{"gene":"SPATA2","run_date":"2026-06-10T07:46:39","timeline":{"discoveries":[{"year":2016,"finding":"SPATA2 was identified as a novel component of the TNF receptor signaling complex (TNF-RSC). The N-terminal PUB domain of SPATA2 interacts with the USP domain of CYLD, while the C-terminus of SPATA2 interacts with HOIP (the catalytically active component of LUBAC). SPATA2 is required for recruitment of CYLD to the TNF-RSC. Loss of SPATA2 augments NF-κB transcriptional activation and inhibits TNF-α-induced necroptosis.","method":"Quantitative mass spectrometry of TNF-RSC composition, Co-IP/pulldown domain mapping, siRNA knockdown with NF-κB and necroptosis readouts","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP with domain mapping, mass spectrometry, functional KD phenotype; independently replicated in three concurrent papers (PMIDs 27307491, 27545878, 27458237)","pmids":["27307491"],"is_preprint":false},{"year":2016,"finding":"SPATA2 is a constitutive direct binding partner of HOIP that bridges the interaction between CYLD and HOIP, enabling CYLD recruitment to TNFR1- and NOD2-signaling complexes. SPATA2 recruitment to these complexes is dependent on HOIP. Loss of SPATA2 abolishes CYLD recruitment and diminishes TNF-induced necroptosis, resembling loss of CYLD.","method":"Co-IP, pulldown, CRISPR/siRNA loss-of-function with necroptosis and NF-κB readouts in multiple signaling complexes","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct binding shown by pulldown/Co-IP, functional KO phenotype, independently replicated across multiple labs","pmids":["27545878"],"is_preprint":false},{"year":2016,"finding":"SPATA2 interacts with CYLD via its PUB domain, while a PUB interaction motif (PIM) of SPATA2 interacts with the PUB domain of HOIP. Beyond scaffolding, SPATA2 acts as an allosteric activator of the K63- and M1-deubiquitinase activity of CYLD. SPATA2 is required for TNF-induced complex II formation, caspase activation, and apoptosis, and substantially attenuates TNF-induced NF-κB and MAPK signaling.","method":"Mass spectrometry screen, Co-IP domain mapping, in vitro deubiquitinase activity assay, loss-of-function with NF-κB/MAPK/apoptosis readouts","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro enzymatic activity assay plus domain mapping Co-IP, replicated across independent labs","pmids":["27458237"],"is_preprint":false},{"year":2017,"finding":"SPATA2-deficient cells show resistance to RIPK1-dependent apoptosis and necroptosis, and partial protection against RIPK1-independent apoptosis. SPATA2 deficiency promotes M1 ubiquitination of RIPK1, thereby inhibiting RIPK1 kinase activity. Biochemical in vitro evidence shows that the CYLD USP domain complexed with the SPATA2 PUB domain preferentially deubiquitinates M1 (linear) ubiquitin chains. SPATA2 deficiency also promotes MKK4 and JNK activation and cytokine production independently of RIPK1 kinase activity.","method":"SPATA2-deficient cell lines (genetic KO), in vitro deubiquitinase assay with M1 and K63 ubiquitin chains, RIPK1 ubiquitination biochemistry, cell death assays","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — in vitro deubiquitinase assay with chain-specificity, genetic KO with multiple cellular readouts, single lab but multiple orthogonal methods","pmids":["28701375"],"is_preprint":false},{"year":2019,"finding":"SPATA2 recruits CYLD to the centrosome to deubiquitinate PLK4 (polo-like kinase 4). Deubiquitination of PLK4 facilitates its phosphorylation of NEK7 at Ser204, which attenuates the NEK7–NLRP3 interaction required for NLRP3 inflammasome activation. SPATA2 deficiency enhances NLRP3 inflammasome activity in macrophages and in a peritonitis animal model.","method":"SPATA2 KO macrophages, Co-IP of PLK4/CYLD/NEK7/NLRP3, in vitro ubiquitination/deubiquitination assay, phosphorylation site mutagenesis (NEK7 S204A), shRNA knockdown, animal peritonitis model","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — site-directed mutagenesis, in vitro deubiquitination assay, Co-IP, in vivo model; multiple orthogonal methods in single lab","pmids":["31762063"],"is_preprint":false},{"year":2023,"finding":"SPATA2 has CYLD-independent functions: SPATA2 competes with OTULIN for binding to HOIP via its PIM and zinc finger domain, thereby promoting LUBAC autoubiquitylation and attenuating LUBAC activity. Double knockout (Cyld-/-Spata2-/-) mice show highly penetrant perinatal lethality absent in single knockouts. Cyld-/-Spata2-/- cells show increased M1-linked TNFR1-SC ubiquitylation and elevated pro-inflammatory gene expression compared to either single KO, and this increased signaling depends on OTULIN.","method":"Double KO mice (CRISPR), OTULIN competition binding assay, M1-ubiquitin chain analysis, pro-inflammatory gene expression in