Affinage

DERL1

Derlin-1 · UniProt Q9BUN8

Length
251 aa
Mass
28.8 kDa
Annotated
2026-06-09
43 papers in source corpus 8 papers cited in narrative 8 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 8 steps
  1. 1996 High

    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

    PMID:8631297

    Open questions at the time
    • Molecular mechanism by which Der1 acts on substrates not defined
    • Membrane topology and partners unknown at this stage
  2. 2004 Medium

    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

    PMID:15093775

    Open questions at the time
    • 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
  3. 2013 High

    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

    PMID:24292014

    Open questions at the time
    • 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
  4. 2013 High

    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

    PMID:23363603

    Open questions at the time
    • How acetylation structurally stabilizes Der1 not defined
    • Whether mammalian DERL1 is similarly regulated untested in this corpus
  5. 2010 Low

    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

    PMID:20682045

    Open questions at the time
    • Single Co-IP from tissue with no functional follow-up
    • Absence of VIMP/p97 association unexplained
    • Direct role in MHC I degradation not demonstrated
  6. 2022 Medium

    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

    PMID:35920704

    Open questions at the time
    • 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
  7. 2024 Medium

    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

    PMID:38858669

    Open questions at the time
    • Relationship between this signaling role and ERAD function unclear
    • In vivo relevance beyond cell-based assays not established
    • Single-lab finding
  8. 2025 Medium

    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

    PMID:41329737

    Open questions at the time
    • Structural basis of the competing substrate paths not resolved
    • How assembly state is regulated in cells unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 2 GO:0060090 molecular adaptor activity 1
Localization
GO:0005783 endoplasmic reticulum 4
Pathway
R-HSA-392499 Metabolism of proteins 3
Partners
HRD1HRD3TMEM63ATRAF6USA1VCP
Complex memberships
Hrd1 ERAD complex

Evidence

Reading pass · 8 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1996 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. Yeast genetic screen, complementation cloning, deletion mutant analysis, substrate stability assays, ER retention assays The EMBO journal High 8631297
2004 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. Topology mapping, complementation assays with C. elegans ortholog, deletion/mutant analysis FEMS yeast research Medium 15093775
2013 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. Site-specific photocrosslinking, transmembrane domain mutagenesis, protein oligomerization assays, substrate retrotranslocation assays Nature cell biology High 24292014
2013 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. NatB deletion mutant analysis, substrate stability assays, acetyltransferase retargeting experiment, epistasis analysis Molecular biology of the cell High 23363603
2022 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. Co-immunoprecipitation, siRNA knockdown, xenograft tumor assays, autophagic degradation assays Autophagy Medium 35920704
2010 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. Co-immunoprecipitation from bovine luteal tissue, Western blot, Northern blot Reproductive biology and endocrinology Low 20682045
2024 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. Co-immunoprecipitation, immunoprecipitation-mass spectrometry, site-directed mutagenesis, Zdock prediction, dual-luciferase assay Cancer cell international Medium 38858669
2025 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. Deep mutational scanning of Hrd1, in vivo ERAD substrate degradation assays, genetic epistasis Proceedings of the National Academy of Sciences of the United States of America Medium 41329737

