{"gene":"SPATA20","run_date":"2026-06-10T07:46:39","timeline":{"discoveries":[{"year":2004,"finding":"SSP411 (SPATA20) was cloned from rat testes and found to contain a conserved thioredoxin-like domain in its N-terminal region; 3D structural modeling supported its classification as a member of the thioredoxin family. The mRNA was exclusively expressed in spermatids (round and elongated) in a stage-dependent manner, with protein detected mainly in elongated spermatids.","method":"cDNA cloning, Western blot, in situ hybridization, immunohistochemistry, 3D structural modeling","journal":"Journal of andrology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (ISH, IHC, Western blot, structural modeling) in a single study establishing domain architecture and cell-type-specific localization","pmids":["15223837"],"is_preprint":false},{"year":2017,"finding":"Disruption of Ssp411 (SPATA20) in mice causes male sterility with defective sperm head shaping: Ssp411-disrupted males show smaller testes, reduced sperm counts, decreased sperm motility, and aberrant manchette structure in spermatids. Ssp411 was found to interact with PSMC3 (a manchette-associated proteasome component) via proteome microarray and GST pull-down assay, implicating Ssp411 in the ubiquitin-proteasome system during spermiogenesis.","method":"PiggyBac transposon mouse knockout, real-time PCR, Western blot, immunohistochemistry, microscopy, proteome microarray, co-IP, GST pull-down assay","journal":"Biochimica et biophysica acta. General subjects","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — loss-of-function mouse model with defined morphological phenotype plus in vitro binding assays (proteome microarray + GST pull-down) identifying PSMC3 as interacting partner","pmids":["29247744"],"is_preprint":false},{"year":2022,"finding":"A nonsense mutation in human SPATA20 (c.619C>T, p.Arg207*) causes acephalic spermatozoa syndrome (ASS) with headless spermatozoa. The variant leads to degradation of SPATA20 protein and is associated with decreased expression of SPATA6, a protein required for sperm head-tail conjunction assembly. ICSI failed to rescue infertility in the affected patient.","method":"Whole-exome sequencing, Sanger sequencing, Western blot (SPATA20 and SPATA6 expression), clinical phenotyping","journal":"Clinical genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — human loss-of-function variant with protein expression confirmation and downstream SPATA6 reduction; single patient/lab but multiple methods","pmids":["36415156"],"is_preprint":false},{"year":2024,"finding":"UBL7 protects SPATA20 from excessive proteasomal degradation in spermatids. Using two-step immunoprecipitation, SPATA20 was identified among essential spermatid factors whose stability depends on UBL7, placing SPATA20 in the head-tail coupling apparatus pathway regulated by UBL7-VCP-proteasome axis.","method":"Two-step immunoprecipitation, UBL7 knockout mouse model, mass spectrometry","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with defined phenotype and two-step IP identifying SPATA20 as a protected substrate; single lab","pmids":["40268954"],"is_preprint":false},{"year":2024,"finding":"SPATA20 depletion in cancer cells increases HIF-1α protein levels and transcriptional activity without affecting HIF-1α degradation, suggesting SPATA20 inhibits de novo HIF-1α synthesis, possibly by repressing cap-dependent translation via AKT phosphorylation. SPATA20 depletion promotes cancer cell migration and invasion in a HIF-1α-dependent manner.","method":"siRNA knockdown, Western blot, transcriptional reporter assay, cell migration/invasion assay, pharmacological HIF-1α inhibition rescue experiment","journal":"American journal of cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — clean KD with defined cellular phenotype and rescue experiment; single lab, AKT/translation mechanism is proposed but not directly confirmed by reconstitution or mutagenesis","pmids":["38455399"],"is_preprint":false},{"year":2024,"finding":"HA-tagged Ssp411 (SPATA20) generated by genome tagging was detected in round spermatids, elongating spermatids, elongated spermatids, and epididymal spermatozoa, but was not detectable in MII oocytes, zygotes, or 2-cell stage embryos, establishing its expression is restricted to male germ cells during spermiogenesis.","method":"Genome tagging (HA-tagged knock-in mouse model), immunofluorescence/immunodetection across germ cell stages","journal":"Asian journal of andrology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct in vivo tagging experiment with precise stage-specific localization across multiple germ cell types","pmids":["39091129"],"is_preprint":false}],"current_model":"SPATA20 (SSP411) is a thioredoxin-domain-containing protein expressed exclusively in spermatids during spermiogenesis; it is required for sperm head shaping and head-tail conjunction formation by interacting with PSMC3 (a manchette-associated proteasome component) and by supporting SPATA6 expression, while in somatic/cancer cells it additionally suppresses HIF-1α synthesis, likely by inhibiting cap-dependent translation via AKT signaling."