{"gene":"YPEL5","run_date":"2026-06-11T09:02:06","timeline":{"discoveries":[{"year":2010,"finding":"YPEL5 protein localizes to the nucleus and centrosome during interphase, then sequentially to spindle poles, mitotic spindle, spindle midzone during mitosis, and finally to the midbody at cytokinesis. Knockdown of YPEL5 by siRNA or antisense morpholino oligonucleotide inhibited growth of cultured COS-7 cells and early development of medaka fish embryos, establishing its role in cell cycle progression.","method":"Immunofluorescence/subcellular fractionation for localization; siRNA knockdown and antisense morpholino oligonucleotide for functional studies in COS-7 cells and medaka embryos","journal":"Genomics","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct localization experiments tied to functional consequence, loss-of-function with specific phenotypic readouts in two independent model systems (cell line + vertebrate embryo)","pmids":["20580816"],"is_preprint":false},{"year":2010,"finding":"YPEL5 physically interacts with RanBPM (encoded by RANBP9) and its paralog RanBP10 (encoded by RANBP10), identifying them as YPEL5-binding proteins and placing YPEL5 within a complex with these Scorpin-family proteins.","method":"Yeast two-hybrid screen","journal":"Genomics","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — yeast two-hybrid interaction, single lab, but later corroborated by structural/biochemical work on CTLH complex containing these subunits","pmids":["20580816"],"is_preprint":false},{"year":2004,"finding":"YPEL5 protein localizes to the centrosome and nucleus during interphase and to the mitotic spindle during mitosis in COS-7 cells, distinct from YPEL1-4 which localize to centrosome and nucleolus during interphase and dot-like structures around the mitotic apparatus during mitosis.","method":"Indirect immunofluorescent staining in COS-7 cells","journal":"Gene","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — direct immunofluorescence localization, replicated in subsequent study (PMID:20580816)","pmids":["15556292"],"is_preprint":false},{"year":2016,"finding":"YPEL5 acts as a negative regulator of IFNB1 production and innate immune responses by physically interacting with the non-canonical IKK kinase IKBKE (and functionally with TBK1). YPEL5 silencing in human HEK293T cells enhanced IFNB1 induction by pattern recognition receptors and increased phosphorylation of TBK1/IKBKE kinases.","method":"Co-immunoprecipitation for physical interaction; siRNA knockdown with IFNB1 induction and TBK1/IKBKE phosphorylation as functional readouts in HEK293T cells and mouse macrophage cell lines","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — reciprocal co-IP plus functional loss-of-function with defined molecular readout, single lab","pmids":["27705791"],"is_preprint":false},{"year":2017,"finding":"Human YPEL5 is functionally conserved with yeast Moh1 (the yeast ortholog) in promoting apoptosis. Expression of YPEL5 in a moh1Δ yeast mutant rescued UV-induced apoptotic events (Annexin V stainability, mitochondrial membrane potential loss, metacaspase activation), demonstrating YPEL5 involvement in mitochondria-dependent apoptosis induced by DNA damage.","method":"Yeast complementation assay; functional complementation of moh1Δ mutant with human YPEL5; FITC-Annexin V staining, mitochondrial membrane potential assay, metacaspase activation assay","journal":"Journal of microbiology and biotechnology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis via functional complementation with multiple orthogonal apoptosis readouts, single lab","pmids":["28173693"],"is_preprint":false},{"year":2021,"finding":"METTL3 epigenetically represses YPEL5 expression in an m6A-YTHDF2-dependent manner by targeting the m6A site in the coding sequence region of the YPEL5 transcript. Overexpression of YPEL5 reduced CCNB1 and PCNA expression in colorectal cancer cells.","method":"m6A sequencing, METTL3 knockdown/overexpression, YTHDF2 interaction studies, YPEL5 overexpression with CCNB1/PCNA protein level readouts in CRC cells","journal":"Molecular oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (m6A-seq, functional KD/OE, downstream protein readouts), single lab","pmids":["33411363"],"is_preprint":false},{"year":2024,"finding":"YPEL5 is a subunit of the CTLH E3 ubiquitin ligase complex and inhibits NMNAT1 ubiquitylation and cellular turnover by WDR26-CTLH E3. The N-terminus of YPEL5 mimics the degron of NMNAT1 (degron mimicry), thereby antagonizing substrate binding to WDR26. Cryo-EM structures of NMNAT1-bound and YPEL5-bound WDR26-CTLH E3 complexes revealed the structural basis of this competition.","method":"Cryo-EM structure determination; in vitro ubiquitylation assays; cellular turnover assays; degron mutagenesis","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — cryo-EM structures combined with in vitro reconstitution of ubiquitylation, mutagenesis of degron, and cellular turnover assays in a single rigorous