fibroblasts/macrophages/intestinal epithelial cells, genetic epistasis with OTULIN","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genetic epistasis with double KO and OTULIN dependence, reciprocal binding competition, multiple cell types; single lab but multiple orthogonal methods","pmids":["36640323"],"is_preprint":false},{"year":2022,"finding":"SPATA2 and CYLD inhibit STAT1 accumulation and activation (and subsequent CXCL10 expression) in colorectal cancer cells. At steady state, STAT1 is highly ubiquitinated in a SPATA2/CYLD-dependent manner, suggesting SPATA2/CYLD deubiquitinate STAT1 to regulate IFN-γ signaling. Tumor-specific deletion of SPATA2 or CYLD enhances anti-PD-1 response in vivo.","method":"Specific deletion of SPATA2/CYLD in human and mouse CRC cell lines, STAT1 ubiquitination analysis, CXCL10 expression measurement, in vivo anti-PD-1 response assay","journal":"Frontiers in oncology","confidence":"Medium","confidence_rationale":"Tier 2–3 / Weak — genetic KO with functional readout, STAT1 ubiquitination shown, but single lab and limited mechanistic depth in abstract","pmids":["36531014"],"is_preprint":false},{"year":2022,"finding":"The SPATA2/CYLD pathway contributes to doxorubicin-induced cardiomyocyte ferroptosis by enhancing ferritinophagy. SPATA2 knockdown reduced NCOA4 deubiquitination, attenuated ferritinophagy, and decreased ferroptosis. The pathway promotes NCOA4 deubiquitination (via CYLD), which stabilizes NCOA4 and drives ferritin degradation and intracellular iron overload.","method":"SPATA2 knockdown in cardiomyocytes, NCOA4 ubiquitination assay, Co-IP of SPATA2/CYLD interaction, ferroptosis markers (iron, ACSL4, LC3), in vivo mouse doxorubicin model","journal":"Chemico-biological interactions","confidence":"Medium","confidence_rationale":"Tier 2–3 / Weak — knockdown with ubiquitination assay and multiple ferroptosis readouts, in vivo confirmation, but single lab and mechanistic chain partially indirect","pmids":["36195186"],"is_preprint":false},{"year":2025,"finding":"SPATA2/CYLD pathway-dependent deubiquitylation of p53 promotes ferroptosis in rat heart after ischemia/reperfusion by stabilizing p53, which suppresses SLC7A11 transcription, reducing GPX4 levels. SPATA2 knockdown restored p53 ubiquitination, increased SLC7A11 and GPX4, and reduced ferroptosis.","method":"SPATA2 knockdown in H9c2 cells and rat I/R model, p53 ubiquitination assay, SLC7A11/GPX4 expression, lurasidone as SPATA2 inhibitor","journal":"Heart, lung & circulation","confidence":"Medium","confidence_rationale":"Tier 2–3 / Weak — KD with ubiquitination assay and pathway readouts in vitro and in vivo, but single lab and mechanistic details compressed in abstract","pmids":["40389334"],"is_preprint":false},{"year":2001,"finding":"SPATA2 protein tagged with GFP is located in the nucleus when expressed in HLtat transfected cells. SPATA2 mRNA is expressed in testis and Sertoli cells, and FSH treatment of Sertoli cells induces changes in steady-state spata2 mRNA in a time-dependent manner.","method":"GFP-fusion protein expression and fluorescence localization, RT-PCR, FSH treatment of Sertoli cells","journal":"Biochemical and biophysical research communications","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single overexpression localization experiment, no functional consequence established, single lab","pmids":["11322771"],"is_preprint":false},{"year":2017,"finding":"SPATA2 global knockout in mice (via CRISPR/Cas9n) results in approximately 40% decrease in testis size/weight, 40% decrease in sperm count, 28% decrease in germ cell proliferation, and approximately 70% increase in inhibin alpha-subunit mRNA and protein in testes, indicating SPATA2 ensures normal secretory function of Sertoli cells and is required for male fertility.","method":"CRISPR/Cas9n global KO mice, histomorphology, sperm count, BrdU proliferation assay, RT-PCR and Western blot for inhibin alpha","journal":"Biology of reproduction","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — clean genetic KO with defined cellular phenotype and molecular readout (inhibin alpha), single lab","pmids":["29025062"],"is_preprint":false},{"year":2023,"finding":"SPATA2 suppresses β-catenin signaling by attenuating DVL1 ubiquitination. Ectopic overexpression of SPATA2 inhibited EMT, impaired motility and invasiveness in vitro, reduced metastasis in vivo, and increased radiosensitivity in NSCLC cells.","method":"SPATA2 overexpression/KD in NSCLC cell lines, DVL1 ubiquitination assay, β-catenin signaling reporter, in vitro invasion/migration assays, in vivo metastasis model","journal":"Thoracic cancer","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, ubiquitination assay with limited mechanistic detail in abstract, pathway placement partially