1 is similarly regulated untested in this corpus\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Provided early tissue-level evidence for a mammalian DERL1 interaction with a client class (MHC I), but without the canonical p97 partner in that context.\",\n      \"evidence\": \"Co-immunoprecipitation from bovine luteal tissue with Western and Northern blot\",\n      \"pmids\": [\"20682045\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single Co-IP from tissue with no functional follow-up\", \"Absence of VIMP/p97 association unexplained\", \"Direct role in MHC I degradation not demonstrated\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Connected mammalian DERL1 to membrane partners regulating its own stability, linking it to tumor progression.\",\n      \"evidence\": \"Co-IP, siRNA knockdown, autophagic degradation assays, and xenograft tumor assays in triple-negative breast cancer\",\n      \"pmids\": [\"35920704\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which TMEM63A blocks TOLLIP-mediated autophagy of DERL1 not detailed\", \"Whether ERAD activity mediates the oncogenic effect unclear\", \"Single-lab, cancer-specific context\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Revealed a non-canonical signaling role for DERL1, binding TRAF6 to drive K63 ubiquitination and activation of AKT in cancer cells.\",\n      \"evidence\": \"Reciprocal Co-IP, IP-mass spectrometry, site-directed mutagenesis (Tyr77 and combinatorial mutants), and dual-luciferase assays in breast cancer cells\",\n      \"pmids\": [\"38858669\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Relationship between this signaling role and ERAD function unclear\", \"In vivo relevance beyond cell-based assays not established\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defined a competition for the shared retrotranslocon cavity between Der1-dependent lumenal and integral-membrane substrate degradation, identifying complex assembly as the tuning determinant.\",\n      \"evidence\": \"Deep mutational scanning of Hrd1 with in vivo ERAD substrate degradation assays and genetic epistasis\",\n      \"pmids\": [\"41329737\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of the competing substrate paths not resolved\", \"How assembly state is regulated in cells unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the yeast retrotranslocon mechanism and the mammalian non-ERAD signaling roles of DERL1 are reconciled, and whether they operate in the same or distinct cellular contexts, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of the human DERL1-containing retrotranslocon\", \"ERAD substrate spectrum of mammalian DERL1 not mapped in this corpus\", \"Mechanistic link between retrotranslocation and AKT/TRAF6 signaling undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [2, 6]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [0, 1, 2, 4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 2, 3]}\n    ],\n    \"complexes\": [\"Hrd1 ERAD complex\"],\n    \"partners\": [\"HRD1\", \"HRD3\", \"USA1\", \"VCP\", \"TMEM63A\", \"TRAF6\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}