study","pmids":["38759627"],"is_preprint":false},{"year":2024,"finding":"WDR26 mediates CTLH E3 complex binding to YPEL5; SKDEAS-associated WDR26 mutations impair this interaction and disrupt CTLH E3 supramolecular assembly, providing mechanistic insight into how YPEL5 is retained in the complex.","method":"Complementation studies in genetically engineered human cells lacking CTLH E3 supramolecular assemblies; structural modeling of WDR26 mutation positions","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional complementation in engineered cells with multiple mutants tested, single lab, structural modeling but not full structure determination","pmids":["38575527"],"is_preprint":false},{"year":2024,"finding":"YPEL5 (as part of the GID/CTLH complex) suppresses host anti-microbial defenses in macrophages; knockout of YPEL5 (among other CTLH members) enhanced anti-mycobacterial and anti-Salmonella activity via enhanced GABAergic signaling, activated AMPK, increased autophagic flux, and resistance to Mtb-induced necrotic cell death.","method":"FACS-based genome-wide CRISPR screen; CRISPR knockout macrophages with intracellular bacterial growth and cell death as functional readouts","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genome-wide CRISPR screen with defined mechanistic pathway readouts, peer-reviewed; YPEL5-specific role confirmed within complex context","pmids":["39472457"],"is_preprint":false},{"year":2023,"finding":"In zebrafish, ypel5 knockout (CRISPR/Cas9) causes liver enlargement associated with hepatic cell proliferation and dysregulated hepatic metabolism. Mechanistically, Ypel5 positively regulates Hnf4a expression via PPARα signaling, which directly binds the transcriptional enhancer of the Hnf4a gene. Zebrafish hnf4a overexpression largely rescued ypel5 deficiency-induced hepatic defects.","method":"CRISPR/Cas9 knockout in zebrafish; metabolomic and transcriptomic analyses; epistasis rescue by hnf4a overexpression; PPARα binding to Hnf4a enhancer","journal":"Journal of molecular cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo KO with specific cellular phenotype, pathway placement by genetic rescue, and mechanistic pathway (PPARα→Hnf4a) supported by multiple orthogonal methods","pmids":["36948605"],"is_preprint":false},{"year":2013,"finding":"A recurrent YPEL5/PPP1CB RNA chimera detected in CLL encodes a truncated PPP1CB protein with diminished phosphatase activity; PPP1CB silencing enhanced proliferation and colony formation of MEC1 and JVM3 CLL cells, linking the chimera to CLL pathogenesis.","method":"Paired-end transcriptome sequencing; qRT-PCR; whole-genome sequencing and Southern blotting to exclude genomic fusion; in vitro phosphatase activity assay; siRNA knockdown with proliferation and colony formation readouts","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods establishing chimera production and functional consequence, single lab; note later contradicted by PMID:26605151 showing the fusion is not CLL-specific","pmids":["23382248"],"is_preprint":false},{"year":2026,"finding":"YPEL5's basic pocket within the CTLH complex can recruit substrates bearing acidic degrons; a sulfinic acid-containing molecular glue (ZZ1) binds this basic pocket in YPEL5 and promotes cooperative binding between CTLH E3 and BET-family proteins, demonstrating a substrate-recruitment capacity for YPEL5 that is distinct from its previously described degron-mimicry/inhibitory role.","method":"Cryo-EM/structural determination; biochemical binding assays; cellular degradation assays with molecular glue ZZ1","journal":"Nature chemical biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — structural determination plus biochemical reconstitution of substrate recruitment via YPEL5 basic pocket, with functional validation of degradation","pmids":["41942733"],"is_preprint":false},{"year":2026,"finding":"Oocyte-specific conditional knockout of Ypel5 in mice causes complete female infertility due to accelerated depletion of the primordial follicle pool, defective antral follicle formation, and impaired oocyte maturation. Mechanistically, Ypel5 loss results in increased DNA damage, disrupted mitochondrial homeostasis, elevated oxidative stress, apoptotic depletion of primordial follicle oocytes, and severe spindle assembly and mitochondrial distribution abnormalities in oocytes.","method":"Oocyte-specific conditional knockout mouse model; phenotypic analysis of folliculogenesis and oocyte maturation; DNA damage markers; mitochondrial homeostasis assays; spindle organization imaging","journal":"Cell death and differentiation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO with specific cellular and molecular phenotypic readouts, single lab, multiple orthogonal assays but no epistasis rescue","pmids":["42086779"],"is_preprint":false}],"current_model":"YPEL5 is a conserved eukaryotic protein that functions as an integral subunit of the CTLH/GID E3 ubiquitin ligase complex, where its N-terminus acts as a degron mimic to inhibit WDR26-mediated substrate (NMNAT1) ubiquitylation—a role whose basic pocket can alternatively recruit acidic-degron substrates via molecular glues—while outside the complex YPEL5 localizes dynamically to centrosomes, spindle poles, and midbody to support cell cycle progression, physically interacts with IKBKE/TBK1 to negatively regulate IFNB1-mediated innate immune signaling, and in vivo regulates liver metabolism via a PPARα–Hnf4a axis and is essential for oocyte maturation and female fertility."