indirect","pmids":["36814090"],"is_preprint":false}],"current_model":"SPATA2 functions as a scaffolding adaptor protein within immune receptor signaling complexes (TNF-RSC, NOD2-SC) where its N-terminal PUB domain binds CYLD and its C-terminal PIM interacts with HOIP (LUBAC), thereby recruiting and allosterically activating CYLD to deubiquitinate K63- and M1-linked ubiquitin chains on RIPK1 and other substrates, attenuating NF-κB/MAPK signaling while promoting cell death (apoptosis, necroptosis); additionally, SPATA2 competes with OTULIN for HOIP binding to independently restrain LUBAC activity, recruits CYLD to the centrosome to deubiquitinate PLK4 and suppress NLRP3 inflammasome activation, and facilitates CYLD-dependent deubiquitination of substrates including STAT1, p53, and NCOA4 in various cellular contexts."},"narrative":{"mechanistic_narrative":"SPATA2 is a scaffolding adaptor protein that controls deubiquitination within immune receptor signaling complexes, recruiting the deubiquitinase CYLD to regulate inflammatory signaling and cell death [PMID:27307491, PMID:27545878]. It is a constitutive component of the TNF receptor signaling complex (TNF-RSC) and NOD2 signaling complex, where its N-terminal PUB domain binds the USP domain of CYLD while a C-terminal PUB-interaction motif (PIM) binds the PUB domain of HOIP, the catalytic subunit of LUBAC; through this bridging, SPATA2 is required for HOIP-dependent recruitment of CYLD to these complexes [PMID:27307491, PMID:27545878, PMID:27458237]. Beyond passive scaffolding, SPATA2 acts as an allosteric activator of the K63- and M1-linked deubiquitinase activity of CYLD, and the CYLD–SPATA2 complex preferentially cleaves M1 (linear) ubiquitin chains on RIPK1, thereby restraining NF-κB and MAPK signaling while licensing complex II formation, caspase activation, apoptosis, and necroptosis [PMID:27458237, PMID:28701375]. SPATA2 additionally exerts CYLD-independent control of LUBAC by competing with OTULIN for HOIP binding via its PIM and zinc finger, promoting LUBAC autoubiquitylation and limiting linear ubiquitination, with combined loss of SPATA2 and CYLD causing perinatal lethality in mice [PMID:36640323]. At the centrosome, SPATA2 directs CYLD-mediated deubiquitination of PLK4 to promote NEK7 phosphorylation and suppress NLRP3 inflammasome activation [PMID:31762063]. SPATA2 is also required for male fertility, with knockout mice showing reduced testis size, sperm count, and germ cell proliferation alongside elevated inhibin alpha [PMID:29025062].","teleology":[{"year":2016,"claim":"Established SPATA2 as a previously unrecognized component of the TNF-RSC that physically bridges CYLD and the LUBAC subunit HOIP, defining how CYLD is recruited to the receptor complex.","evidence":"Quantitative mass spectrometry of TNF-RSC, reciprocal Co-IP with domain mapping, and siRNA knockdown with NF-κB/necroptosis readouts; independently replicated across three concurrent papers","pmids":["27307491","27545878","27458237"],"confidence":"High","gaps":["Did not resolve whether SPATA2 affects CYLD catalysis beyond recruitment","Structural basis of the PUB/PIM interactions not determined in these studies"]},{"year":2016,"claim":"Showed SPATA2 is not merely a scaffold but an allosteric activator of CYLD's K63- and M1-deubiquitinase activity, linking complex assembly to enzymatic output and to apoptosis/NF-κB/MAPK control.","evidence":"In vitro deubiquitinase activity assays plus Co-IP domain mapping and loss-of-function with apoptosis and signaling readouts","pmids":["27458237"],"confidence":"High","gaps":["Mechanism of allosteric activation at the structural level not defined","Full substrate range within the TNF-RSC not enumerated"]},{"year":2017,"claim":"Defined RIPK1 as a key substrate, showing the CYLD–SPATA2 complex preferentially cleaves M1 chains on RIPK1 to sustain its kinase activity and dictate RIPK1-dependent death versus RIPK1-independent cytokine output.","evidence":"Genetic SPATA2 KO cell lines, in vitro deubiquitinase assays with M1 vs K63 chains, and RIPK1 ubiquitination biochemistry with cell death readouts","pmids":["28701375"],"confidence":"High","gaps":["Did not separate scaffolding from activating contributions to chain specificity in vivo","RIPK1-independent JNK/cytokine branch mechanism not fully resolved"]},{"year":2019,"claim":"Extended SPATA2 function beyond death-receptor signaling by showing it recruits CYLD to the centrosome to deubiquitinate PLK4 and suppress NLRP3 inflammasome activation.","evidence":"SPATA2 KO macrophages, Co-IP of PLK4/CYLD/NEK7/NLRP3, in vitro deubiquitination assay, NEK7 S204A mutagenesis, and an in vivo peritonitis model","pmids":["31762063"],"confidence":"High","gaps":["How SPATA2 targets CYLD specifically to the centrosome is unclear","Relationship between