Affinage

DCAF10

DDB1- and CUL4-associated factor 10 · UniProt Q5QP82

Round 2 corrected
Length
559 aa
Mass
60.6 kDa
Annotated
2026-04-28
36 papers in source corpus 4 papers cited in narrative 4 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

DCAF10 is the substrate receptor subunit of the CUL4A–DDB1–DCAF10 E3 ubiquitin ligase complex, directing polyubiquitination and proteasomal degradation of specific substrates. It recognizes N-terminally acetylated Src-family kinases via an Ac/N-degron mechanism that monitors myristoylation status, defining a quality-control pathway for lipid-modified kinases (PMID:41484149). The same complex is co-opted by adenovirus E1A to degrade the AAA+ ATPases RUVBL1 and RUVBL2, suppressing IRF3-dependent innate immune signaling (PMID:37962355), and mediates degradation of depalmitoylated ALOX15B in KRAS-mutant pancreatic cancer to enable ferroptosis evasion (PMID:40569151). DCAF10 protein stability is itself regulated by the deubiquitinase OTUD1, which stabilizes DCAF10 to promote CUL4A–DDB1–DCAF10-dependent degradation of the anti-apoptotic protein MCL1 (PMID:33898171).

Mechanistic history

Synthesis pass · year-by-year structured walk · 4 steps
  1. 2021 Medium

    Establishing that DCAF10 operates within the CUL4A–DDB1 E3 ligase axis to degrade MCL1 answered how this substrate receptor connects to apoptotic signaling, and revealed that DCAF10 itself is regulated by OTUD1-mediated deubiquitination.

    Evidence Co-immunoprecipitation, deubiquitination assays, and overexpression/knockdown studies with apoptosis readouts in cell lines

    PMID:33898171

    Open questions at the time
    • Single-lab study; independent replication of the OTUD1–DCAF10–MCL1 axis is lacking
    • Direct binding interface between DCAF10 and MCL1 is undefined
    • In vivo physiological relevance of OTUD1 regulation of DCAF10 is unexplored
  2. 2023 Medium

    Demonstrating that adenovirus E1A hijacks CUL4–DDB1–DCAF10 to degrade RUVBL1/2 and suppress interferon signaling revealed that DCAF10 can be redirected to non-endogenous substrates by viral factors, expanding the functional scope of DCAF-based E3 ligases in host–pathogen interactions.

    Evidence Affinity purification–mass spectrometry identification of E1A–DCAF10 interaction, siRNA knockdown of DCAF10, and IRF3/ISG expression readouts during adenovirus infection

    PMID:37962355

    Open questions at the time
    • Single-lab finding; mechanism of E1A-mediated substrate redirection to RUVBL1/2 is not structurally resolved
    • Whether RUVBL1/2 are endogenous DCAF10 substrates in uninfected cells is unknown
    • Generalizability to other adenovirus serotypes not tested
  3. 2025 Medium

    Identification of ALOX15B as a DCAF10-dependent substrate in KRAS-mutant cancer demonstrated that depalmitoylation-triggered cytoplasmic translocation is the recognition switch, linking lipid modification status to CUL4/DDB1/DCAF10-mediated degradation and ferroptosis evasion.

    Evidence Co-immunoprecipitation, proteasomal degradation assays, KRAS/ERK pathway manipulation, and in vitro/in vivo pancreatic tumor models

    PMID:40569151

    Open questions at the time
    • Single-lab study; the direct degron motif on ALOX15B recognized by DCAF10 is not defined
    • Whether DCAF10 recognizes depalmitoylated ALOX15B via the same binding mode as acetylated substrates is unknown
    • Therapeutic relevance of targeting the DCAF10–ALOX15B axis is untested
  4. 2026 High

    Reconstitution of CUL4A–DDB1–DCAF10-mediated ubiquitination of N-terminally acetylated Src-family kinases in vitro defined the Ac/N-degron pathway, establishing that DCAF10 monitors myristoylation status by specifically recognizing Nt-acetylated glycine as a degradation signal.

