{"gene":"ANAPC5","run_date":"2026-06-09T22:02:43","timeline":{"discoveries":[{"year":1998,"finding":"ANAPC5 (APC5) was identified as one of four previously uncharacterized human APC subunits (alongside APC2, APC4, APC7) and shown to be a core component of the anaphase-promoting complex, an eight-subunit E3 ubiquitin ligase responsible for targeting cell cycle regulators for degradation.","method":"Biochemical purification and cloning of human APC subunits","journal":"Science","confidence":"High","confidence_rationale":"Tier 2 / Strong — foundational biochemical identification replicated and built upon extensively by subsequent independent studies","pmids":["9469815"],"is_preprint":false},{"year":2003,"finding":"APC5, together with APC1 and APC4, forms a subcomplex that can assemble multiubiquitin chains but cannot bind CDH1 or ubiquitinate substrates. APC5 likely acts as a scaffold connecting the catalytic module (APC2/APC11) with the TPR subunits that recruit co-activators.","method":"Biochemical fractionation and reconstitution of human APC subcomplexes; in vitro ubiquitination assays; CDH1 binding assays","journal":"Current Biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution of subcomplexes with functional ubiquitination and binding assays, replicated in structural studies","pmids":["12956947"],"is_preprint":false},{"year":2011,"finding":"Cryo-EM and mass spectrometry structural analysis of the APC/C places APC5 (along with APC1 and APC4) as a scaffolding subunit that coordinates the juxtaposition of the catalytic module (APC2, APC11, APC10) and TPR subunits, providing a pseudo-atomic model for APC/C organization.","method":"Recombinant reconstitution of holo-APC/C; electron microscopy; mass spectrometry; crystallographic docking","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 / Strong — cryo-EM structure with mass spectrometry and crystallographic docking in a single rigorous study, defining APC5 position within the complex","pmids":["21307936"],"is_preprint":false},{"year":2015,"finding":"Crystal structures of Apc4 and the N-terminal domain of Apc5 (Apc5N) were determined; Apc5N adopts an α-helical fold, and in the context of the APC/C, shows small conformational changes and contacts Apc4 to order regions disordered in the crystal.","method":"Protein crystallography; fitting into cryo-EM map","journal":"Journal of Molecular Biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure of Apc5N with cryo-EM validation in single study","pmids":["26343760"],"is_preprint":false},{"year":2016,"finding":"APC5 (as part of the APC/C platform with APC1, APC4, and APC15) supports the coactivator-induced allosteric conformational change required for UbcH10-dependent ubiquitination; the platform structurally coordinates the catalytic and substrate-recognition modules.","method":"Crystal structure of Apc1 WD40 domain; cryo-EM of APC/C-Cdh1 with Apc1 WD40 deletion; in vitro ubiquitination assays","journal":"PNAS","confidence":"High","confidence_rationale":"Tier 1 / Moderate — structure plus in vitro reconstitution and mutagenesis in a single study defining platform role","pmids":["27601667"],"is_preprint":false},{"year":2005,"finding":"APC5 and APC7 directly interact with transcriptional coactivators CBP and p300 through protein-protein interaction domains evolutionarily conserved in adenovirus E1A; this interaction stimulates intrinsic CBP/p300 acetyltransferase activity and potentiates CBP/p300-dependent transcription.","method":"Co-immunoprecipitation; in vitro acetyltransferase assays; reporter gene transcription assays; RNAi knockdown of CBP","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP plus in vitro enzymatic assay plus transcription assay plus functional RNAi, multiple orthogonal methods in one study","pmids":["16319895"],"is_preprint":false},{"year":2005,"finding":"APC5 and APC7 suppress E1A-mediated cellular transformation in a CBP/p300-dependent manner, indicating these subunits are functionally targeted during cellular transformation.","method":"Transformation assay with APC5/APC7 expression in CBP/p300-proficient vs. -deficient contexts","journal":"Nature","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional cell-based assay, single lab, multiple methods in the same study","pmids":["16319895"],"is_preprint":false},{"year":2004,"finding":"Apc5 binds poly(A) binding protein (PABP) and represses IRES-mediated translation of PDGF-2 mRNA; overexpression of Apc5 counteracts PABP-enhanced IRES activity, and Apc5 co-sediments with the ribosomal fraction, indicating a role outside the APC/C in translational regulation.","method":"Yeast three-hybrid screen; co-immunoprecipitation; sucrose gradient sedimentation; IRES reporter assays; overexpression in differentiated cells","journal":"Molecular and Cellular Biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — yeast three-hybrid plus Co-IP plus functional IRES assays, single lab","pmids":["15082755"],"is_preprint":false},{"year":2012,"finding":"APC5 binds E2F1 directly (confirmed by in vivo and in vitro Co-IP/GST pulldown) and is essential for E2F1 ubiquitination by APC/C-Cdh1, which targets E2F1 for K11-linked ubiquitin chain-mediated proteasomal degradation after S phase.","method":"Co-immunoprecipitation in vivo and in vitro; GST pulldown mapping; ubiquitination assays with K11-specific ubiquitin","journal":"Cell Cycle","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP plus in vitro pulldown plus ubiquitination assay, single lab","pmids":["22580462"],"is_preprint":false},{"year":2013,"finding":"ANAPC5 binds IL-17RA and IL-17RC and associates with the deubiquitinase A20 (TNFAIP3); siRNA-mediated knockdown of ANAPC5 enhances IL-17-induced gene expression, demonstrating that ANAPC5 acts as a negative regulator of IL-17 signaling.","method":"Yeast two-hybrid screen; co-immunoprecipitation; siRNA knockdown with cytokine-stimulated gene expression readout","journal":"PLoS ONE","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — yeast two-hybrid plus Co-IP plus siRNA functional assay, single lab","pmids":["23922952"],"is_preprint":false},{"year":2010,"finding":"During HCMV infection, APC5 and APC4 subunits undergo proteasome-dependent degradation, which is temporally associated with disassembly of the APC/C core complex and requires viral early gene expression (not immediate early genes alone), leading to APC/C inactivation.","method":"Immunoblotting; proteasome inhibitor treatment; UV-inactivated and deletion mutant virus infections; phosphatase assays; mass spectrometry","journal":"Journal of Virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple viral mutant analyses plus proteasome inhibition, single lab","pmids":["20686030"],"is_preprint":false},{"year":2012,"finding":"HCMV protein pUL21a physically binds the APC/C and is necessary and sufficient to induce proteasome-dependent degradation of APC5 and APC4, thereby disrupting APC/C integrity; residues P109-R110 of pUL21a are critical for APC binding and APC5/APC4 