},"narrative":{"mechanistic_narrative":"SPATA20 (SSP411) is a thioredoxin-domain-containing protein expressed in a stage-dependent manner restricted to round and elongated spermatids during spermiogenesis [PMID:15223837, PMID:39091129]. It is required for sperm head shaping and head-tail conjunction: loss of function in mice produces male sterility with smaller testes, reduced sperm counts and motility, and aberrant manchette structure, and SPATA20 physically interacts with the manchette-associated proteasome component PSMC3, linking it to the ubiquitin-proteasome system during spermatid morphogenesis [PMID:29247744]. In humans, a nonsense mutation (p.Arg207*) destabilizes the protein and causes acephalic spermatozoa syndrome, accompanied by reduced expression of the head-tail coupling factor SPATA6 [PMID:36415156]. SPATA20 stability is itself controlled by the UBL7-VCP-proteasome axis, which protects it from excessive proteasomal degradation within the head-tail coupling apparatus pathway [PMID:40268954]. Beyond the male germ line, SPATA20 depletion in cancer cells elevates HIF-1α protein and transcriptional activity without altering HIF-1α degradation—consistent with inhibition of de novo HIF-1α synthesis—and promotes migration and invasion in a HIF-1α-dependent manner [PMID:38455399].","teleology":[{"year":2004,"claim":"Established the molecular identity, domain architecture, and expression pattern of the protein, defining it as a thioredoxin-family member confined to spermatids.","evidence":"cDNA cloning, in situ hybridization, IHC, Western blot, and 3D structural modeling in rat testes","pmids":["15223837"],"confidence":"Medium","gaps":["No functional assay of the predicted thioredoxin activity","No in vivo loss-of-function phenotype"]},{"year":2017,"claim":"Demonstrated SPATA20 is essential for spermiogenesis by linking its loss to defective head shaping and manchette structure, and connected it mechanistically to the proteasome via PSMC3 binding.","evidence":"PiggyBac transposon mouse knockout with morphological phenotyping plus proteome microarray and GST pull-down","pmids":["29247744"],"confidence":"High","gaps":["PSMC3 interaction not validated reciprocally in vivo","Functional consequence of the SPATA20-PSMC3 interaction for proteasome activity not defined"]},{"year":2022,"claim":"Translated the germ-cell role to human disease, showing a loss-of-function SPATA20 variant causes acephalic spermatozoa syndrome and reduces the head-tail coupling factor SPATA6.","evidence":"Whole-exome/Sanger sequencing and Western blot in a patient with clinical phenotyping","pmids":["36415156"],"confidence":"Medium","gaps":["Single patient/lab","Mechanistic link between SPATA20 loss and reduced SPATA6 not established","ICSI rescue failure unexplained mechanistically"]},{"year":2024,"claim":"Placed SPATA20 within a defined proteostatic pathway by showing its stability depends on UBL7-mediated protection from proteasomal degradation in the head-tail coupling apparatus.","evidence":"Two-step immunoprecipitation and mass spectrometry in a UBL7 knockout mouse model","pmids":["40268954"],"confidence":"Medium","gaps":["Direct UBL7-SPATA20 binding interface not mapped","Single lab"]},{"year":2024,"claim":"Revealed an unexpected somatic role, implicating SPATA20 as a suppressor of HIF-1α synthesis and of cancer cell migration/invasion.","evidence":"siRNA knockdown, transcriptional reporter, migration/invasion assays, and HIF-1α inhibitor rescue in cancer cells","pmids":["38455399"],"confidence":"Medium","gaps":["Proposed AKT/cap-dependent translation mechanism not confirmed by reconstitution or mutagenesis","Single lab"]},{"year":null,"claim":"Whether SPATA20's thioredoxin domain has catalytic redox activity and how this connects to its roles in spermatid morphogenesis and HIF-1α regulation remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No demonstrated enzymatic thioredoxin activity","No structural model of SPATA20 