centrosomal and TNF-RSC pools of SPATA2 not addressed"]},{"year":2023,"claim":"Revealed a CYLD-independent role: SPATA2 competes with OTULIN for HOIP to restrain LUBAC activity, with genetic epistasis showing combined SPATA2/CYLD loss is lethal and signaling hyperactivation is OTULIN-dependent.","evidence":"Cyld-/-Spata2-/- double KO mice, OTULIN competition binding assays, M1-ubiquitin chain analysis, and pro-inflammatory gene expression across multiple cell types","pmids":["36640323"],"confidence":"High","gaps":["Quantitative balance between CYLD-dependent and OTULIN-competitive functions unresolved","Domain requirements for OTULIN competition only partially mapped"]},{"year":2022,"claim":"Implicated SPATA2/CYLD in deubiquitination of broader substrates, stabilizing or destabilizing STAT1 and NCOA4 to modulate IFN-γ signaling, anti-PD-1 response, and ferritinophagy-driven ferroptosis.","evidence":"Genetic deletion/knockdown in CRC and cardiomyocyte models with STAT1 and NCOA4 ubiquitination assays, functional readouts, and in vivo models","pmids":["36531014","36195186"],"confidence":"Medium","gaps":["Direct deubiquitination of these substrates by the SPATA2/CYLD complex not reconstituted in vitro","Context-specificity of substrate selection unexplained"]},{"year":2017,"claim":"Demonstrated a physiological requirement for SPATA2 in spermatogenesis and Sertoli cell function distinct from its inflammatory signaling roles.","evidence":"CRISPR/Cas9n global KO mice with testis histomorphology, sperm counts, BrdU proliferation, and inhibin alpha measurement","pmids":["29025062"],"confidence":"Medium","gaps":["Molecular pathway linking SPATA2 to inhibin alpha regulation not defined","Whether the fertility role depends on CYLD/LUBAC is unknown"]},{"year":null,"claim":"How SPATA2's biochemical activities (CYLD recruitment/activation, OTULIN competition, substrate selection) are integrated and spatially partitioned across distinct cellular contexts remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of the SPATA2–CYLD–HOIP assembly","Unclear how distinct substrate engagements (RIPK1, PLK4, STAT1, p53, NCOA4, DVL1) are determined","Connection between reproductive and immune signaling functions unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,1,2]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[2,5]}],"localization":[{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[4]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[9]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,1,4]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[2,3]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,2]}],"complexes":["TNF-RSC","NOD2 signaling complex","LUBAC"],"partners":["CYLD","HOIP","OTULIN","RIPK1","PLK4"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9UM82","full_name":"Spermatogenesis-associated protein 2","aliases":[],"length_aa":520,"mass_kda":58.4,"function":"Bridging factor that mediates the recruitment of CYLD to the LUBAC complex, thereby regulating TNF-induced necroptosis (PubMed:27307491, PubMed:27458237, PubMed:27545878, PubMed:27591049). Acts as a direct binding intermediate that bridges RNF31/HOIP, the catalytic subunit of the LUBAC complex, and the deubiquitinase (CYLD), thereby recruiting CYLD to the TNF-R1 signaling complex (TNF-RSC) (PubMed:27458237, PubMed:27545878, PubMed:27591049). Required to activate the 'Met-1'- (linear) and 'Lys-63'-linked deubiquitinase activities of CYLD (PubMed:27458237, PubMed:27591049). Controls the kinase activity of RIPK1 and TNF-induced necroptosis by promoting 'Met-1'-linked deubiquitination of RIPK1 by CYLD (By similarity)","subcellular_location":"Cytoplasm; Nucleus","url":"https://www.uniprot.org/uniprotkb/Q9UM82/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SPATA2","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/SPATA2","total_profiled":1310},"omim":[{"mim_id":"617670","title":"MEIOSIS-SPECIFIC PROTEIN WITH OB DOMAINS; MEIOB","url":"https://www.omim.org/entry/617670"},{"mim_id":"607662","title":"SPERMATOGENESIS-ASSOCIATED PROTEIN 2; SPATA2","url":"https://www.omim.org/entry/607662"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoli fibrillar center","reliability":"Approved"},{"location":"Nucleoplasm","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/SPATA2"},"hgnc":{"alias_symbol":["KIAA0757","PD1","tamo","PPP1R145"],"prev_symbol":[]},"alphafold":{"accession":"Q9UM82","domains":[{"cath_id":"1.20.58.2190","chopping":"10-31_38-215","consensus_level":"high","plddt":91.7665,"start":10,"end":215},{"cath_id":"-","chopping":"471-505","consensus_level":"high","plddt":83.9486,"start":471,"end":505}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UM82","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UM82-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UM82-F1-predicted_aligned_error_v6.png","plddt_mean":68.38},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SPATA2","jax_strain_url":"https://www.jax.org/strain/search?query=SPATA2"},"sequence":{"accession":"Q9UM82","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9UM82.