degradation.","method":"Co-immunoprecipitation; expression of pUL21a alone; point mutant virus construction; proteasome inhibitor assays; proteomics","journal":"PLoS Pathogens","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP plus point mutant virus plus proteasome inhibitor plus proteomics, multiple orthogonal methods establishing mechanism","pmids":["22792066"],"is_preprint":false},{"year":2015,"finding":"HCMV protein UL21a also targets APC1 for degradation (in addition to APC4 and APC5); furthermore, depletion of any single platform subunit (APC1, APC4, or APC5) or APC8 triggers coordinated co-degradation of all three platform subunits, revealing a cellular mechanism for platform subunit co-regulation.","method":"siRNA knockdown of individual APC subunits; immunoblotting; UL21a expression in uninfected cells","journal":"Journal of Virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA knockdown with systematic immunoblotting, single lab, multiple conditions","pmids":["25903336"],"is_preprint":false},{"year":2002,"finding":"In Drosophila, IDA (the APC5 homolog) is required for APC/C-dependent degradation of cyclin B but not for degradation of substrates controlling sister-chromatid separation; ida mutants display high mitotic index with aneuploid, overcondensed chromosomes, defining a subfunction-specific role for APC5 within the APC/C.","method":"Genetic mutant analysis; cytological examination of mitotic stages; immunostaining for APC/C substrate levels","journal":"Journal of Cell Science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic loss-of-function with substrate-level readouts distinguishing APC/C subfunctions, single study","pmids":["11870214"],"is_preprint":false},{"year":2003,"finding":"Yeast Apc5 physically interacts with Cdc23 and Apc1 in co-expression in vitro transcription/translation; yeast two-hybrid and co-purification experiments confirmed Mnd2 and Swm1 interact with Apc5 and Cdc23 as core APC subunits.","method":"In vitro transcription/translation co-expression; mass spectrometry identification; co-purification with epitope-tagged subunits","journal":"Journal of Biological Chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro co-expression interaction plus co-purification, single lab","pmids":["12609981"],"is_preprint":false},{"year":2002,"finding":"In yeast, APC5 (RMC1) is required for in vitro chromatin assembly; apc5 mutants display UV sensitivity, plasmid loss, G2/M accumulation, and genetic interactions with apc9Δ, apc10Δ, and cdc26Δ, linking APC5 function to chromatin metabolism and APC complex integrity.","method":"In vitro chromatin assembly screen; genetic epistasis analysis; phenotypic characterization of ts mutants","journal":"Genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro chromatin assembly assay plus genetic interaction analysis, single lab","pmids":["12399376"],"is_preprint":false},{"year":2013,"finding":"The APC (via Apc5) targets Fob1 for degradation specifically in G1; Fob1 is unstable in G1, stabilized in apc5(CA) and proteasome mutants, and Fob1 deletion suppresses apc5(CA) cell cycle and rDNA recombination defects, placing APC5-dependent Fob1 degradation in a pathway linking APC to replicative longevity and genomic stability.","method":"Yeast two-hybrid (Apc5 as bait, Fob1 as prey); protein stability assays; genetic epistasis; rDNA recombination assays","journal":"Genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — yeast two-hybrid plus protein stability plus genetic epistasis, single lab","pmids":["24361936"],"is_preprint":false},{"year":2009,"finding":"Fission yeast Atf1 physically binds the APC/C in vivo; purified Atf1 stimulates ubiquitylation of cyclin B and securin by the APC/C in a cell-free system, independent of Atf1's DNA-binding (bZIP) domain; atf1+ is a dose-dependent suppressor of apc5-1 mitotic arrest.","method":"Genetic suppressor analysis; co-immunoprecipitation; cell-free APC/C ubiquitination assay with purified Atf1","journal":"Journal of Biological Chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstituted ubiquitination assay plus Co-IP plus genetic suppressor, multiple orthogonal methods, single lab","pmids":["19584054"],"is_preprint":false},{"year":2010,"finding":"In C. elegans, SUCH-1/APC5 is required for normal mitotic timing; a novel such-1(t1668) allele causes prolonged mitosis in embryos with monopolar spindles, and this delay is SAC-dependent (rescued by mdf-1/MAD1 or mdf-2/MAD2 inactivation), suggesting the APC/C negatively regulates the SAC.","method":"Genetic characterization of new allele; time-lapse imaging; epistasis with SAC components by RNAi","journal":"Genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — live imaging plus genetic epistasis, single lab","pmids":["20944014"],"is_preprint":false},{"year":2010,"finding":"C. elegans has two APC5 paralogs (such-1 and gfi-3) that are coexpressed in the germline; co-depletion (but not individual depletion) causes meiotic arrest, demonstrating functionally redundant roles for APC5 paralogs in meiosis.","method":"RNAi co-depletion; germline expression analysis; phenotypic characterization of meiotic arrest","journal":"Genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNAi genetic analysis with meiotic phenotype readout, single lab","pmids":["20944012"],"is_preprint":false},{"year":2024,"finding":"Co-depletion of ANAPC5 in cell lines exacerbates KIF18A-depletion-induced mitotic arrest, whereas co-depletion of ANAPC7 partially rescues this arrest, indicating opposing roles for ANAPC5 and ANAPC7 in modulating mitotic progression downstream of KIF18A.","method":"siRNA co-depletion in cell lines; mitotic arrest quantification by flow cytometry and microscopy","journal":"Scientific Reports / bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA co-depletion with phenotypic readout, published in peer-reviewed journal and preprint, single lab","pmids":["39677807","40596695"],"is_preprint":false},{"year":2026,"finding":"Radiation inhibits the APC/C complex, reducing ANAPC5-mediated ubiquitination of GPAA1 (a catalytic subunit of GPI transamidase); the resulting accumulation of GPAA1 enhances GPI anchoring and CD24 membrane localization, promoting phagocytosis resistance and immune evasion in irradiated tumor cells.","method":"ANAPC5 knockdown/overexpression; ubiquitination assays; flow cytometry for CD24 surface expression; in vivo tumor models with T cell and macrophage depletion","journal":"Cancer Research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ubiquitination assay plus functional in vivo rescue experiments, single lab","pmids":["41512182"],"is_preprint":false},{"year":2025,"finding":"ANAPC5 overexpression in macrophages induces ubiquitination and suppression of EGFR, thereby promoting M2 macrophage polarization over M1; this effect is mediated through the EGFR/CD24 axis, and ANAPC5 overexpression reduces lung inflammation in an LPS-induced ALI mouse model.","method":"ANAPC5 overexpression in vitro and in vivo; ubiquitination assays; EGFR inhibitor rescue; ALI mouse model with pathological and cytokine analysis","journal":"Cellular Immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ubiquitination assay plus in vivo model plus rescue experiments, single lab","pmids":["40834712"],"is_preprint":false}],"current_model":"ANAPC5 (APC5) is a core scaffolding subunit of the APC/C E3 ubiquitin ligase that, together with APC1 and APC4, forms the platform subcomplex bridging the catalytic module (APC2/APC11) with the TPR co-activator-binding subunits; beyond its structural role, APC5 directly binds substrates (e.g., E2F1) and regulatory proteins (e.g., Fob1, Atf1) to facilitate ubiquitination, interacts with CBP/p300 to stimulate acetyltransferase activity and transcription, binds poly(A)-binding protein to repress IRES-mediated translation, and associates with IL-17 receptors and A20 to negatively regulate IL-17 signaling, while also serving as an E3 that ubiquitinates EGFR and GPAA1 to modulate macrophage polarization and immune evasion."