complexes","Mechanism unifying germ-cell and cancer roles unknown"]}],"mechanism_profile":{"molecular_activity":[],"localization":[],"pathway":[],"complexes":[],"partners":["PSMC3","UBL7"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8TB22","full_name":"Spermatogenesis-associated protein 20","aliases":["Sperm-specific protein 411","Ssp411"],"length_aa":786,"mass_kda":87.9,"function":"May play a role in fertility regulation","subcellular_location":"Secreted","url":"https://www.uniprot.org/uniprotkb/Q8TB22/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SPATA20","classification":"Not Classified","n_dependent_lines":8,"n_total_lines":1208,"dependency_fraction":0.006622516556291391},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/SPATA20","total_profiled":1310},"omim":[{"mim_id":"613939","title":"SPERMATOGENESIS-ASSOCIATED PROTEIN 20; SPATA20","url":"https://www.omim.org/entry/613939"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Principal piece","reliability":"Approved"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"testis","ntpm":112.8}],"url":"https://www.proteinatlas.org/search/SPATA20"},"hgnc":{"alias_symbol":["FLJ21347","SSP411","Tisp78"],"prev_symbol":[]},"alphafold":{"accession":"Q8TB22","domains":[{"cath_id":"3.40.30.10","chopping":"65-228","consensus_level":"high","plddt":92.5401,"start":65,"end":228},{"cath_id":"-","chopping":"241-502","consensus_level":"medium","plddt":96.742,"start":241,"end":502},{"cath_id":"1.50.10","chopping":"504-785","consensus_level":"medium","plddt":94.0786,"start":504,"end":785}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8TB22","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8TB22-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8TB22-F1-predicted_aligned_error_v6.png","plddt_mean":89.69},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SPATA20","jax_strain_url":"https://www.jax.org/strain/search?query=SPATA20"},"sequence":{"accession":"Q8TB22","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8TB22.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8TB22/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8TB22"}},"corpus_meta":[{"pmid":"23118872","id":"PMC_23118872","title":"Comparative proteomic profiling of human bile reveals SSP411 as a novel biomarker of cholangiocarcinoma.","date":"2012","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/23118872","citation_count":63,"is_preprint":false},{"pmid":"28582417","id":"PMC_28582417","title":"Genome-wide alteration in DNA hydroxymethylation in the sperm from bisphenol A-exposed men.","date":"2017","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/28582417","citation_count":55,"is_preprint":false},{"pmid":"32678325","id":"PMC_32678325","title":"High fat diet causes distinct aberrations in the testicular proteome.","date":"2020","source":"International journal of obesity (2005)","url":"https://pubmed.ncbi.nlm.nih.gov/32678325","citation_count":26,"is_preprint":false},{"pmid":"36415156","id":"PMC_36415156","title":"Identification of nonfunctional SPATA20 causing acephalic spermatozoa syndrome in humans.","date":"2022","source":"Clinical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/36415156","citation_count":25,"is_preprint":false},{"pmid":"35173218","id":"PMC_35173218","title":"Using publicly available transcriptomic data to identify mechanistic and diagnostic biomarkers in azoospermia and overall male infertility.","date":"2022","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/35173218","citation_count":24,"is_preprint":false},{"pmid":"38244704","id":"PMC_38244704","title":"Intrahepatic cholangiocarcinoma biomarkers: Towards early detection and personalized pharmacological treatments.","date":"2024","source":"Molecular and cellular probes","url":"https://pubmed.ncbi.nlm.nih.gov/38244704","citation_count":21,"is_preprint":false},{"pmid":"15223837","id":"PMC_15223837","title":"Cloning and characterization of rat spermatid protein SSP411: a thioredoxin-like protein.","date":"2004","source":"Journal of andrology","url":"https://pubmed.ncbi.nlm.nih.gov/15223837","citation_count":19,"is_preprint":false},{"pmid":"29247744","id":"PMC_29247744","title":"Disruption of Ssp411 causes impaired sperm head formation and male sterility in mice.","date":"2017","source":"Biochimica et biophysica acta. General subjects","url":"https://pubmed.ncbi.nlm.nih.gov/29247744","citation_count":17,"is_preprint":false},{"pmid":"39417902","id":"PMC_39417902","title":"Genetic etiological spectrum of sperm morphological abnormalities.","date":"2024","source":"Journal of assisted