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9UM82/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UM82"}},"corpus_meta":[{"pmid":"27307491","id":"PMC_27307491","title":"SPATA2 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circulation","url":"https://pubmed.ncbi.nlm.nih.gov/40389334","citation_count":1,"is_preprint":false},{"pmid":"40069269","id":"PMC_40069269","title":"Clinical and functional significance of SPATA2 in cancer particularly in LIHC.","date":"2025","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/40069269","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":11389,"output_tokens":3655,"usd":0.044496,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11252,"output_tokens":3182,"usd":0.067905,"stage2_stop_reason":"end_turn"},"total_usd":0.112401,"stage1_batch_id":"msgbatch_013LWZZT6MWaqB9qyTSeQBmU","stage2_batch_id":"msgbatch_0194ZzQaTGNpruoNJBbEMbt3","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2016,\n      \"finding\": \"SPATA2 was identified as a novel component of the TNF receptor signaling complex (TNF-RSC). The N-terminal PUB domain of SPATA2 interacts with the USP domain of CYLD, while the C-terminus of SPATA2 interacts with HOIP (the catalytically active component of LUBAC). SPATA2 is required for recruitment of CYLD to the TNF-RSC. Loss of SPATA2 augments NF-κB transcriptional activation and inhibits TNF-α-induced necroptosis.\",\n      \"method\": \"Quantitative mass spectrometry of TNF-RSC composition, Co-IP/pulldown domain mapping, siRNA knockdown with NF-κB and necroptosis readouts\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP with domain mapping, mass spectrometry, functional KD phenotype; independently replicated in three concurrent papers (PMIDs 27307491, 27545878, 27458237)\",\n      \"pmids\": [\"27307491\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"SPATA2 is a constitutive direct binding partner of HOIP that bridges the interaction between CYLD and HOIP, enabling CYLD recruitment to TNFR1- and NOD2-signaling complexes. SPATA2 recruitment to these complexes is dependent on HOIP. Loss of SPATA2 abolishes CYLD recruitment and diminishes TNF-induced necroptosis, resembling loss of CYLD.\",\n      \"method\": \"Co-IP, pulldown, CRISPR/siRNA loss-of-function with necroptosis and NF-κB readouts in multiple signaling complexes\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct binding shown by pulldown/Co-IP, functional KO phenotype, independently replicated across multiple labs\",\n      \"pmids\": [\"27545878\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"SPATA2 interacts with CYLD via its PUB domain, while a PUB interaction motif (PIM) of SPATA2 interacts with the PUB domain of HOIP. Beyond scaffolding, SPATA2 acts as an allosteric activator of the K63- and M1-deubiquitinase activity of CYLD. SPATA2 is required for TNF-induced complex II formation, caspase activation, and apoptosis, and substantially attenuates TNF-induced NF-κB and MAPK signaling.\",\n      \"method\": \"Mass spectrometry screen, Co-IP domain mapping, in vitro deubiquitinase activity assay, loss-of-function with NF-κB/MAPK/apoptosis readouts\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro enzymatic activity assay plus domain mapping Co-IP, replicated across independent labs\",\n      \"pmids\": [\"27458237\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"SPATA2-deficient cells show resistance to RIPK1-dependent apoptosis and necroptosis, and partial protection against RIPK1-independent apoptosis. SPATA2 deficiency promotes M1 ubiquitination of RIPK1, thereby inhibiting RIPK1 kinase activity. Biochemical in vitro evidence shows that the CYLD USP domain complexed with the SPATA2 PUB domain preferentially deubiquitinates M1 (linear) ubiquitin chains. SPATA2 deficiency also promotes MKK4 and JNK activation and cytokine production independently of RIPK1 kinase activity.\",\n      \"method\": \"SPATA2-deficient cell lines (genetic KO), in vitro deubiquitinase assay with M1 and K63 ubiquitin chains, RIPK1 ubiquitination biochemistry, cell death assays\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro deubiquitinase assay with chain-specificity, genetic KO with multiple cellular readouts, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"28701375\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SPATA2 recruits CYLD to the centrosome to deubiquitinate PLK4 (polo-like kinase 4). Deubiquitination of PLK4 facilitates its phosphorylation of NEK7 at Ser204, which attenuates the NEK7–NLRP3 interaction required for NLRP3 inflammasome activation. SPATA2 deficiency enhances NLRP3 inflammasome activity in macrophages and in a peritonitis animal model.