},"narrative":{"mechanistic_narrative":"YPEL5 is a conserved eukaryotic protein that operates both as a regulatory subunit of the CTLH/GID E3 ubiquitin ligase and as a cell cycle-associated factor at microtubule-organizing structures [PMID:20580816, PMID:38759627]. Within the CTLH complex, YPEL5 is retained through WDR26, and its N-terminus mimics the NMNAT1 degron to competitively block WDR26-mediated NMNAT1 ubiquitylation and turnover, an inhibitory mechanism resolved by cryo-EM of NMNAT1- and YPEL5-bound WDR26-CTLH assemblies [PMID:38759627, PMID:38575527]. The same basic pocket in YPEL5 can instead serve as a substrate-recruitment surface, engaging acidic-degron proteins when bridged by a sulfinic acid-containing molecular glue that drives cooperative binding of CTLH E3 to BET-family proteins [PMID:41942733]. Independently, YPEL5 localizes dynamically through the cell cycle—to the nucleus and centrosome in interphase and to spindle poles, the spindle midzone, and the midbody during mitosis and cytokinesis—and its depletion impairs proliferation and embryonic development [PMID:20580816, PMID:15556292]. YPEL5 also negatively regulates innate immunity by physically interacting with IKBKE and functionally with TBK1 to restrain IFNB1 production [PMID:27705791], and acts in vivo as a metabolic and developmental regulator: zebrafish ypel5 controls hepatic metabolism through a PPARα–Hnf4a axis [PMID:36948605], while oocyte-specific loss in mice causes female infertility with defective folliculogenesis, spindle assembly, and mitochondrial homeostasis [PMID:42086779].","teleology":[{"year":2004,"claim":"Established the basic cell-biological behavior of YPEL5 by showing it occupies distinct subcellular sites across the cell cycle, separating it from the YPEL1-4 paralogs.","evidence":"Indirect immunofluorescence in COS-7 cells","pmids":["15556292"],"confidence":"Medium","gaps":["No functional consequence of localization tested","No interacting partners identified"]},{"year":2010,"claim":"Connected YPEL5 localization to function, demonstrating that loss disrupts cell cycle progression and development, and identified its first physical partners.","evidence":"Immunofluorescence and siRNA/morpholino knockdown in COS-7 cells and medaka embryos; yeast two-hybrid screen identifying RanBPM (RANBP9) and RanBP10","pmids":["20580816"],"confidence":"High","gaps":["RANBP9/RANBP10 interaction is yeast two-hybrid only, not validated in mammalian cells","Mechanism linking localization to proliferation undefined"]},{"year":2013,"claim":"Documented a YPEL5/PPP1CB RNA chimera in CLL, raising the possibility that the locus contributes to malignancy, though the functional defect mapped to truncated PPP1CB rather than YPEL5.","evidence":"Transcriptome sequencing, phosphatase assays, and siRNA proliferation readouts in CLL cell lines","pmids":["23382248"],"confidence":"Medium","gaps":["Functional consequence attributed to PPP1CB truncation, not YPEL5","Chimera later reported not to be CLL-specific"]},{"year":2016,"claim":"Defined a signaling role for YPEL5 as a negative regulator of innate immunity through direct association with the non-canonical IKK kinase machinery.","evidence":"Reciprocal co-IP with IKBKE and siRNA knockdown with IFNB1 induction and TBK1/IKBKE phosphorylation readouts in HEK293T and macrophage lines","pmids":["27705791"],"confidence":"Medium","gaps":["Single lab","Whether this depends on CTLH complex membership not addressed","No structural basis for IKBKE binding"]},{"year":2017,"claim":"Demonstrated cross-species functional conservation by showing human YPEL5 substitutes for yeast Moh1 in DNA-damage-induced apoptosis.","evidence":"Functional complementation of moh1Δ yeast with human YPEL5 and apoptosis readouts","pmids":["28173693"],"confidence":"Medium","gaps":["Pro-apoptotic mechanism in human cells not defined","Molecular partners in apoptosis unknown"]},{"year":2021,"claim":"Placed YPEL5 expression under m6A epigenetic control and tied its overexpression to suppression of proliferation markers in cancer cells.","evidence":"m6A-seq, METTL3 knockdown/overexpression, YTHDF2 studies, and YPEL5 overexpression with CCNB1/PCNA readouts in colorectal cancer cells","pmids":["33411363"],"confidence":"Medium","gaps":["Direct mechanism linking YPEL5 to CCNB1/PCNA reduction unknown","Single lab"]},{"year":2023,"claim":"Established an in vivo metabolic function, defining a PPARα→Hnf4a regulatory axis through which YPEL5 