},"narrative":{"mechanistic_narrative":"ANAPC5 (APC5) is a core scaffolding subunit of the anaphase-promoting complex/cyclosome (APC/C), the multisubunit E3 ubiquitin ligase that targets cell-cycle regulators for proteasomal degradation [PMID:9469815]. Together with APC1 and APC4, APC5 builds the platform subcomplex that bridges the catalytic module (APC2/APC11/APC10) to the TPR co-activator-binding subunits; this subcomplex assembles polyubiquitin chains but cannot itself bind CDH1 or ubiquitinate substrates, marking its role as structural rather than catalytic [PMID:12956947, PMID:21307936]. Structural work resolved the APC5 N-terminal α-helical fold and its contacts with APC4, and showed that the platform supports the coactivator-induced allosteric change required for UbcH10-dependent ubiquitination [PMID:26343760, PMID:27601667]. Within the complex, APC5 directly binds substrates such as E2F1, mediating its K11-linked ubiquitination and degradation after S phase [PMID:22580462], and genetic studies across organisms reveal substrate-selective contributions: Drosophila IDA/APC5 is required for cyclin B degradation but not sister-chromatid separation [PMID:11870214], and C. elegans SUCH-1/APC5 governs SAC-dependent mitotic timing with a redundant paralog acting in meiosis [PMID:20944014, PMID:20944012]. Beyond the APC/C, APC5 engages CBP/p300 to stimulate their acetyltransferase activity and transcription and to suppress E1A-mediated transformation [PMID:16319895], binds poly(A)-binding protein to repress IRES-mediated translation [PMID:15082755], and negatively regulates IL-17 signaling through association with IL-17 receptors and the deubiquitinase A20 [PMID:23922952]. APC5 is also a target of viral subversion: HCMV pUL21a binds the APC/C and drives proteasomal degradation of APC5 (and APC4/APC1) to inactivate the complex [PMID:20686030, PMID:22792066]. More recent work implicates ANAPC5-mediated ubiquitination of GPAA1 and EGFR in tumor immune evasion and macrophage polarization [PMID:41512182, PMID:40834712].","teleology":[{"year":1998,"claim":"Established APC5 as a bona fide subunit of the APC/C, defining its membership in the cell-cycle ubiquitin ligase before any mechanistic role was known.","evidence":"Biochemical purification and cloning of human APC subunits","pmids":["9469815"],"confidence":"High","gaps":["Did not assign a specific function to APC5 within the complex","No structural placement"]},{"year":2003,"claim":"Answered whether APC5 is catalytic or structural by reconstituting an APC1/APC4/APC5 subcomplex that builds ubiquitin chains but cannot bind CDH1 or ubiquitinate substrates, defining APC5 as a scaffold bridging the catalytic and co-activator-recruiting modules.","evidence":"Biochemical fractionation, subcomplex reconstitution, in vitro ubiquitination and CDH1 binding assays","pmids":["12956947"],"confidence":"High","gaps":["No atomic-resolution view of contacts","Mechanism of coactivator-induced activation unresolved"]},{"year":2011,"claim":"Placed APC5 spatially within the holo-complex, showing it coordinates juxtaposition of the catalytic module and TPR subunits in a pseudo-atomic model.","evidence":"Cryo-EM, mass spectrometry and crystallographic docking of reconstituted APC/C","pmids":["21307936"],"confidence":"High","gaps":["Limited resolution of APC5 internal architecture"]},{"year":2015,"claim":"Resolved the APC5 N-terminal fold and its APC4 contacts, refining the structural basis of platform assembly.","evidence":"Crystallography of Apc4 and Apc5N fitted into cryo-EM","pmids":["26343760"],"confidence":"High","gaps":["Full-length APC5 structure not determined","Functional consequence of conformational changes untested"]},{"year":2016,"claim":"Defined how the APC5-containing platform contributes to catalysis by supporting the coactivator-induced allosteric change required for UbcH10-dependent ubiquitination.","evidence":"Crystal structure of Apc1 WD40, cryo-EM of APC/C-Cdh1, and in vitro ubiquitination assays","pmids":["27601667"],"confidence":"High","gaps":["APC5-specific contribution not isolated from APC1/APC4"]},{"year":2005,"claim":"Revealed an APC/C-independent role by showing APC5 (with APC7) binds CBP/p300 to stimulate acetyltransferase activity, potentiate transcription, and suppress E1A-mediated transformation.","evidence":"Reciprocal Co-IP, in vitro acetyltransferase and reporter assays, RNAi, and transformation assays","pmids":["16319895"],"confidence":"High","gaps":["Whether this occurs within or independent of assembled APC/C unclear","Physiological transcriptional targets not mapped"]},{"year":2004,"claim":"Identified APC5 as a translational regulator that binds PABP and represses IRES-mediated translation, expanding its function beyond ubiquitination.","evidence":"Yeast three-hybrid, Co-IP, sucrose gradient sedimentation, and IRES reporter assays","pmids":["15082755"],"confidence":"Medium","gaps":["Single lab","Generality across IRES-containing mRNAs untested","Mechanism of translational repression unresolved"]},{"year":2012,"claim":"Showed APC5 directly binds E2F1 and is required for its K11-linked ubiquitination and S-phase-coupled degradation, identifying a specific substrate-recognition contribution.","evidence":"In vivo/in vitro Co-IP, GST pulldown mapping, K11-specific ubiquitination assays","pmids":["22580462"],"confidence":"Medium","gaps":["Single lab","Whether APC5 is a dedicated substrate receptor or adaptor unclear"]},{"year":2013,"claim":"Identified APC5 as a negative regulator of IL-17 signaling through binding IL-17RA/RC and the deubiquitinase A20.","evidence":"Yeast two-hybrid, Co-IP, and siRNA knockdown with cytokine-stimulated gene expression","pmids":["23922952"],"confidence":"Medium","gaps":["Single lab","Whether ubiquitin ligase activity is involved unclear","No in vivo validation"]},{"year":2010,"claim":"Demonstrated that APC5 is a target of viral attack, undergoing proteasomal degradation during HCMV infection coincident with APC/C disassembly.","evidence":"Immunoblotting, proteasome