    Evidence Peptide pull-downs, mass spectrometry, AlphaFold 3 structural predictions, CRISPR/Cas9 knockout, inducible Lyn-GFP variants, and in vitro ubiquitination reconstitution

    PMID:41484149

    Open questions at the time
    • No experimental high-resolution structure of DCAF10 bound to an Ac/N-degron peptide exists
    • Full physiological substrate repertoire of DCAF10 beyond SFKs remains undefined
    • Whether the Ac/N-degron pathway is conserved across species is not addressed

Open questions

Synthesis pass · forward-looking unresolved questions
  • The unifying principle governing DCAF10 substrate selection — whether all substrates share a lipid-modification-dependent degron or whether distinct recognition modes exist — remains an open mechanistic question.
  • No experimental crystal or cryo-EM structure of DCAF10 in complex with DDB1 or any substrate
  • No systematic proteomics-based identification of the full endogenous substrate repertoire
  • In vivo knockout phenotype in animal models has not been reported

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 4 GO:0140096 catalytic activity, acting on a protein 4
Localization
GO:0005829 cytosol 2
Pathway
R-HSA-392499 Metabolism of proteins 4 R-HSA-168256 Immune System 1 R-HSA-5357801 Programmed Cell Death 1
Partners
ALOX15BCUL4ADDB1MCL1OTUD1RUVBL1RUVBL2
Complex memberships
CUL4A–DDB1–DCAF10 E3 ubiquitin ligase

Evidence

Reading pass · 4 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2021 OTUD1 stabilizes DCAF10 and recruits the CUL4A-DDB1-DCAF10 E3 ligase complex to promote polyubiquitination and proteasomal degradation of MCL1, thereby activating caspase-dependent apoptotic signaling. OTUD1 deubiquitinates and stabilizes DCAF10, linking the deubiquitinase to the CUL4A-based ubiquitin ligase machinery. Co-immunoprecipitation, deubiquitination assays, overexpression/knockdown with apoptosis readouts, MCL1 degradation assays Advanced science (Weinheim, Baden-Wurttemberg, Germany) Medium 33898171
2023 Adenovirus E1A binds DCAF10 to co-opt the CUL4-DDB1-DCAF10 E3 ligase complex, redirecting it to polyubiquitinate RUVBL1 and RUVBL2 AAA+ ATPases for proteasomal degradation. This degradation inhibits IRF3 activation and suppresses innate immune interferon-stimulated gene expression, enabling viral replication. Affinity purification-mass spectrometry, proteasomal degradation assays, siRNA knockdown of DCAF10, IRF3/ISG expression readouts Journal of virology Medium 37962355
2025 The CUL4/DDB1/DCAF10 E3 ligase complex mediates proteasome-dependent degradation of ALOX15B in KRAS-mutant pancreatic cancer. ABHD17C-mediated depalmitoylation and cytoplasmic translocation of ALOX15B facilitates its recognition and ubiquitination by CUL4/DDB1/DCAF10, enabling ferroptosis evasion. Co-immunoprecipitation, proteasomal degradation assays, KRAS/ERK pathway manipulation, in vitro and in vivo tumor models Advanced science (Weinheim, Baden-Wurttemberg, Germany) Medium 40569151
2026 DCAF10 is the substrate receptor within the CUL4A-DDB1-DCAF10 E3 ubiquitin ligase complex that specifically recognizes N-terminally acetylated Src-family kinases (SFKs). When SFKs lack N-terminal myristoylation and are instead N-terminally acetylated, DCAF10 recognizes the acetylated glycine residue as an N-degron, and the reconstituted CUL4A-DDB1-DCAF10 complex ubiquitinates these SFKs in vitro, defining a novel Ac/N-degron pathway that monitors myristoylation status. Peptide pull-downs, mass spectrometry, AlphaFold 3 structural predictions, siRNA knockdown and CRISPR/Cas9 knockout of Lyn, inducible Lyn-GFP variants, in vitro ubiquitination reconstitution assay Nature communications High 41484149