controls hepatic metabolism and proliferation.","evidence":"CRISPR/Cas9 ypel5 knockout in zebrafish with metabolomics, transcriptomics, and hnf4a overexpression rescue","pmids":["36948605"],"confidence":"High","gaps":["How YPEL5 protein activates PPARα signaling mechanistically unclear","Connection to CTLH E3 function not addressed"]},{"year":2024,"claim":"Resolved YPEL5's defining biochemical role as a CTLH E3 subunit whose N-terminal degron mimicry competitively inhibits WDR26-mediated NMNAT1 ubiquitylation, and showed WDR26 is required to retain YPEL5 in the complex.","evidence":"Cryo-EM structures, in vitro ubiquitylation and cellular turnover assays with degron mutagenesis; complementation in CTLH-deficient cells with WDR26 disease mutants","pmids":["38759627","38575527"],"confidence":"High","gaps":["Full repertoire of substrates antagonized by YPEL5 unknown","Whether degron mimicry operates on substrates other than NMNAT1 untested"]},{"year":2024,"claim":"Connected the CTLH-resident YPEL5 to host defense, showing its loss enhances anti-bacterial activity through GABAergic signaling, AMPK activation, and autophagy.","evidence":"Genome-wide CRISPR screen and CRISPR knockout macrophages with intracellular bacterial growth and cell death readouts","pmids":["39472457"],"confidence":"Medium","gaps":["YPEL5-specific contribution within the complex not isolated","Direct substrate driving the antimicrobial phenotype not identified"]},{"year":2026,"claim":"Revealed a substrate-recruitment capacity for YPEL5 distinct from its inhibitory role, showing its basic pocket can engage acidic degrons and be co-opted by a molecular glue to recruit BET proteins for degradation.","evidence":"Cryo-EM/structural determination, biochemical binding, and cellular degradation assays with molecular glue ZZ1","pmids":["41942733"],"confidence":"High","gaps":["Endogenous acidic-degron substrates recruited by the basic pocket unknown","Physiological versus glue-induced recruitment not distinguished"]},{"year":2026,"claim":"Demonstrated an essential in vivo role in reproduction, with oocyte-specific loss causing infertility through follicle depletion, DNA damage, oxidative stress, and spindle/mitochondrial defects.","evidence":"Oocyte-specific conditional knockout mouse with folliculogenesis, DNA damage, mitochondrial, and spindle imaging readouts","pmids":["42086779"],"confidence":"Medium","gaps":["No epistasis rescue to assign causality","Whether phenotype reflects CTLH E3 function or its mitotic localization role untested"]},{"year":null,"claim":"How YPEL5's distinct activities—CTLH-resident ubiquitylation control, mitotic localization, innate-immune signaling, and metabolic/reproductive regulation—are integrated within a single protein remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model linking complex membership to localization-dependent roles","Endogenous substrate spectrum incompletely defined","Mechanistic basis of IKBKE and PPARα regulation not structurally resolved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[6,11]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[6,11,3]}],"localization":[{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[0,2]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,2]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[6,11]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[0]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[3,8]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[9]}],"complexes":["CTLH/GID E3 ubiquitin ligase complex"],"partners":["WDR26","NMNAT1","IKBKE","TBK1","RANBP9","RANBP10"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P62699","full_name":"Protein yippee-like 5","aliases":[],"length_aa":121,"mass_kda":13.8,"function":"Component of the CTLH E3 ubiquitin-protein ligase complex that selectively accepts ubiquitin from UBE2H and mediates ubiquitination and subsequent proteasomal degradation of the transcription factor HBP1 (PubMed:29911972). Required for normal cell proliferation (By similarity)","subcellular_location":"Nucleus; Cytoplasm, cytoskeleton, microtubule organizing center, centrosome; Cytoplasm, cytoskeleton, spindle pole; Midbody","url":"https://www.uniprot.org/uniprotkb/P62699/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/YPEL5","classification":"Common Essential","n_dependent_lines":941,"n_total_lines":1208,"dependency_fraction":0.7789735099337748},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"RANBP9","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/YPEL5","total_profiled":1310},"omim":[{"mim_id":"609726","title":"YIPPEE-LIKE 5; YPEL5","url":"https://www.omim.org/entry/609726"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Cytosol","reliability":"Approved"},{"location":"Nucleoplasm","reliability":"Additional"}],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"bone 