inhibition, viral mutant infections, phosphatase assays, MS","pmids":["20686030"],"confidence":"Medium","gaps":["Viral effector not yet identified at this stage","Direct vs. indirect degradation unresolved"]},{"year":2012,"claim":"Identified HCMV pUL21a as the effector that binds the APC/C and is necessary and sufficient to degrade APC5/APC4, defining the mechanism of viral APC/C inactivation.","evidence":"Co-IP, pUL21a expression alone, point-mutant virus, proteasome inhibitor assays, proteomics","pmids":["22792066"],"confidence":"High","gaps":["Ubiquitin ligase responsible for degradation not identified"]},{"year":2015,"claim":"Revealed co-regulation of platform subunits: loss of any single platform subunit (APC1/APC4/APC5) triggers co-degradation of all three, and pUL21a also targets APC1.","evidence":"siRNA knockdown of individual subunits, immunoblotting, UL21a expression","pmids":["25903336"],"confidence":"Medium","gaps":["Single lab","Mechanism sensing platform integrity unknown"]},{"year":2013,"claim":"Defined cross-organism substrate roles: yeast Apc5 interacts with core subunits and targets Fob1 for G1-specific degradation linking APC5 to genomic stability and longevity.","evidence":"Yeast two-hybrid, protein stability assays, genetic epistasis, rDNA recombination assays (with prior subunit-interaction co-purification)","pmids":["24361936","12609981"],"confidence":"Medium","gaps":["Single lab","Conservation of Fob1-like substrates in metazoans unknown"]},{"year":2009,"claim":"Showed fission yeast Atf1 binds and stimulates APC/C ubiquitylation of cyclin B and securin independent of its DNA-binding domain and suppresses apc5-1 arrest, revealing a regulatory protein acting through APC5.","evidence":"Genetic suppressor analysis, Co-IP, cell-free APC/C ubiquitination with purified Atf1","pmids":["19584054"],"confidence":"High","gaps":["Whether contact is on APC5 itself or another subunit not pinpointed","Human ortholog relevance untested"]},{"year":2010,"claim":"Genetically distinguished APC5 functions in animal mitosis and meiosis, including SAC-dependent mitotic timing and redundant paralog roles in the germline.","evidence":"C. elegans allele characterization, time-lapse imaging, RNAi epistasis and co-depletion (with Drosophila ida mutant analysis)","pmids":["20944014","20944012","11870214"],"confidence":"Medium","gaps":["Single-organism findings","Molecular basis of substrate selectivity unresolved"]},{"year":2024,"claim":"Showed opposing roles for ANAPC5 and ANAPC7 in modulating mitotic progression downstream of KIF18A.","evidence":"siRNA co-depletion in cell lines with flow-cytometric and microscopic mitotic-arrest quantification","pmids":["39677807","40596695"],"confidence":"Medium","gaps":["Single lab","Mechanistic basis for opposing effects unknown"]},{"year":2025,"claim":"Linked ANAPC5 to immune regulation by showing its overexpression ubiquitinates and suppresses EGFR to drive M2 macrophage polarization via the EGFR/CD24 axis.","evidence":"Overexpression in vitro/in vivo, ubiquitination assays, EGFR inhibitor rescue, ALI mouse model","pmids":["40834712"],"confidence":"Medium","gaps":["Single lab","Whether EGFR is a direct APC/C substrate unclear"]},{"year":2026,"claim":"Connected radiation-induced APC/C inhibition to immune evasion via loss of ANAPC5-mediated GPAA1 ubiquitination, stabilizing GPAA1 and enhancing CD24 surface display and phagocytosis resistance.","evidence":"ANAPC5 knockdown/overexpression, ubiquitination assays, CD24 flow cytometry, in vivo tumor models with immune cell depletion","pmids":["41512182"],"confidence":"Medium","gaps":["Single lab","Direct vs. indirect ubiquitination of GPAA1 not fully established"]},{"year":null,"claim":"How APC5's structural scaffolding role is mechanistically partitioned from its multiple moonlighting activities (transcription, translation, immune signaling, non-cell-cycle substrate targeting) remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural basis for direct substrate binding by APC5 within the assembled complex","Whether moonlighting functions require free vs. complex-bound APC5 untested","Human in vivo physiological relevance of non-mitotic roles largely undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[8,21,22]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[1,2]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[1,2,3,4]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[5,9]}],"localization":[{"term_id":"GO:0005840","term_label":"ribosome","supporting_discovery_ids":[7]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[5]}],"pathway":[{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[0,1,8,13,18]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,1,8]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[9,21,22]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[5]}],"complexes":["APC/C (anaphase-promoting complex/cyclosome)"],"partners":["ANAPC1","ANAPC4","ANAPC7","E2F1","CREBBP","EP300","PABP","TNFAIP3"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9UJX4","full_name":"Anaphase-promoting complex subunit 5","aliases":["Cyclosome subunit 5"],"length_aa":755,"mass_kda":85.1,"function":"Component of the anaphase promoting complex/cyclosome (APC/C), a cell cycle-regulated E3 ubiquitin ligase that controls progression through mitosis and the G1 phase of the cell cycle (PubMed:18485873). The APC/C complex acts by mediating ubiquitination and subsequent degradation of target proteins: it mainly mediates the formation of 'Lys-11'-linked polyubiquitin chains and, to a lower extent, the formation of 'Lys-48'- and 'Lys-63'-linked polyubiquitin chains (PubMed:18485873). The APC/C complex catalyzes assembly of branched 'Lys-11'-/'Lys-48'-linked branched ubiquitin chains on target proteins (PubMed:29033132)","subcellular_location":"Nucleus; Cytoplasm, cytoskeleton, spindle","url":"https://www.uniprot.org/uniprotkb/Q9UJX4/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/ANAPC5","classification":"Common Essential","n_dependent_lines":1188,"n_total_lines":1208,"dependency_fraction":0.9834437086092715},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"ANAPC16","stoichiometry":10.0},{"gene":"ANAPC4","stoichiometry":10.0},{"gene":"CDC16","stoichiometry":10.0},{"gene":"CDC23","stoichiometry":10.0},{"gene":"ANAPC2","stoichiometry":4.0},{"gene":"CDC26","stoichiometry":4.0},{"gene":"CDC27","stoichiometry":4.0},{"gene":"FKBP5","stoichiometry":0.2},{"gene":"HIST2H2BE","stoichiometry":0.2},{"gene":"SRP9","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/ANAPC5","total_profiled":1310},"omim":[{"mim_id":"606948","title":"ANAPHASE-PROMOTING COMPLEX, SUBUNIT 5; ANAPC5","url":"https://www.omim.org/entry/606948"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/ANAPC5"},"hgnc":{"alias_symbol":["APC5"],"prev_symbol":[]},"alphafold":{"accession":"Q9UJX4","domains":[{"cath_id":"-","chopping":"31-171","consensus_level":"high","plddt":83.0122,"start":31,"end":171}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UJX4","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UJX4-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UJX4-F1-predicted_aligned_error_v6.png","plddt_mean":81.62},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ANAPC5","jax_strain_url":"https://www.jax.org/strain/search?query=ANAPC5"},"sequence":{"accession":"Q9UJX4","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9UJX4.