\",\n      \"method\": \"SPATA2 KO macrophages, Co-IP of PLK4/CYLD/NEK7/NLRP3, in vitro ubiquitination/deubiquitination assay, phosphorylation site mutagenesis (NEK7 S204A), shRNA knockdown, animal peritonitis model\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — site-directed mutagenesis, in vitro deubiquitination assay, Co-IP, in vivo model; multiple orthogonal methods in single lab\",\n      \"pmids\": [\"31762063\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"SPATA2 has CYLD-independent functions: SPATA2 competes with OTULIN for binding to HOIP via its PIM and zinc finger domain, thereby promoting LUBAC autoubiquitylation and attenuating LUBAC activity. Double knockout (Cyld-/-Spata2-/-) mice show highly penetrant perinatal lethality absent in single knockouts. Cyld-/-Spata2-/- cells show increased M1-linked TNFR1-SC ubiquitylation and elevated pro-inflammatory gene expression compared to either single KO, and this increased signaling depends on OTULIN.\",\n      \"method\": \"Double KO mice (CRISPR), OTULIN competition binding assay, M1-ubiquitin chain analysis, pro-inflammatory gene expression in fibroblasts/macrophages/intestinal epithelial cells, genetic epistasis with OTULIN\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis with double KO and OTULIN dependence, reciprocal binding competition, multiple cell types; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"36640323\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"SPATA2 and CYLD inhibit STAT1 accumulation and activation (and subsequent CXCL10 expression) in colorectal cancer cells. At steady state, STAT1 is highly ubiquitinated in a SPATA2/CYLD-dependent manner, suggesting SPATA2/CYLD deubiquitinate STAT1 to regulate IFN-γ signaling. Tumor-specific deletion of SPATA2 or CYLD enhances anti-PD-1 response in vivo.\",\n      \"method\": \"Specific deletion of SPATA2/CYLD in human and mouse CRC cell lines, STAT1 ubiquitination analysis, CXCL10 expression measurement, in vivo anti-PD-1 response assay\",\n      \"journal\": \"Frontiers in oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Weak — genetic KO with functional readout, STAT1 ubiquitination shown, but single lab and limited mechanistic depth in abstract\",\n      \"pmids\": [\"36531014\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"The SPATA2/CYLD pathway contributes to doxorubicin-induced cardiomyocyte ferroptosis by enhancing ferritinophagy. SPATA2 knockdown reduced NCOA4 deubiquitination, attenuated ferritinophagy, and decreased ferroptosis. The pathway promotes NCOA4 deubiquitination (via CYLD), which stabilizes NCOA4 and drives ferritin degradation and intracellular iron overload.\",\n      \"method\": \"SPATA2 knockdown in cardiomyocytes, NCOA4 ubiquitination assay, Co-IP of SPATA2/CYLD interaction, ferroptosis markers (iron, ACSL4, LC3), in vivo mouse doxorubicin model\",\n      \"journal\": \"Chemico-biological interactions\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Weak — knockdown with ubiquitination assay and multiple ferroptosis readouts, in vivo confirmation, but single lab and mechanistic chain partially indirect\",\n      \"pmids\": [\"36195186\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SPATA2/CYLD pathway-dependent deubiquitylation of p53 promotes ferroptosis in rat heart after ischemia/reperfusion by stabilizing p53, which suppresses SLC7A11 transcription, reducing GPX4 levels. SPATA2 knockdown restored p53 ubiquitination, increased SLC7A11 and GPX4, and reduced ferroptosis.\",\n      \"method\": \"SPATA2 knockdown in H9c2 cells and rat I/R model, p53 ubiquitination assay, SLC7A11/GPX4 expression, lurasidone as SPATA2 inhibitor\",\n      \"journal\": \"Heart, lung & circulation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Weak — KD with ubiquitination assay and pathway readouts in vitro and in vivo, but single lab and mechanistic details compressed in abstract\",\n      \"pmids\": [\"40389334\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"SPATA2 protein tagged with GFP is located in the nucleus when expressed in HLtat transfected cells. SPATA2 mRNA is expressed in testis and Sertoli cells, and FSH treatment of Sertoli cells induces changes in steady-state spata2 mRNA in a time-dependent manner.