reproduction and genetics","url":"https://pubmed.ncbi.nlm.nih.gov/39417902","citation_count":17,"is_preprint":false},{"pmid":"35887156","id":"PMC_35887156","title":"Characterization of MicroRNAs Associated with Reproduction in the Brown Planthopper, Nilaparvata lugens.","date":"2022","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/35887156","citation_count":13,"is_preprint":false},{"pmid":"34045552","id":"PMC_34045552","title":"Exome sequencing of early-onset patients supports genetic heterogeneity in colorectal cancer.","date":"2021","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/34045552","citation_count":10,"is_preprint":false},{"pmid":"31145760","id":"PMC_31145760","title":"Regional fat depot masses are influenced by protein-coding gene variants.","date":"2019","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/31145760","citation_count":9,"is_preprint":false},{"pmid":"37812598","id":"PMC_37812598","title":"Differentially expressed genes in the testes from early to mature development of banana shrimp (Fenneropenaeus merguiensis).","date":"2023","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/37812598","citation_count":4,"is_preprint":false},{"pmid":"40268954","id":"PMC_40268954","title":"UBL7 is indispensable for spermiogenesis through protecting critical factors from excessive degradation by proteasomes.","date":"2025","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/40268954","citation_count":2,"is_preprint":false},{"pmid":"39091129","id":"PMC_39091129","title":"Application of genome tagging technology in elucidating the function of sperm-specific protein 411 (Ssp411).","date":"2024","source":"Asian journal of andrology","url":"https://pubmed.ncbi.nlm.nih.gov/39091129","citation_count":1,"is_preprint":false},{"pmid":"38455399","id":"PMC_38455399","title":"SPATA20 deficiency enhances the metastatic and angiogenic potential of cancer cells by promoting HIF-1α synthesis.","date":"2024","source":"American journal of cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/38455399","citation_count":1,"is_preprint":false},{"pmid":"41261704","id":"PMC_41261704","title":"Association between mitochondria-related genes and systemic lupus erythematosus: Findings from Mendelian randomization study.","date":"2025","source":"Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/41261704","citation_count":0,"is_preprint":false},{"pmid":"41488603","id":"PMC_41488603","title":"Identification of potential therapeutic targets for stroke and its subtypes by integrating proteomes and genetics from human plasma.","date":"2025","source":"Brain communications","url":"https://pubmed.ncbi.nlm.nih.gov/41488603","citation_count":0,"is_preprint":false},{"pmid":"42255490","id":"PMC_42255490","title":"Integrative Analysis of Genetic Risk Factors for Acute Myeloid Leukemia Using Mendelian Randomization and Single-Cell RNA Sequencing Validation.","date":"2026","source":"International journal of genomics","url":"https://pubmed.ncbi.nlm.nih.gov/42255490","citation_count":0,"is_preprint":false},{"pmid":"42239272","id":"PMC_42239272","title":"Proteome-wide serology reveals immune-defined subtypes of gastrointestinal disease in systemic sclerosis.","date":"2026","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/42239272","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":12626,"output_tokens":1650,"usd":0.031314,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8451,"output_tokens":1851,"usd":0.044265,"stage2_stop_reason":"end_turn"},"total_usd":0.075579,"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\": 2004,\n      \"finding\": \"SSP411 (SPATA20) was cloned from rat testes and found to contain a conserved thioredoxin-like domain in its N-terminal region; 3D structural modeling supported its classification as a member of the thioredoxin family. The mRNA was exclusively expressed in spermatids (round and elongated) in a stage-dependent manner, with protein detected mainly in elongated spermatids.\",\n      \"method\": \"cDNA cloning, Western blot, in situ hybridization, immunohistochemistry, 3D structural modeling\",\n      \"journal\": \"Journal of andrology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (ISH, IHC, Western blot, structural modeling) in a single study establishing domain architecture and cell-type-specific localization\",\n      \"pmids\": [\"15223837\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Disruption of Ssp411 (SPATA20) in mice causes male sterility with defective sperm head shaping: Ssp411-disrupted males show smaller testes, reduced sperm counts, decreased sperm motility, and aberrant manchette structure in spermatids. Ssp411 was found to interact with PSMC3 (a manchette-associated proteasome component) via proteome microarray and GST pull-down assay, implicating Ssp411 in the ubiquitin-proteasome system during spermiogenesis.