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biology","url":"https://pubmed.ncbi.nlm.nih.gov/38766174","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":14192,"output_tokens":3531,"usd":0.047771,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11103,"output_tokens":3792,"usd":0.075158,"stage2_stop_reason":"end_turn"},"total_usd":0.122929,"stage1_batch_id":"msgbatch_01UT1AahFPCAyn2uVweS7A9z","stage2_batch_id":"msgbatch_01HuKWtKNT4Pqj1bc8eEP5RV","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2010,\n      \"finding\": \"YPEL5 protein localizes to the nucleus and centrosome during interphase, then sequentially to spindle poles, mitotic spindle, spindle midzone during mitosis, and finally to the midbody at cytokinesis. Knockdown of YPEL5 by siRNA or antisense morpholino oligonucleotide inhibited growth of cultured COS-7 cells and early development of medaka fish embryos, establishing its role in cell cycle progression.\",\n      \"method\": \"Immunofluorescence/subcellular fractionation for localization; siRNA knockdown and antisense morpholino oligonucleotide for functional studies in COS-7 cells and medaka embryos\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct localization experiments tied to functional consequence, loss-of-function with specific phenotypic readouts in two independent model systems (cell line + vertebrate embryo)\",\n      \"pmids\": [\"20580816\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"YPEL5 physically interacts with RanBPM (encoded by RANBP9) and its paralog RanBP10 (encoded by RANBP10), identifying them as YPEL5-binding proteins and placing YPEL5 within a complex with these Scorpin-family proteins.\",\n      \"method\": \"Yeast two-hybrid screen\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — yeast two-hybrid interaction, single lab, but later corroborated by structural/biochemical work on CTLH complex containing these subunits\",\n      \"pmids\": [\"20580816\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"YPEL5 protein localizes to the centrosome and nucleus during interphase and to the mitotic spindle during mitosis in COS-7 cells, distinct from YPEL1-4 which localize to centrosome and nucleolus during interphase and dot-like structures around the mitotic apparatus during mitosis.\",\n      \"method\": \"Indirect immunofluorescent staining in COS-7 cells\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — direct immunofluorescence localization, replicated in subsequent study (PMID:20580816)\",\n      \"pmids\": [\"15556292\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"YPEL5 acts as a negative regulator of IFNB1 production and innate immune responses by physically interacting with the non-canonical IKK kinase IKBKE (and functionally with TBK1). YPEL5 silencing in human HEK293T cells enhanced IFNB1 induction by pattern recognition receptors and increased phosphorylation of TBK1/IKBKE kinases.\",\n      \"method\": \"Co-immunoprecipitation for physical interaction; siRNA knockdown with IFNB1 induction and TBK1/IKBKE phosphorylation as functional readouts in HEK293T cells and mouse macrophage cell lines\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — reciprocal co-IP plus functional loss-of-function with defined molecular readout, single lab\",\n      \"pmids\": [\"27705791\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Human YPEL5 is functionally conserved with yeast Moh1 (the yeast ortholog) in promoting apoptosis. Expression of YPEL5 in a moh1Δ yeast mutant rescued UV-induced apoptotic events (Annexin V stainability, mitochondrial membrane potential loss, metacaspase activation), demonstrating YPEL5 involvement in mitochondria-dependent apoptosis induced by DNA damage.\",\n      \"method\": \"Yeast complementation assay; functional complementation of moh1Δ mutant with human YPEL5; FITC-Annexin V staining, mitochondrial membrane potential assay, metacaspase activation assay\",\n      \"journal\": \"Journal of microbiology and biotechnology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis via functional complementation with multiple orthogonal apoptosis readouts, single lab\",\n      \"pmids\": [\"28173693\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"METTL3 epigenetically represses YPEL5 expression in an m6A-YTHDF2-dependent manner by targeting the m6A site in the coding sequence region of the YPEL5 transcript. Overexpression of YPEL5 reduced CCNB1 and PCNA expression in colorectal cancer cells.\",\n      \"method\": \"m6A sequencing, METTL3 knockdown/overexpression, YTHDF2 interaction studies, YPEL5 overexpression with CCNB1/PCNA protein level readouts in CRC cells\",\n      \"journal\": \"Molecular oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (m6A-seq, functional KD/OE, downstream protein readouts), single lab\",\n      \"pmids\": [\"33411363\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"YPEL5 is a subunit of the CTLH E3 ubiquitin ligase complex and inhibits NMNAT1 ubiquitylation and cellular turnover by WDR26-CTLH E3. The N-terminus of YPEL5 mimics the degron of NMNAT1 (degron mimicry), thereby antagonizing substrate binding to WDR26. Cryo-EM structures of NMNAT1-bound and YPEL5-bound WDR26-CTLH E3 complexes revealed the structural basis of this competition.