\",\n      \"method\": \"GFP-fusion protein expression and fluorescence localization, RT-PCR, FSH treatment of Sertoli cells\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single overexpression localization experiment, no functional consequence established, single lab\",\n      \"pmids\": [\"11322771\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"SPATA2 global knockout in mice (via CRISPR/Cas9n) results in approximately 40% decrease in testis size/weight, 40% decrease in sperm count, 28% decrease in germ cell proliferation, and approximately 70% increase in inhibin alpha-subunit mRNA and protein in testes, indicating SPATA2 ensures normal secretory function of Sertoli cells and is required for male fertility.\",\n      \"method\": \"CRISPR/Cas9n global KO mice, histomorphology, sperm count, BrdU proliferation assay, RT-PCR and Western blot for inhibin alpha\",\n      \"journal\": \"Biology of reproduction\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — clean genetic KO with defined cellular phenotype and molecular readout (inhibin alpha), single lab\",\n      \"pmids\": [\"29025062\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"SPATA2 suppresses β-catenin signaling by attenuating DVL1 ubiquitination. Ectopic overexpression of SPATA2 inhibited EMT, impaired motility and invasiveness in vitro, reduced metastasis in vivo, and increased radiosensitivity in NSCLC cells.\",\n      \"method\": \"SPATA2 overexpression/KD in NSCLC cell lines, DVL1 ubiquitination assay, β-catenin signaling reporter, in vitro invasion/migration assays, in vivo metastasis model\",\n      \"journal\": \"Thoracic cancer\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, ubiquitination assay with limited mechanistic detail in abstract, pathway placement partially indirect\",\n      \"pmids\": [\"36814090\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SPATA2 functions as a scaffolding adaptor protein within immune receptor signaling complexes (TNF-RSC, NOD2-SC) where its N-terminal PUB domain binds CYLD and its C-terminal PIM interacts with HOIP (LUBAC), thereby recruiting and allosterically activating CYLD to deubiquitinate K63- and M1-linked ubiquitin chains on RIPK1 and other substrates, attenuating NF-κB/MAPK signaling while promoting cell death (apoptosis, necroptosis); additionally, SPATA2 competes with OTULIN for HOIP binding to independently restrain LUBAC activity, recruits CYLD to the centrosome to deubiquitinate PLK4 and suppress NLRP3 inflammasome activation, and facilitates CYLD-dependent deubiquitination of substrates including STAT1, p53, and NCOA4 in various cellular contexts.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SPATA2 is a scaffolding adaptor protein that controls deubiquitination within immune receptor signaling complexes, recruiting the deubiquitinase CYLD to regulate inflammatory signaling and cell death [#0, #1]. It is a constitutive component of the TNF receptor signaling complex (TNF-RSC) and NOD2 signaling complex, where its N-terminal PUB domain binds the USP domain of CYLD while a C-terminal PUB-interaction motif (PIM) binds the PUB domain of HOIP, the catalytic subunit of LUBAC; through this bridging, SPATA2 is required for HOIP-dependent recruitment of CYLD to these complexes [#0, #1, #2]. Beyond passive scaffolding, SPATA2 acts as an allosteric activator of the K63- and M1-linked deubiquitinase activity of CYLD, and the CYLD–SPATA2 complex preferentially cleaves M1 (linear) ubiquitin chains on RIPK1, thereby restraining NF-\\u03baB and MAPK signaling while licensing complex II formation, caspase activation, apoptosis, and necroptosis [#2, #3]. SPATA2 additionally exerts CYLD-independent control of LUBAC by competing with OTULIN for HOIP binding via its PIM and zinc finger, promoting LUBAC autoubiquitylation and limiting linear ubiquitination, with combined loss of SPATA2 and CYLD causing perinatal lethality in mice [#5]. At the centrosome, SPATA2 directs CYLD-mediated deubiquitination of PLK4 to promote NEK7 phosphorylation and suppress NLRP3 inflammasome activation [#4]. SPATA2 is also required for male fertility, with knockout mice showing reduced testis size, sperm count, and germ cell proliferation alongside elevated inhibin alpha [#10].\",\n  \"teleology\": [\n    {\n      \"year\": 2016,\n      \"claim\": \"Established SPATA2 as a previously unrecognized component of the TNF-RSC that physically bridges CYLD and the LUBAC subunit HOIP, defining how CYLD is recruited to the receptor complex.\",\n      \"evidence\": \"Quantitative mass spectrometry of TNF-RSC, reciprocal Co-IP with domain mapping, and siRNA knockdown with NF-\\u03baB/necroptosis readouts; independently replicated across three concurrent papers\",\n      \"pmids\": [\"27307491\", \"27545878\", \"27458237\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve whether SPATA2 affects CYLD catalysis beyond recruitment\", \"Structural basis of the PUB/PIM interactions not determined in these studies\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Showed SPATA2 is not merely a scaffold but an allosteric activator of CYLD's K63- and M1-deubiquitinase activity, linking complex assembly to enzymatic output and to apoptosis/NF-\\u03baB/MAPK control.