\",\n      \"method\": \"PiggyBac transposon mouse knockout, real-time PCR, Western blot, immunohistochemistry, microscopy, proteome microarray, co-IP, GST pull-down assay\",\n      \"journal\": \"Biochimica et biophysica acta. General subjects\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — loss-of-function mouse model with defined morphological phenotype plus in vitro binding assays (proteome microarray + GST pull-down) identifying PSMC3 as interacting partner\",\n      \"pmids\": [\"29247744\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"A nonsense mutation in human SPATA20 (c.619C>T, p.Arg207*) causes acephalic spermatozoa syndrome (ASS) with headless spermatozoa. The variant leads to degradation of SPATA20 protein and is associated with decreased expression of SPATA6, a protein required for sperm head-tail conjunction assembly. ICSI failed to rescue infertility in the affected patient.\",\n      \"method\": \"Whole-exome sequencing, Sanger sequencing, Western blot (SPATA20 and SPATA6 expression), clinical phenotyping\",\n      \"journal\": \"Clinical genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — human loss-of-function variant with protein expression confirmation and downstream SPATA6 reduction; single patient/lab but multiple methods\",\n      \"pmids\": [\"36415156\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"UBL7 protects SPATA20 from excessive proteasomal degradation in spermatids. Using two-step immunoprecipitation, SPATA20 was identified among essential spermatid factors whose stability depends on UBL7, placing SPATA20 in the head-tail coupling apparatus pathway regulated by UBL7-VCP-proteasome axis.\",\n      \"method\": \"Two-step immunoprecipitation, UBL7 knockout mouse model, mass spectrometry\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with defined phenotype and two-step IP identifying SPATA20 as a protected substrate; single lab\",\n      \"pmids\": [\"40268954\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SPATA20 depletion in cancer cells increases HIF-1α protein levels and transcriptional activity without affecting HIF-1α degradation, suggesting SPATA20 inhibits de novo HIF-1α synthesis, possibly by repressing cap-dependent translation via AKT phosphorylation. SPATA20 depletion promotes cancer cell migration and invasion in a HIF-1α-dependent manner.\",\n      \"method\": \"siRNA knockdown, Western blot, transcriptional reporter assay, cell migration/invasion assay, pharmacological HIF-1α inhibition rescue experiment\",\n      \"journal\": \"American journal of cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — clean KD with defined cellular phenotype and rescue experiment; single lab, AKT/translation mechanism is proposed but not directly confirmed by reconstitution or mutagenesis\",\n      \"pmids\": [\"38455399\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"HA-tagged Ssp411 (SPATA20) generated by genome tagging was detected in round spermatids, elongating spermatids, elongated spermatids, and epididymal spermatozoa, but was not detectable in MII oocytes, zygotes, or 2-cell stage embryos, establishing its expression is restricted to male germ cells during spermiogenesis.\",\n      \"method\": \"Genome tagging (HA-tagged knock-in mouse model), immunofluorescence/immunodetection across germ cell stages\",\n      \"journal\": \"Asian journal of andrology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct in vivo tagging experiment with precise stage-specific localization across multiple germ cell types\",\n      \"pmids\": [\"39091129\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SPATA20 (SSP411) is a thioredoxin-domain-containing protein expressed exclusively in spermatids during spermiogenesis; it is required for sperm head shaping and head-tail conjunction formation by interacting with PSMC3 (a manchette-associated proteasome component) and by supporting SPATA6 expression, while in somatic/cancer cells it additionally suppresses HIF-1α synthesis, likely by inhibiting cap-dependent translation via AKT signaling.