Source papers

Stage 0 corpus · 36 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2005 A human protein-protein interaction network: a resource for annotating the proteome. Cell 1704 16169070
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2015 The BioPlex Network: A Systematic Exploration of the Human Interactome. Cell 1118 26186194
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
2015 A human interactome in three quantitative dimensions organized by stoichiometries and abundances. Cell 1015 26496610
2020 A reference map of the human binary protein interactome. Nature 849 32296183
2003 Complete sequencing and characterization of 21,243 full-length human cDNAs. Nature genetics 754 14702039
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2006 Molecular architecture and assembly of the DDB1-CUL4A ubiquitin ligase machinery. Nature 585 16964240
2020 Comparative host-coronavirus protein interaction networks reveal pan-viral disease mechanisms. Science (New York, N.Y.) 564 33060197
2006 A family of diverse Cul4-Ddb1-interacting proteins includes Cdt2, which is required for S phase destruction of the replication factor Cdt1. Molecular cell 538 16949367
2019 Nrf2 Activation Promotes Lung Cancer Metastasis by Inhibiting the Degradation of Bach1. Cell 460 31257023
2022 OpenCell: Endogenous tagging for the cartography of human cellular organization. Science (New York, N.Y.) 432 35271311
2010 Systematic analysis of human protein complexes identifies chromosome segregation proteins. Science (New York, N.Y.) 421 20360068
2015 Gain-of-function p53 mutants co-opt chromatin pathways to drive cancer growth. Nature 391 26331536
2009 Mammalian BTBD12/SLX4 assembles a Holliday junction resolvase and is required for DNA repair. Cell 375 19596235
2010 Dynamics of cullin-RING ubiquitin ligase network revealed by systematic quantitative proteomics. Cell 318 21145461
2014 Global mapping of herpesvirus-host protein complexes reveals a transcription strategy for late genes. Molecular cell 173 25544563
2017 RNA-binding activity of TRIM25 is mediated by its PRY/SPRY domain and is required for ubiquitination. BMC biology 135 29117863
2021 CRL4AMBRA1 is a master regulator of D-type cyclins. Nature 134 33854235
2020 Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread Protein Aggregation in Affected Brains. Cell reports 79 32814053
2016 Substrate-Trapped Interactors of PHD3 and FIH Cluster in Distinct Signaling Pathways. Cell reports 77 26972000
2022 SARS-CoV-2 N Protein Antagonizes Stress Granule Assembly and IFN Production by Interacting with G3BPs to Facilitate Viral Replication. Journal of virology 75 35652658
2009 An interaction network of the mammalian COP9 signalosome identifies Dda1 as a core subunit of multiple Cul4-based E3 ligases. Journal of cell science 71 19295130
2014 TRIM65 regulates microRNA activity by ubiquitination of TNRC6. Proceedings of the National Academy of Sciences of the United States of America 69 24778252
2021 OTUD1 Activates Caspase-Independent and Caspase-Dependent Apoptosis by Promoting AIF Nuclear Translocation and MCL1 Degradation. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 65 33898171
2020 PIKES Analysis Reveals Response to Degraders and Key Regulatory Mechanisms of the CRL4 Network. Molecular cell 63 31973889
2017 Systematic protein-protein interaction mapping for clinically relevant human GPCRs. Molecular systems biology 58 28298427
2023 Protein interaction studies in human induced neurons indicate convergent biology underlying autism spectrum disorders. Cell genomics 38 36950384
2015 SR protein kinases promote splicing of nonconsensus introns. Nature structural & molecular biology 37 26167880
2017 Integrative analysis of multi-omics data reveals distinct impacts of DDB1-CUL4 associated factors in human lung adenocarcinomas. Scientific reports 16 28336923
2025 KRAS/ABHD17C/ALOX15B Axis Promotes Pancreatic Cancer Progression via Ferroptosis Evasion. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 6 40569151
2022 Integrated microarray for identifying the hub mRNAs and constructed miRNA-mRNA network in coronary in-stent restenosis. Physiological genomics 3 35968900
2023 Adenovirus E1A binding to DCAF10 targets proteasomal degradation of RUVBL1/2 AAA+ ATPases required for quaternary assembly of multiprotein machines, innate immunity, and responses to metabolic stress. Journal of virology 1 37962355
2026 CUL4A-DDB1-DCAF10 is an N-recognin for N-terminally acetylated Src kinases. Nature communications 0 41484149