\",\n      \"method\": \"Cryo-EM structure determination; in vitro ubiquitylation assays; cellular turnover assays; degron mutagenesis\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cryo-EM structures combined with in vitro reconstitution of ubiquitylation, mutagenesis of degron, and cellular turnover assays in a single rigorous study\",\n      \"pmids\": [\"38759627\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"WDR26 mediates CTLH E3 complex binding to YPEL5; SKDEAS-associated WDR26 mutations impair this interaction and disrupt CTLH E3 supramolecular assembly, providing mechanistic insight into how YPEL5 is retained in the complex.\",\n      \"method\": \"Complementation studies in genetically engineered human cells lacking CTLH E3 supramolecular assemblies; structural modeling of WDR26 mutation positions\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional complementation in engineered cells with multiple mutants tested, single lab, structural modeling but not full structure determination\",\n      \"pmids\": [\"38575527\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"YPEL5 (as part of the GID/CTLH complex) suppresses host anti-microbial defenses in macrophages; knockout of YPEL5 (among other CTLH members) enhanced anti-mycobacterial and anti-Salmonella activity via enhanced GABAergic signaling, activated AMPK, increased autophagic flux, and resistance to Mtb-induced necrotic cell death.\",\n      \"method\": \"FACS-based genome-wide CRISPR screen; CRISPR knockout macrophages with intracellular bacterial growth and cell death as functional readouts\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genome-wide CRISPR screen with defined mechanistic pathway readouts, peer-reviewed; YPEL5-specific role confirmed within complex context\",\n      \"pmids\": [\"39472457\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"In zebrafish, ypel5 knockout (CRISPR/Cas9) causes liver enlargement associated with hepatic cell proliferation and dysregulated hepatic metabolism. Mechanistically, Ypel5 positively regulates Hnf4a expression via PPARα signaling, which directly binds the transcriptional enhancer of the Hnf4a gene. Zebrafish hnf4a overexpression largely rescued ypel5 deficiency-induced hepatic defects.\",\n      \"method\": \"CRISPR/Cas9 knockout in zebrafish; metabolomic and transcriptomic analyses; epistasis rescue by hnf4a overexpression; PPARα binding to Hnf4a enhancer\",\n      \"journal\": \"Journal of molecular cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo KO with specific cellular phenotype, pathway placement by genetic rescue, and mechanistic pathway (PPARα→Hnf4a) supported by multiple orthogonal methods\",\n      \"pmids\": [\"36948605\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"A recurrent YPEL5/PPP1CB RNA chimera detected in CLL encodes a truncated PPP1CB protein with diminished phosphatase activity; PPP1CB silencing enhanced proliferation and colony formation of MEC1 and JVM3 CLL cells, linking the chimera to CLL pathogenesis.\",\n      \"method\": \"Paired-end transcriptome sequencing; qRT-PCR; whole-genome sequencing and Southern blotting to exclude genomic fusion; in vitro phosphatase activity assay; siRNA knockdown with proliferation and colony formation readouts\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods establishing chimera production and functional consequence, single lab; note later contradicted by PMID:26605151 showing the fusion is not CLL-specific\",\n      \"pmids\": [\"23382248\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"YPEL5's basic pocket within the CTLH complex can recruit substrates bearing acidic degrons; a sulfinic acid-containing molecular glue (ZZ1) binds this basic pocket in YPEL5 and promotes cooperative binding between CTLH E3 and BET-family proteins, demonstrating a substrate-recruitment capacity for YPEL5 that is distinct from its previously described degron-mimicry/inhibitory role.\",\n      \"method\": \"Cryo-EM/structural determination; biochemical binding assays; cellular degradation assays with molecular glue ZZ1\",\n      \"journal\": \"Nature chemical biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — structural determination plus biochemical reconstitution of substrate recruitment via YPEL5 basic pocket, with functional validation of degradation\",\n      \"pmids\": [\"41942733\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Oocyte-specific conditional knockout of Ypel5 in mice causes complete female infertility due to accelerated depletion of the primordial follicle pool, defective antral follicle formation, and impaired oocyte maturation. Mechanistically, Ypel5 loss results in increased DNA damage, disrupted mitochondrial homeostasis, elevated oxidative stress, apoptotic depletion of primordial follicle oocytes, and severe spindle assembly and mitochondrial distribution abnormalities in oocytes.