{"gene":"SPAG4","run_date":"2026-06-10T07:46:38","timeline":{"discoveries":[{"year":1999,"finding":"SPAG4 (Spag4) protein specifically interacts with the outer dense fiber protein Odf1 (ODF27), but not Odf2, via a leucine zipper motif. SPAG4 also self-associates. The protein localizes to microtubules of the manchette and axoneme in elongating spermatids and epididymal sperm.","method":"Yeast two-hybrid interaction screen, co-immunoprecipitation, leucine zipper mutagenesis, immunofluorescence localization","journal":"Developmental biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal interaction demonstrated, leucine zipper-mediated binding confirmed, replicated by independent human SPAG4 paper (PMID:9691178), localization directly demonstrated","pmids":["10373309","9691178"],"is_preprint":false},{"year":2015,"finding":"SUN4/SPAG4 is an inner nuclear membrane protein essential for coupling the manchette to the nuclear periphery during spermiogenesis. In SUN4-null mice, manchette microtubules are highly disorganized, the nucleus fails to elongate, and mice display globozoospermia and infertility.","method":"Knockout mouse model, immunofluorescence, nuclear morphology analysis","journal":"Developmental biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean KO mouse with defined cellular phenotype (globozoospermia), replicated independently in two separate labs (PMID:26417726, PMID:26621829)","pmids":["26417726"],"is_preprint":false},{"year":2015,"finding":"Sun4/SPAG4 localizes to the posterior nuclear envelope of spermatids, likely interacting with Sun3/Nesprin1 LINC components. Sun4 deficiency causes mislocalization of other LINC components and failure of manchette formation, resulting in a globozoospermia-like phenotype.","method":"Knockout mouse model, immunofluorescence, co-localization studies","journal":"Biology open","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO mouse with defined phenotype, LINC component mislocalization shown, independently corroborates PMID:26417726","pmids":["26621829"],"is_preprint":false},{"year":2015,"finding":"SPAG4 (SUN4) interacts with SEPT12 in male germ cells, and SEPT12/SPAG4/LAMINB1 form a complex at the nuclear periphery of round spermatids. A SEPT12 mutation from an infertile man disrupts the integration of this nuclear envelope complex.","method":"Yeast two-hybrid, co-immunoprecipitation, co-localization by immunofluorescence","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP shown, Y2H interaction, single lab with two orthogonal methods","pmids":["25775403"],"is_preprint":false},{"year":2018,"finding":"SPAG4-deficient sperm develop the head-to-tail coupling apparatus (HTCA) structurally, but the lateral attachment of the basal plate to the implantation fossa is diminished, indicating SPAG4 is required for tight anchorage of the sperm head-to-tail linkage rather than HTCA formation per se.","method":"Knockout mouse model, electron microscopy ultrastructural analysis","journal":"Histochemistry and cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mouse with ultrastructural analysis by EM, single lab","pmids":["29663073"],"is_preprint":false},{"year":2010,"finding":"Drosophila Spag4 (SUN protein ortholog) is required for centriole/basal body attachment to the spermatid nucleus. In spag4 mutants, nuclei and centrioles dissociate after meiosis. Epistasis studies placed Yuri Gagarin and dynein-dynactin activities downstream of spag4 in this centriole attachment pathway. This function does not involve either Drosophila KASH protein (Klarsicht or MSP-300).","method":"Genetic mutant analysis, immunofluorescence localization, epistasis/double-mutant analysis","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis in Drosophila ortholog, localization and mutant phenotype, single lab","pmids":["20647369"],"is_preprint":false},{"year":2023,"finding":"SUN4/SPAG4 is an inner nuclear membrane protein with a classical SUN domain protein topology: the C-terminal SUN domain localizes to the perinuclear space and the N-terminus is directed to the nucleoplasm where it interacts with the spermiogenesis-specific lamin B3. SUN4 also forms heteromeric assemblies with SUN3 in vivo and regulates SUN3 expression.","method":"Topology analysis by protease protection/membrane fractionation, co-immunoprecipitation, immunofluorescence, Western blot","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — direct topology determination, co-IP for lamin B3 and SUN3 interactions, multiple orthogonal methods in single study","pmids":["36825599"],"is_preprint":false},{"year":2018,"finding":"SPAG4 interacts with Nesprin3 in lung cancer cells, as determined by co-immunoprecipitation and bimolecular fluorescence complementation. SPAG4 knockdown reduces migration of A549 lung cancer cells, and SPAG4 acts as a positive regulator of Nesprin3 localization and expression. Silencing Nesprin3 also reduces cell migration.","method":"Co-immunoprecipitation, bimolecular fluorescence complementation (BiFC), RNAi knockdown, scratch migration assay, immunofluorescence","journal":"Oncology reports","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — reciprocal Co-IP plus BiFC for interaction, functional KD phenotype, single