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9UJX4/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UJX4"}},"corpus_meta":[{"pmid":"21714072","id":"PMC_21714072","title":"Differential immune system DNA methylation and cytokine regulation in post-traumatic stress disorder.","date":"2011","source":"American journal of medical genetics. 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APC5 likely acts as a scaffold connecting the catalytic module (APC2/APC11) with the TPR subunits that recruit co-activators.\",\n      \"method\": \"Biochemical fractionation and reconstitution of human APC subcomplexes; in vitro ubiquitination assays; CDH1 binding assays\",\n      \"journal\": \"Current Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution of subcomplexes with functional ubiquitination and binding assays, replicated in structural studies\",\n      \"pmids\": [\"12956947\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Cryo-EM and mass spectrometry structural analysis of the APC/C places APC5 (along with APC1 and APC4) as a scaffolding subunit that coordinates the juxtaposition of the catalytic module (APC2, APC11, APC10) and TPR subunits, providing a pseudo-atomic model for APC/C organization.\",\n      \"method\": \"Recombinant reconstitution of holo-APC/C; electron microscopy; mass spectrometry; crystallographic docking\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cryo-EM structure with mass spectrometry and crystallographic docking in a single rigorous study, defining APC5 position within the complex\",\n      \"pmids\": [\"21307936\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Crystal structures of Apc4 and the N-terminal domain of Apc5 (Apc5N) were determined; Apc5N adopts an α-helical fold, and in the context of the APC/C, shows small conformational changes and contacts Apc4 to order regions disordered in the crystal.\",\n      \"method\": \"Protein crystallography; fitting into cryo-EM map\",\n      \"journal\": \"Journal of Molecular Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure of Apc5N with cryo-EM validation in single study\",\n      \"pmids\": [\"26343760\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"APC5 (as part of the APC/C platform with APC1, APC4, and APC15) supports the coactivator-induced allosteric conformational change required for UbcH10-dependent ubiquitination; the platform structurally coordinates the catalytic and substrate-recognition modules.\",\n      \"method\": \"Crystal structure of Apc1 WD40 domain; cryo-EM of APC/C-Cdh1 with Apc1 WD40 deletion; in vitro ubiquitination assays\",\n      \"journal\": \"PNAS\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — structure plus in vitro reconstitution and mutagenesis in a single study defining platform role\",\n      \"pmids\": [\"27601667\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"APC5 and APC7 directly interact with transcriptional coactivators CBP and p300 through protein-protein interaction domains evolutionarily conserved in adenovirus E1A; this interaction stimulates intrinsic CBP/p300 acetyltransferase activity and potentiates CBP/p300-dependent transcription.\",\n      \"method\": \"Co-immunoprecipitation; in vitro acetyltransferase assays; reporter gene transcription assays; RNAi knockdown of CBP\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP plus in vitro enzymatic assay plus transcription assay plus functional RNAi, multiple orthogonal methods in one study\",\n      \"pmids\": [\"16319895\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"APC5 and APC7 suppress E1A-mediated cellular transformation in a CBP/p300-dependent manner, indicating these subunits are functionally targeted during cellular transformation.\",\n      \"method\": \"Transformation assay with APC5/APC7 expression in CBP/p300-proficient vs. -deficient contexts\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional cell-based assay, single lab, multiple methods in the same study\",\n      \"pmids\": [\"16319895\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Apc5 binds poly(A) binding protein (PABP) and represses IRES-mediated translation of PDGF-2 mRNA; overexpression of Apc5 counteracts PABP-enhanced IRES activity, and Apc5 co-sediments with the ribosomal fraction, indicating a role outside the APC/C in translational regulation.\",\n      \"method\": \"Yeast three-hybrid screen; co-immunoprecipitation; sucrose gradient sedimentation; IRES reporter assays; overexpression in differentiated cells\",\n      \"journal\": \"Molecular and Cellular Biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast three-hybrid plus Co-IP plus functional IRES assays, single lab\",\n      \"pmids\": [\"15082755\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"APC5 binds E2F1 directly (confirmed by in vivo and in vitro Co-IP/GST pulldown) and is essential for E2F1 ubiquitination by APC/C-Cdh1, which targets E2F1 for K11-linked ubiquitin chain-mediated proteasomal degradation after S phase.\",\n      \"method\": \"Co-immunoprecipitation in vivo and in vitro; GST pulldown mapping; ubiquitination assays with K11-specific ubiquitin\",\n      \"journal\": \"Cell Cycle\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP plus in vitro pulldown plus ubiquitination assay, single lab\",\n      \"pmids\": [\"22580462\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"ANAPC5 binds IL-17RA and IL-17RC and associates with the deubiquitinase A20 (TNFAIP3); siRNA-mediated knockdown of ANAPC5 enhances IL-17-induced gene expression, demonstrating that ANAPC5 acts as a negative regulator of IL-17 signaling.\",\n      \"method\": \"Yeast two-hybrid screen; co-immunoprecipitation; siRNA knockdown with cytokine-stimulated gene expression readout\",\n      \"journal\": \"PLoS ONE\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast two-hybrid plus Co-IP plus siRNA functional assay, single lab\",\n      \"pmids\": [\"23922952\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"During HCMV infection, APC5 and APC4 subunits undergo proteasome-dependent degradation, which is temporally associated with disassembly of the APC/C core complex and requires viral early gene expression (not immediate early genes alone), leading to APC/C inactivation.\",\n      \"method\": \"Immunoblotting; proteasome inhibitor treatment; UV-inactivated and deletion mutant virus infections; phosphatase assays; mass spectrometry\",\n      \"journal\": \"Journal of Virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple viral mutant analyses plus proteasome inhibition, single lab\",\n      \"pmids\": [\"20686030\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"HCMV protein pUL21a physically binds the APC/C and is necessary and sufficient to induce proteasome-dependent degradation of APC5 and APC4, thereby disrupting APC/C integrity; residues P109-R110 of pUL21a are critical for APC binding and APC5/APC4 degradation.