\",\n      \"method\": \"Oocyte-specific conditional knockout mouse model; phenotypic analysis of folliculogenesis and oocyte maturation; DNA damage markers; mitochondrial homeostasis assays; spindle organization imaging\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with specific cellular and molecular phenotypic readouts, single lab, multiple orthogonal assays but no epistasis rescue\",\n      \"pmids\": [\"42086779\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"YPEL5 is a conserved eukaryotic protein that functions as an integral subunit of the CTLH/GID E3 ubiquitin ligase complex, where its N-terminus acts as a degron mimic to inhibit WDR26-mediated substrate (NMNAT1) ubiquitylation—a role whose basic pocket can alternatively recruit acidic-degron substrates via molecular glues—while outside the complex YPEL5 localizes dynamically to centrosomes, spindle poles, and midbody to support cell cycle progression, physically interacts with IKBKE/TBK1 to negatively regulate IFNB1-mediated innate immune signaling, and in vivo regulates liver metabolism via a PPARα–Hnf4a axis and is essential for oocyte maturation and female fertility.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"YPEL5 is a conserved eukaryotic protein that operates both as a regulatory subunit of the CTLH/GID E3 ubiquitin ligase and as a cell cycle-associated factor at microtubule-organizing structures [#0, #6]. Within the CTLH complex, YPEL5 is retained through WDR26, and its N-terminus mimics the NMNAT1 degron to competitively block WDR26-mediated NMNAT1 ubiquitylation and turnover, an inhibitory mechanism resolved by cryo-EM of NMNAT1- and YPEL5-bound WDR26-CTLH assemblies [#6, #7]. The same basic pocket in YPEL5 can instead serve as a substrate-recruitment surface, engaging acidic-degron proteins when bridged by a sulfinic acid-containing molecular glue that drives cooperative binding of CTLH E3 to BET-family proteins [#11]. Independently, YPEL5 localizes dynamically through the cell cycle\\u2014to the nucleus and centrosome in interphase and to spindle poles, the spindle midzone, and the midbody during mitosis and cytokinesis\\u2014and its depletion impairs proliferation and embryonic development [#0, #2]. YPEL5 also negatively regulates innate immunity by physically interacting with IKBKE and functionally with TBK1 to restrain IFNB1 production [#3], and acts in vivo as a metabolic and developmental regulator: zebrafish ypel5 controls hepatic metabolism through a PPAR\\u03b1\\u2013Hnf4a axis [#9], while oocyte-specific loss in mice causes female infertility with defective folliculogenesis, spindle assembly, and mitochondrial homeostasis [#12].\",\n  \"teleology\": [\n    {\n      \"year\": 2004,\n      \"claim\": \"Established the basic cell-biological behavior of YPEL5 by showing it occupies distinct subcellular sites across the cell cycle, separating it from the YPEL1-4 paralogs.\",\n      \"evidence\": \"Indirect immunofluorescence in COS-7 cells\",\n      \"pmids\": [\"15556292\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No functional consequence of localization tested\", \"No interacting partners identified\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Connected YPEL5 localization to function, demonstrating that loss disrupts cell cycle progression and development, and identified its first physical partners.\",\n      \"evidence\": \"Immunofluorescence and siRNA/morpholino knockdown in COS-7 cells and medaka embryos; yeast two-hybrid screen identifying RanBPM (RANBP9) and RanBP10\",\n      \"pmids\": [\"20580816\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"RANBP9/RANBP10 interaction is yeast two-hybrid only, not validated in mammalian cells\", \"Mechanism linking localization to proliferation undefined\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Documented a YPEL5/PPP1CB RNA chimera in CLL, raising the possibility that the locus contributes to malignancy, though the functional defect mapped to truncated PPP1CB rather than YPEL5.\",\n      \"evidence\": \"Transcriptome sequencing, phosphatase assays, and siRNA proliferation readouts in CLL cell lines\",\n      \"pmids\": [\"23382248\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence attributed to PPP1CB truncation, not YPEL5\", \"Chimera later reported not to be CLL-specific\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Defined a signaling role for YPEL5 as a negative regulator of innate immunity through direct association with the non-canonical IKK kinase machinery.\",\n      \"evidence\": \"Reciprocal co-IP with IKBKE and siRNA knockdown with IFNB1 induction and TBK1/IKBKE phosphorylation readouts in HEK293T and macrophage lines\",\n      \"pmids\": [\"27705791\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Whether this depends on CTLH complex membership not addressed\", \"No structural basis for IKBKE binding\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Demonstrated cross-species functional conservation by showing human YPEL5 substitutes for yeast Moh1 in DNA-damage-induced apoptosis.