Source papers

Stage 0 corpus · 43 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1996 Der1, a novel protein specifically required for endoplasmic reticulum degradation in yeast. The EMBO journal 310 8631297
2006 Identification of der(1;19)(q10;p10) in five oligodendrogliomas suggests mechanism of concurrent 1p and 19q loss. Journal of neuropathology and experimental neurology 222 17021403
2013 Der1 promotes movement of misfolded proteins through the endoplasmic reticulum membrane. Nature cell biology 126 24292014
2007 Der1-mediated preprotein import into the periplastid compartment of chromalveolates? Molecular biology and evolution 115 17244602
2004 Der1p, a protein required for degradation of malfolded soluble proteins of the endoplasmic reticulum: topology and Der1-like proteins. FEMS yeast research 66 15093775
1993 Two-color FISH characterization of i(1q) and der(1;16) in human breast cancer cells. Genes, chromosomes & cancer 59 7688559
2003 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. Human genetics 49 14579147
2022 TOLLIP-mediated autophagic degradation pathway links the VCP-TMEM63A-DERL1 signaling axis to triple-negative breast cancer progression. Autophagy 47 35920704
2013 N-terminal acetylation of the yeast Derlin Der1 is essential for Hrd1 ubiquitin-ligase activity toward luminal ER substrates. Molecular biology of the cell 38 23363603
2010 The combined expression pattern of BMP2, LTBP4, and DERL1 discriminates malignant from benign canine mammary tumors. Veterinary pathology 38 20375427
1998 Highly recurrent der(1;16)(q10;p10) and other 16q arm alterations in lobular breast cancer. Genes, chromosomes & cancer 35 9824202
2003 Molecular characterization of the recurrent unbalanced translocation der(1;7)(q10;p10). Blood 31 12816870
1997 Renal oncocytoma with t(5;12;11), der(1)1;8) and add(19): "true" oncocytoma or chromophobe adenoma? International journal of cancer 28 9389566
1999 Karyotypic evolution in breast carcinomas with i(1)(q10) and der(1;16)(q10;p10) as the primary chromosome abnormality. Cancer genetics and cytogenetics 25 10484983
1989 der(1)t(1;9): a specific chromosome abnormality in polycythemia vera? Cytogenetic and in situ hybridization studies. Cancer genetics and cytogenetics 21 2758394
2005 Molecular cytogenetic characterization of a familial der(1)del(1)(p36.33)dup(1)(p36.33p36.22) with variable phenotype. American journal of medical genetics. Part A 17 16278888
2002 Novel der(1)t(1;19) in two patients with myeloid neoplasias. Cancer genetics and cytogenetics 14 11890991
2019 Comprehensive analysis of isolated der(1;7)(q10;p10) in a large international homogenous cohort of patients with myelodysplastic syndromes. Genes, chromosomes & cancer 12 30994215
1996 Major Dermatophagoides mite allergen, Der 1, in soft toys. Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology 12 8735872
2022 Circular RNA circTTBK2 facilitates non-small-cell lung cancer malignancy through the miR-873-5p/TEAD1/DERL1 axis. Epigenomics 8 35916080
2014 Quantitative multigene FISH on breast carcinomas identifies der(1;16)(q10;p10) as an early event in luminal A tumors. Genes, chromosomes & cancer 8 25546585
2021 Melatonin enhances cisplatin-induced cell death through inhibition of DERL1 in mesenchymal-like CD44high OSCC cells. Journal of oral pathology & medicine : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology 7 34551150
2004 Therapy-related myelodysplastic syndrome with trisomy 1q due to der(1;7) and megakaryoblastic proliferation developing during complete remission of therapy-related acute myeloid leukemia with t(8;21). Internal medicine (Tokyo, Japan) 7 15335185
2024 miR-181c-5p/DERL1 pathway controls breast cancer progression mediated by TRAF6-linked K63 ubiquitination of AKT. Cancer cell international 6 38858669
2005 Supernumerary der(1) marker chromosome derived from a ring chromosome 1 which has retained the original centromere and euchromatin from 1q21.1 --> q21.3 with substantial loss of 1q12 heterochromatin in a female with dysmorphic features and psychomotoric developmental delay. American journal of medical genetics. Part A 5 15633178
2000 Preferential occurrence of breast carcinomas with loss of chromosome 16q and der (16) t (1;16) / der (1;16) in middle-aged patients with hyperplasia of mammary glands. Japanese journal of cancer research : Gann 5 10920276
1992 [der(1;7) (q10;p10) in three patients with malignant hematologic disorders]. [Rinsho ketsueki] The Japanese journal of clinical hematology 5 1479694
1997 der(1)t(1;19)(p12;p11): a new nonrandom chromosomal abnormality in myelodysplastic syndrome. Cancer genetics and cytogenetics 4 9109932
2013 A new der(1;7)(q10;p10) leading to a singular 1p loss in a case of glioblastoma with oligodendroglioma component. Neuropathology : official journal of the Japanese Society of Neuropathology 3 24118308
2008 Clinical and molecular cytogenetic characterization of four patients with unbalanced translocation der(1)t(1;22)(p36;q13). American journal of medical genetics. Part A 3 18958851
2006 Array-based comparative genomic hybridization facilitates identification of breakpoints of a novel der(1)t(1;18)(p36.3;q23)dn in a child presenting with mental retardation. American journal of medical genetics. Part A 3 16688748
2022 Outcomes after allogeneic hematopoietic stem cell transplantation in acute myeloid leukemia patients with der(1;7)(q10;p10). EJHaem 2 36819182
2010 Molecular characterization and expression of DERL1 in bovine ovarian follicles and corpora lutea. Reproductive biology and endocrinology : RB&E 2 20682045
2007 Molecular cytogenetic analysis of complex karyotypes with derivative chromosome der(1)t(1;5) found in two patients with myeloid leukemia. Cancer genetics and cytogenetics 2 17656259
2005 A dysmorphic newborn with 45,X,der(1)inv(1)(p13;qter)t(Y;1)(pter-->q11;p13),-Y de novo karyotype. Genetic counseling (Geneva, Switzerland) 2 16080298
2024 The der(1;7)(q10;p10) defining a distinct profile from -7/del(7q) in myelodysplastic syndromes: A systematic review and meta-analysis. Cancer medicine 1 38164059
2023 [Myelodysplastic syndrome with der (1;7)(q10;p10) complicated with eosinophilia and organizing pneumonia]. [Rinsho ketsueki] The Japanese journal of clinical hematology 1 37544721
2025 Competition between Der1 and ERAD-M substrates controls Hrd1 complex function. Proceedings of the National Academy of Sciences of the United States of America 0 41329737
2024 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. Taiwanese journal of obstetrics & gynecology 0 39482002
2023 [Characteristics of myelodysplastic syndromes with der(1;7)(q10;p10)]. [Rinsho ketsueki] The Japanese journal of clinical hematology 0 38220152
2019 A rare case of acute myeloid leukemia with der(1)t(1;19)(p13;p13.1). Leukemia research reports 0 31245275
2018 An isolated der(1;21)(q10;q10) translocation in a patient with myelodysplastic syndrome: a case report. American journal of blood research 0 30498621
2016 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. Gene 0 27664585

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