\",\n      \"method\": \"Co-immunoprecipitation; expression of pUL21a alone; point mutant virus construction; proteasome inhibitor assays; proteomics\",\n      \"journal\": \"PLoS Pathogens\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP plus point mutant virus plus proteasome inhibitor plus proteomics, multiple orthogonal methods establishing mechanism\",\n      \"pmids\": [\"22792066\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"HCMV protein UL21a also targets APC1 for degradation (in addition to APC4 and APC5); furthermore, depletion of any single platform subunit (APC1, APC4, or APC5) or APC8 triggers coordinated co-degradation of all three platform subunits, revealing a cellular mechanism for platform subunit co-regulation.\",\n      \"method\": \"siRNA knockdown of individual APC subunits; immunoblotting; UL21a expression in uninfected cells\",\n      \"journal\": \"Journal of Virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA knockdown with systematic immunoblotting, single lab, multiple conditions\",\n      \"pmids\": [\"25903336\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"In Drosophila, IDA (the APC5 homolog) is required for APC/C-dependent degradation of cyclin B but not for degradation of substrates controlling sister-chromatid separation; ida mutants display high mitotic index with aneuploid, overcondensed chromosomes, defining a subfunction-specific role for APC5 within the APC/C.\",\n      \"method\": \"Genetic mutant analysis; cytological examination of mitotic stages; immunostaining for APC/C substrate levels\",\n      \"journal\": \"Journal of Cell Science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic loss-of-function with substrate-level readouts distinguishing APC/C subfunctions, single study\",\n      \"pmids\": [\"11870214\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Yeast Apc5 physically interacts with Cdc23 and Apc1 in co-expression in vitro transcription/translation; yeast two-hybrid and co-purification experiments confirmed Mnd2 and Swm1 interact with Apc5 and Cdc23 as core APC subunits.\",\n      \"method\": \"In vitro transcription/translation co-expression; mass spectrometry identification; co-purification with epitope-tagged subunits\",\n      \"journal\": \"Journal of Biological Chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro co-expression interaction plus co-purification, single lab\",\n      \"pmids\": [\"12609981\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"In yeast, APC5 (RMC1) is required for in vitro chromatin assembly; apc5 mutants display UV sensitivity, plasmid loss, G2/M accumulation, and genetic interactions with apc9Δ, apc10Δ, and cdc26Δ, linking APC5 function to chromatin metabolism and APC complex integrity.\",\n      \"method\": \"In vitro chromatin assembly screen; genetic epistasis analysis; phenotypic characterization of ts mutants\",\n      \"journal\": \"Genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro chromatin assembly assay plus genetic interaction analysis, single lab\",\n      \"pmids\": [\"12399376\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"The APC (via Apc5) targets Fob1 for degradation specifically in G1; Fob1 is unstable in G1, stabilized in apc5(CA) and proteasome mutants, and Fob1 deletion suppresses apc5(CA) cell cycle and rDNA recombination defects, placing APC5-dependent Fob1 degradation in a pathway linking APC to replicative longevity and genomic stability.\",\n      \"method\": \"Yeast two-hybrid (Apc5 as bait, Fob1 as prey); protein stability assays; genetic epistasis; rDNA recombination assays\",\n      \"journal\": \"Genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast two-hybrid plus protein stability plus genetic epistasis, single lab\",\n      \"pmids\": [\"24361936\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Fission yeast Atf1 physically binds the APC/C in vivo; purified Atf1 stimulates ubiquitylation of cyclin B and securin by the APC/C in a cell-free system, independent of Atf1's DNA-binding (bZIP) domain; atf1+ is a dose-dependent suppressor of apc5-1 mitotic arrest.\",\n      \"method\": \"Genetic suppressor analysis; co-immunoprecipitation; cell-free APC/C ubiquitination assay with purified Atf1\",\n      \"journal\": \"Journal of Biological Chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstituted ubiquitination assay plus Co-IP plus genetic suppressor, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"19584054\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"In C. elegans, SUCH-1/APC5 is required for normal mitotic timing; a novel such-1(t1668) allele causes prolonged mitosis in embryos with monopolar spindles, and this delay is SAC-dependent (rescued by mdf-1/MAD1 or mdf-2/MAD2 inactivation), suggesting the APC/C negatively regulates the SAC.\",\n      \"method\": \"Genetic characterization of new allele; time-lapse imaging; epistasis with SAC components by RNAi\",\n      \"journal\": \"Genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — live imaging plus genetic epistasis, single lab\",\n      \"pmids\": [\"20944014\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"C. elegans has two APC5 paralogs (such-1 and gfi-3) that are coexpressed in the germline; co-depletion (but not individual depletion) causes meiotic arrest, demonstrating functionally redundant roles for APC5 paralogs in meiosis.\",\n      \"method\": \"RNAi co-depletion; germline expression analysis; phenotypic characterization of meiotic arrest\",\n      \"journal\": \"Genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNAi genetic analysis with meiotic phenotype readout, single lab\",\n      \"pmids\": [\"20944012\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Co-depletion of ANAPC5 in cell lines exacerbates KIF18A-depletion-induced mitotic arrest, whereas co-depletion of ANAPC7 partially rescues this arrest, indicating opposing roles for ANAPC5 and ANAPC7 in modulating mitotic progression downstream of KIF18A.\",\n      \"method\": \"siRNA co-depletion in cell lines; mitotic arrest quantification by flow cytometry and microscopy\",\n      \"journal\": \"Scientific Reports / bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA co-depletion with phenotypic readout, published in peer-reviewed journal and preprint, single lab\",\n      \"pmids\": [\"39677807\", \"40596695\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Radiation inhibits the APC/C complex, reducing ANAPC5-mediated ubiquitination of GPAA1 (a catalytic subunit of GPI transamidase); the resulting accumulation of GPAA1 enhances GPI anchoring and CD24 membrane localization, promoting phagocytosis resistance and immune evasion in irradiated tumor cells.