\",\n      \"evidence\": \"Functional complementation of moh1\\u0394 yeast with human YPEL5 and apoptosis readouts\",\n      \"pmids\": [\"28173693\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Pro-apoptotic mechanism in human cells not defined\", \"Molecular partners in apoptosis unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Placed YPEL5 expression under m6A epigenetic control and tied its overexpression to suppression of proliferation markers in cancer cells.\",\n      \"evidence\": \"m6A-seq, METTL3 knockdown/overexpression, YTHDF2 studies, and YPEL5 overexpression with CCNB1/PCNA readouts in colorectal cancer cells\",\n      \"pmids\": [\"33411363\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct mechanism linking YPEL5 to CCNB1/PCNA reduction unknown\", \"Single lab\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Established an in vivo metabolic function, defining a PPAR\\u03b1\\u2192Hnf4a regulatory axis through which YPEL5 controls hepatic metabolism and proliferation.\",\n      \"evidence\": \"CRISPR/Cas9 ypel5 knockout in zebrafish with metabolomics, transcriptomics, and hnf4a overexpression rescue\",\n      \"pmids\": [\"36948605\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How YPEL5 protein activates PPAR\\u03b1 signaling mechanistically unclear\", \"Connection to CTLH E3 function not addressed\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Resolved YPEL5's defining biochemical role as a CTLH E3 subunit whose N-terminal degron mimicry competitively inhibits WDR26-mediated NMNAT1 ubiquitylation, and showed WDR26 is required to retain YPEL5 in the complex.\",\n      \"evidence\": \"Cryo-EM structures, in vitro ubiquitylation and cellular turnover assays with degron mutagenesis; complementation in CTLH-deficient cells with WDR26 disease mutants\",\n      \"pmids\": [\"38759627\", \"38575527\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full repertoire of substrates antagonized by YPEL5 unknown\", \"Whether degron mimicry operates on substrates other than NMNAT1 untested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Connected the CTLH-resident YPEL5 to host defense, showing its loss enhances anti-bacterial activity through GABAergic signaling, AMPK activation, and autophagy.\",\n      \"evidence\": \"Genome-wide CRISPR screen and CRISPR knockout macrophages with intracellular bacterial growth and cell death readouts\",\n      \"pmids\": [\"39472457\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"YPEL5-specific contribution within the complex not isolated\", \"Direct substrate driving the antimicrobial phenotype not identified\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Revealed a substrate-recruitment capacity for YPEL5 distinct from its inhibitory role, showing its basic pocket can engage acidic degrons and be co-opted by a molecular glue to recruit BET proteins for degradation.\",\n      \"evidence\": \"Cryo-EM/structural determination, biochemical binding, and cellular degradation assays with molecular glue ZZ1\",\n      \"pmids\": [\"41942733\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Endogenous acidic-degron substrates recruited by the basic pocket unknown\", \"Physiological versus glue-induced recruitment not distinguished\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Demonstrated an essential in vivo role in reproduction, with oocyte-specific loss causing infertility through follicle depletion, DNA damage, oxidative stress, and spindle/mitochondrial defects.\",\n      \"evidence\": \"Oocyte-specific conditional knockout mouse with folliculogenesis, DNA damage, mitochondrial, and spindle imaging readouts\",\n      \"pmids\": [\"42086779\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No epistasis rescue to assign causality\", \"Whether phenotype reflects CTLH E3 function or its mitotic localization role untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How YPEL5's distinct activities\\u2014CTLH-resident ubiquitylation control, mitotic localization, innate-immune signaling, and metabolic/reproductive regulation\\u2014are integrated within a single protein remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model linking complex membership to localization-dependent roles\", \"Endogenous substrate spectrum incompletely defined\", \"Mechanistic basis of IKBKE and PPAR\\u03b1 regulation not structurally resolved\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [6, 11]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [6, 11, 3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [6, 11]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [3, 8]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [9]}\n    ],\n    \"complexes\": [\"CTLH/GID E3 ubiquitin ligase complex\"],\n    \"partners\": [\"WDR26\", \"NMNAT1\", \"IKBKE\", \"TBK1\", \"RANBP9\", \"RANBP10\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}