\",\n      \"evidence\": \"In vitro deubiquitinase activity assays plus Co-IP domain mapping and loss-of-function with apoptosis and signaling readouts\",\n      \"pmids\": [\"27458237\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of allosteric activation at the structural level not defined\", \"Full substrate range within the TNF-RSC not enumerated\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Defined RIPK1 as a key substrate, showing the CYLD–SPATA2 complex preferentially cleaves M1 chains on RIPK1 to sustain its kinase activity and dictate RIPK1-dependent death versus RIPK1-independent cytokine output.\",\n      \"evidence\": \"Genetic SPATA2 KO cell lines, in vitro deubiquitinase assays with M1 vs K63 chains, and RIPK1 ubiquitination biochemistry with cell death readouts\",\n      \"pmids\": [\"28701375\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not separate scaffolding from activating contributions to chain specificity in vivo\", \"RIPK1-independent JNK/cytokine branch mechanism not fully resolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Extended SPATA2 function beyond death-receptor signaling by showing it recruits CYLD to the centrosome to deubiquitinate PLK4 and suppress NLRP3 inflammasome activation.\",\n      \"evidence\": \"SPATA2 KO macrophages, Co-IP of PLK4/CYLD/NEK7/NLRP3, in vitro deubiquitination assay, NEK7 S204A mutagenesis, and an in vivo peritonitis model\",\n      \"pmids\": [\"31762063\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How SPATA2 targets CYLD specifically to the centrosome is unclear\", \"Relationship between centrosomal and TNF-RSC pools of SPATA2 not addressed\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Revealed a CYLD-independent role: SPATA2 competes with OTULIN for HOIP to restrain LUBAC activity, with genetic epistasis showing combined SPATA2/CYLD loss is lethal and signaling hyperactivation is OTULIN-dependent.\",\n      \"evidence\": \"Cyld-/-Spata2-/- double KO mice, OTULIN competition binding assays, M1-ubiquitin chain analysis, and pro-inflammatory gene expression across multiple cell types\",\n      \"pmids\": [\"36640323\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Quantitative balance between CYLD-dependent and OTULIN-competitive functions unresolved\", \"Domain requirements for OTULIN competition only partially mapped\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Implicated SPATA2/CYLD in deubiquitination of broader substrates, stabilizing or destabilizing STAT1 and NCOA4 to modulate IFN-\\u03b3 signaling, anti-PD-1 response, and ferritinophagy-driven ferroptosis.\",\n      \"evidence\": \"Genetic deletion/knockdown in CRC and cardiomyocyte models with STAT1 and NCOA4 ubiquitination assays, functional readouts, and in vivo models\",\n      \"pmids\": [\"36531014\", \"36195186\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct deubiquitination of these substrates by the SPATA2/CYLD complex not reconstituted in vitro\", \"Context-specificity of substrate selection unexplained\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Demonstrated a physiological requirement for SPATA2 in spermatogenesis and Sertoli cell function distinct from its inflammatory signaling roles.\",\n      \"evidence\": \"CRISPR/Cas9n global KO mice with testis histomorphology, sperm counts, BrdU proliferation, and inhibin alpha measurement\",\n      \"pmids\": [\"29025062\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular pathway linking SPATA2 to inhibin alpha regulation not defined\", \"Whether the fertility role depends on CYLD/LUBAC is unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How SPATA2's biochemical activities (CYLD recruitment/activation, OTULIN competition, substrate selection) are integrated and spatially partitioned across distinct cellular contexts remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of the SPATA2–CYLD–HOIP assembly\", \"Unclear how distinct substrate engagements (RIPK1, PLK4, STAT1, p53, NCOA4, DVL1) are determined\", \"Connection between reproductive and immune signaling functions unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 1, 2]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [2, 5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [9]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 1, 4]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [2, 3]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 2]}\n    ],\n    \"complexes\": [\"TNF-RSC\", \"NOD2 signaling complex\", \"LUBAC\"],\n    \"partners\": [\"CYLD\", \"HOIP\", \"OTULIN\", \"RIPK1\", \"PLK4\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":5,"faith_total":6,"faith_pct":83.33333333333333}}