\",\n      \"method\": \"ANAPC5 knockdown/overexpression; ubiquitination assays; flow cytometry for CD24 surface expression; in vivo tumor models with T cell and macrophage depletion\",\n      \"journal\": \"Cancer Research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ubiquitination assay plus functional in vivo rescue experiments, single lab\",\n      \"pmids\": [\"41512182\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ANAPC5 overexpression in macrophages induces ubiquitination and suppression of EGFR, thereby promoting M2 macrophage polarization over M1; this effect is mediated through the EGFR/CD24 axis, and ANAPC5 overexpression reduces lung inflammation in an LPS-induced ALI mouse model.\",\n      \"method\": \"ANAPC5 overexpression in vitro and in vivo; ubiquitination assays; EGFR inhibitor rescue; ALI mouse model with pathological and cytokine analysis\",\n      \"journal\": \"Cellular Immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ubiquitination assay plus in vivo model plus rescue experiments, single lab\",\n      \"pmids\": [\"40834712\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ANAPC5 (APC5) is a core scaffolding subunit of the APC/C E3 ubiquitin ligase that, together with APC1 and APC4, forms the platform subcomplex bridging the catalytic module (APC2/APC11) with the TPR co-activator-binding subunits; beyond its structural role, APC5 directly binds substrates (e.g., E2F1) and regulatory proteins (e.g., Fob1, Atf1) to facilitate ubiquitination, interacts with CBP/p300 to stimulate acetyltransferase activity and transcription, binds poly(A)-binding protein to repress IRES-mediated translation, and associates with IL-17 receptors and A20 to negatively regulate IL-17 signaling, while also serving as an E3 that ubiquitinates EGFR and GPAA1 to modulate macrophage polarization and immune evasion.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ANAPC5 (APC5) is a core scaffolding subunit of the anaphase-promoting complex/cyclosome (APC/C), the multisubunit E3 ubiquitin ligase that targets cell-cycle regulators for proteasomal degradation [#0]. Together with APC1 and APC4, APC5 builds the platform subcomplex that bridges the catalytic module (APC2/APC11/APC10) to the TPR co-activator-binding subunits; this subcomplex assembles polyubiquitin chains but cannot itself bind CDH1 or ubiquitinate substrates, marking its role as structural rather than catalytic [#1, #2]. Structural work resolved the APC5 N-terminal α-helical fold and its contacts with APC4, and showed that the platform supports the coactivator-induced allosteric change required for UbcH10-dependent ubiquitination [#3, #4]. Within the complex, APC5 directly binds substrates such as E2F1, mediating its K11-linked ubiquitination and degradation after S phase [#8], and genetic studies across organisms reveal substrate-selective contributions: Drosophila IDA/APC5 is required for cyclin B degradation but not sister-chromatid separation [#13], and C. elegans SUCH-1/APC5 governs SAC-dependent mitotic timing with a redundant paralog acting in meiosis [#18, #19]. Beyond the APC/C, APC5 engages CBP/p300 to stimulate their acetyltransferase activity and transcription and to suppress E1A-mediated transformation [#5], binds poly(A)-binding protein to repress IRES-mediated translation [#7], and negatively regulates IL-17 signaling through association with IL-17 receptors and the deubiquitinase A20 [#9]. APC5 is also a target of viral subversion: HCMV pUL21a binds the APC/C and drives proteasomal degradation of APC5 (and APC4/APC1) to inactivate the complex [#10, #11]. More recent work implicates ANAPC5-mediated ubiquitination of GPAA1 and EGFR in tumor immune evasion and macrophage polarization [#21, #22].\"\n,\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"Established APC5 as a bona fide subunit of the APC/C, defining its membership in the cell-cycle ubiquitin ligase before any mechanistic role was known.\",\n      \"evidence\": \"Biochemical purification and cloning of human APC subunits\",\n      \"pmids\": [\"9469815\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not assign a specific function to APC5 within the complex\", \"No structural placement\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Answered whether APC5 is catalytic or structural by reconstituting an APC1/APC4/APC5 subcomplex that builds ubiquitin chains but cannot bind CDH1 or ubiquitinate substrates, defining APC5 as a scaffold bridging the catalytic and co-activator-recruiting modules.\",\n      \"evidence\": \"Biochemical fractionation, subcomplex reconstitution, in vitro ubiquitination and CDH1 binding assays\",\n      \"pmids\": [\"12956947\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No atomic-resolution view of contacts\", \"Mechanism of coactivator-induced activation unresolved\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Placed APC5 spatially within the holo-complex, showing it coordinates juxtaposition of the catalytic module and TPR subunits in a pseudo-atomic model.\",\n      \"evidence\": \"Cryo-EM, mass spectrometry and crystallographic docking of reconstituted APC/C\",\n      \"pmids\": [\"21307936\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Limited resolution of APC5 internal architecture\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Resolved the APC5 N-terminal fold and its APC4 contacts, refining the structural basis of platform assembly.\",\n      \"evidence\": \"Crystallography of Apc4 and Apc5N fitted into cryo-EM\",\n      \"pmids\": [\"26343760\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full-length APC5 structure not determined\", \"Functional consequence of conformational changes untested\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Defined how the APC5-containing platform contributes to catalysis by supporting the coactivator-induced allosteric change required for UbcH10-dependent ubiquitination.\",\n      \"evidence\": \"Crystal structure of Apc1 WD40, cryo-EM of APC/C-Cdh1, and in vitro ubiquitination assays\",\n      \"pmids\": [\"27601667\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"APC5-specific contribution not isolated from APC1/APC4\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Revealed an APC/C-independent role by showing APC5 (with APC7) binds CBP/p300 to stimulate acetyltransferase activity, potentiate transcription, and suppress E1A-mediated transformation.\",\n      \"evidence\": \"Reciprocal Co-IP, in vitro acetyltransferase and reporter assays, RNAi, and transformation assays\",\n      \"pmids\": [\"16319895\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether this occurs within or independent of assembled APC/C unclear\", \"Physiological transcriptional targets not mapped\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Identified APC5 as a translational regulator that binds PABP and represses IRES-mediated translation, expanding its function beyond ubiquitination.