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SPATA20 (SSP411) is a thioredoxin-domain-containing protein expressed in a stage-dependent manner restricted to round and elongated spermatids during spermiogenesis [#0, #5]. It is required for sperm head shaping and head-tail conjunction: loss of function in mice produces male sterility with smaller testes, reduced sperm counts and motility, and aberrant manchette structure, and SPATA20 physically interacts with the manchette-associated proteasome component PSMC3, linking it to the ubiquitin-proteasome system during spermatid morphogenesis [#1]. In humans, a nonsense mutation (p.Arg207*) destabilizes the protein and causes acephalic spermatozoa syndrome, accompanied by reduced expression of the head-tail coupling factor SPATA6 [#2]. SPATA20 stability is itself controlled by the UBL7-VCP-proteasome axis, which protects it from excessive proteasomal degradation within the head-tail coupling apparatus pathway [#3]. Beyond the male germ line, SPATA20 depletion in cancer cells elevates HIF-1\\u03b1 protein and transcriptional activity without altering HIF-1\\u03b1 degradation\\u2014consistent with inhibition of de novo HIF-1\\u03b1 synthesis\\u2014and promotes migration and invasion in a HIF-1\\u03b1-dependent manner [#4].\",\n  \"teleology\": [\n    {\n      \"year\": 2004,\n      \"claim\": \"Established the molecular identity, domain architecture, and expression pattern of the protein, defining it as a thioredoxin-family member confined to spermatids.\",\n      \"evidence\": \"cDNA cloning, in situ hybridization, IHC, Western blot, and 3D structural modeling in rat testes\",\n      \"pmids\": [\"15223837\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No functional assay of the predicted thioredoxin activity\", \"No in vivo loss-of-function phenotype\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Demonstrated SPATA20 is essential for spermiogenesis by linking its loss to defective head shaping and manchette structure, and connected it mechanistically to the proteasome via PSMC3 binding.\",\n      \"evidence\": \"PiggyBac transposon mouse knockout with morphological phenotyping plus proteome microarray and GST pull-down\",\n      \"pmids\": [\"29247744\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"PSMC3 interaction not validated reciprocally in vivo\", \"Functional consequence of the SPATA20-PSMC3 interaction for proteasome activity not defined\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Translated the germ-cell role to human disease, showing a loss-of-function SPATA20 variant causes acephalic spermatozoa syndrome and reduces the head-tail coupling factor SPATA6.\",\n      \"evidence\": \"Whole-exome/Sanger sequencing and Western blot in a patient with clinical phenotyping\",\n      \"pmids\": [\"36415156\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single patient/lab\", \"Mechanistic link between SPATA20 loss and reduced SPATA6 not established\", \"ICSI rescue failure unexplained mechanistically\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Placed SPATA20 within a defined proteostatic pathway by showing its stability depends on UBL7-mediated protection from proteasomal degradation in the head-tail coupling apparatus.\",\n      \"evidence\": \"Two-step immunoprecipitation and mass spectrometry in a UBL7 knockout mouse model\",\n      \"pmids\": [\"40268954\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct UBL7-SPATA20 binding interface not mapped\", \"Single lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Revealed an unexpected somatic role, implicating SPATA20 as a suppressor of HIF-1\\u03b1 synthesis and of cancer cell migration/invasion.\",\n      \"evidence\": \"siRNA knockdown, transcriptional reporter, migration/invasion assays, and HIF-1\\u03b1 inhibitor rescue in cancer cells\",\n      \"pmids\": [\"38455399\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Proposed AKT/cap-dependent translation mechanism not confirmed by reconstitution or mutagenesis\", \"Single lab\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Whether SPATA20's thioredoxin domain has catalytic redox activity and how this connects to its roles in spermatid morphogenesis and HIF-1\\u03b1 regulation remains unresolved.\",\n      \"evidence\": null,\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No demonstrated enzymatic thioredoxin activity\", \"No structural model of SPATA20 complexes\", \"Mechanism unifying germ-cell and cancer roles unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [],\n    \"localization\": [],\n    \"pathway\": [],\n    \"complexes\": [],\n    \"partners\": [\"PSMC3\", \"UBL7\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"faith_supported":4,"faith_total":5,"faith_pct":80.0}}