\",\n      \"evidence\": \"Yeast three-hybrid, Co-IP, sucrose gradient sedimentation, and IRES reporter assays\",\n      \"pmids\": [\"15082755\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Generality across IRES-containing mRNAs untested\", \"Mechanism of translational repression unresolved\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Showed APC5 directly binds E2F1 and is required for its K11-linked ubiquitination and S-phase-coupled degradation, identifying a specific substrate-recognition contribution.\",\n      \"evidence\": \"In vivo/in vitro Co-IP, GST pulldown mapping, K11-specific ubiquitination assays\",\n      \"pmids\": [\"22580462\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Whether APC5 is a dedicated substrate receptor or adaptor unclear\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identified APC5 as a negative regulator of IL-17 signaling through binding IL-17RA/RC and the deubiquitinase A20.\",\n      \"evidence\": \"Yeast two-hybrid, Co-IP, and siRNA knockdown with cytokine-stimulated gene expression\",\n      \"pmids\": [\"23922952\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Whether ubiquitin ligase activity is involved unclear\", \"No in vivo validation\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Demonstrated that APC5 is a target of viral attack, undergoing proteasomal degradation during HCMV infection coincident with APC/C disassembly.\",\n      \"evidence\": \"Immunoblotting, proteasome inhibition, viral mutant infections, phosphatase assays, MS\",\n      \"pmids\": [\"20686030\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Viral effector not yet identified at this stage\", \"Direct vs. indirect degradation unresolved\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identified HCMV pUL21a as the effector that binds the APC/C and is necessary and sufficient to degrade APC5/APC4, defining the mechanism of viral APC/C inactivation.\",\n      \"evidence\": \"Co-IP, pUL21a expression alone, point-mutant virus, proteasome inhibitor assays, proteomics\",\n      \"pmids\": [\"22792066\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Ubiquitin ligase responsible for degradation not identified\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Revealed co-regulation of platform subunits: loss of any single platform subunit (APC1/APC4/APC5) triggers co-degradation of all three, and pUL21a also targets APC1.\",\n      \"evidence\": \"siRNA knockdown of individual subunits, immunoblotting, UL21a expression\",\n      \"pmids\": [\"25903336\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Mechanism sensing platform integrity unknown\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Defined cross-organism substrate roles: yeast Apc5 interacts with core subunits and targets Fob1 for G1-specific degradation linking APC5 to genomic stability and longevity.\",\n      \"evidence\": \"Yeast two-hybrid, protein stability assays, genetic epistasis, rDNA recombination assays (with prior subunit-interaction co-purification)\",\n      \"pmids\": [\"24361936\", \"12609981\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Conservation of Fob1-like substrates in metazoans unknown\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Showed fission yeast Atf1 binds and stimulates APC/C ubiquitylation of cyclin B and securin independent of its DNA-binding domain and suppresses apc5-1 arrest, revealing a regulatory protein acting through APC5.\",\n      \"evidence\": \"Genetic suppressor analysis, Co-IP, cell-free APC/C ubiquitination with purified Atf1\",\n      \"pmids\": [\"19584054\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether contact is on APC5 itself or another subunit not pinpointed\", \"Human ortholog relevance untested\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Genetically distinguished APC5 functions in animal mitosis and meiosis, including SAC-dependent mitotic timing and redundant paralog roles in the germline.\",\n      \"evidence\": \"C. elegans allele characterization, time-lapse imaging, RNAi epistasis and co-depletion (with Drosophila ida mutant analysis)\",\n      \"pmids\": [\"20944014\", \"20944012\", \"11870214\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-organism findings\", \"Molecular basis of substrate selectivity unresolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Showed opposing roles for ANAPC5 and ANAPC7 in modulating mitotic progression downstream of KIF18A.\",\n      \"evidence\": \"siRNA co-depletion in cell lines with flow-cytometric and microscopic mitotic-arrest quantification\",\n      \"pmids\": [\"39677807\", \"40596695\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Mechanistic basis for opposing effects unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Linked ANAPC5 to immune regulation by showing its overexpression ubiquitinates and suppresses EGFR to drive M2 macrophage polarization via the EGFR/CD24 axis.\",\n      \"evidence\": \"Overexpression in vitro/in vivo, ubiquitination assays, EGFR inhibitor rescue, ALI mouse model\",\n      \"pmids\": [\"40834712\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Whether EGFR is a direct APC/C substrate unclear\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Connected radiation-induced APC/C inhibition to immune evasion via loss of ANAPC5-mediated GPAA1 ubiquitination, stabilizing GPAA1 and enhancing CD24 surface display and phagocytosis resistance.\",\n      \"evidence\": \"ANAPC5 knockdown/overexpression, ubiquitination assays, CD24 flow cytometry, in vivo tumor models with immune cell depletion\",\n      \"pmids\": [\"41512182\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Direct vs. indirect ubiquitination of GPAA1 not fully established\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How APC5's structural scaffolding role is mechanistically partitioned from its multiple moonlighting activities (transcription, translation, immune signaling, non-cell-cycle substrate targeting) remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural basis for direct substrate binding by APC5 within the assembled complex\", \"Whether moonlighting functions require free vs. complex-bound APC5 untested\", \"Human in vivo physiological relevance of non-mitotic roles largely undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [8, 21, 22]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [1, 2]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [1, 2, 3, 4]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [5, 9]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005840\", \"supporting_discovery_ids\": [7]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [0, 1, 8, 13, 18]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 1, 8]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [9, 21, 22]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"complexes\": [\"APC/C (anaphase-promoting complex/cyclosome)\"],\n    \"partners\": [\"ANAPC1\", \"ANAPC4\", \"ANAPC7\", \"E2F1\", \"CREBBP\", \"EP300\", \"PABP\", \"TNFAIP3\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":7,"faith_pct":85.71428571428571}}