lab","pmids":["29901114"],"is_preprint":false},{"year":2013,"finding":"SPAG4 expression is regulated by hypoxia via a HIF-1 and VHL-dependent mechanism. SPAG4 knockdown reduces invasion capability of renal clear cell carcinoma (RCC) cells in vitro, while overexpression enhances tumor cell migration.","method":"siRNA knockdown, transient overexpression, scratch assay, invasion assay, immunofluorescence, RNase protection assay","journal":"Molecular carcinogenesis","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — HIF/VHL regulation shown mechanistically, functional KD and OE with defined phenotypic readout, single lab","pmids":["23818324"],"is_preprint":false},{"year":2024,"finding":"SPAG4 overexpression activates the PI3K/Akt/mTOR signaling pathway and elevates HIF-1α in colorectal cancer cells, promoting mitochondrial respiration and aerobic glycolysis. Pharmacological inhibition of PI3K (LY294002) reverses SPAG4 overexpression-induced effects on proliferation, migration, invasion, and glycolysis.","method":"siRNA knockdown, overexpression, XF24 extracellular flux analysis, CCK-8, Transwell assay, Western blot, pharmacological inhibition","journal":"Journal of biochemical and molecular toxicology","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — gain- and loss-of-function with pharmacological rescue, multiple metabolic readouts, single lab","pmids":["39410830"],"is_preprint":false},{"year":2025,"finding":"SPAG4 promotes glycolytic metabolism in HT29 colorectal cancer cells through a c-MYC/SULT2B1 axis: SPAG4 knockdown reduces c-MYC expression, which decreases SULT2B1 expression, suppressing glycolysis and cell proliferation. Elevated SULT2B1 counteracts the glycolytic reduction induced by SPAG4 or c-MYC silencing.","method":"siRNA knockdown, overexpression, CCK-8, colony formation, glucose uptake, lactate production, ATP/ADP ratio, Western blot, qRT-PCR, 2-DG rescue","journal":"Discovery medicine","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — epistasis-like rescue experiment with SULT2B1 OE, multiple metabolic readouts, single lab","pmids":["40287810"],"is_preprint":false},{"year":2026,"finding":"DEHP-induced upregulation of SPAG4 activates the MAPK/ERK signaling pathway, driving epithelial-mesenchymal transition (EMT) and reduced lenvatinib responsiveness in hepatocellular carcinoma cells. Genetic silencing of SPAG4 or pharmacological MAPK/ERK inhibition reverses DEHP-induced EMT and drug resistance.","method":"siRNA knockdown, overexpression, pharmacological inhibition, EMT marker analysis, migration/invasion assays, Western blot","journal":"Chemical research in toxicology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — genetic and pharmacological rescue experiments, multiple orthogonal functional readouts, single lab","pmids":["42126986"],"is_preprint":false},{"year":2026,"finding":"tRF-3005a binds RALY, enhancing its interaction with SPAG4 mRNA and suppressing exon 8 skipping of SPAG4, leading to increased production of the oncogenic SPAG4-L isoform that activates GRB14/PI3K/AKT signaling to promote gastric cancer progression.","method":"RNA sequencing, RNA-protein interaction assays, alternative splicing analysis, co-immunoprecipitation, Western blot, functional cell assays","journal":"Cell death discovery","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — mechanistic splicing regulation with RALY interaction shown, isoform-specific downstream pathway identified, single lab","pmids":["41872130"],"is_preprint":false}],"current_model":"SPAG4/SUN4 is a testis-specific (and cancer-reactivated) inner nuclear membrane SUN-domain protein that forms LINC complexes by localizing its N-terminus to the nucleoplasm—where it interacts with lamin B3 and SEPT12—and its C-terminal SUN domain to the perinuclear space; in spermatids it couples the manchette microtubule structure to the nuclear periphery (interacting with SUN3/Nesprin1 and Odf1 via leucine zipper), is essential for nuclear elongation and sperm head-to-tail anchorage, and in cancer contexts activates PI3K/Akt/mTOR and MAPK/ERK signaling to promote glycolysis, migration, and invasion, with its expression regulated by HIF-1/VHL-dependent hypoxia and by alternative splicing controlled by the tRF-3005a/RALY axis."},"narrative":{"mechanistic_narrative":"SPAG4 (SUN4) is a testis-enriched SUN-domain protein of the inner nuclear membrane that builds LINC complexes coupling the spermatid nuclear periphery to the cytoskeletal machinery of sperm head morphogenesis [PMID:26417726, PMID:36825599]. It adopts classical SUN-protein topology, projecting its C-terminal SUN domain into the perinuclear space while its N-terminus faces the nucleoplasm, where it engages the spermiogenesis-specific lamin B3, and it forms heteromeric assemblies with SUN3 whose expression it also regulates [PMID:36825599]. Within germ cells SPAG4 anchors a nuclear-envelope complex with SEPT12 and lamin, partners with SUN3/Nesprin1 LINC components at the posterior nuclear envelope, and binds the outer dense fiber protein Odf1 through a leucine zipper, while also self-associating [PMID:10373309, PMID:9691178, PMID:26621829, PMID:25775403]. Loss of SPAG4 disorganizes the manchette, prevents nuclear elongation, and produces globozoospermia and infertility, and it is required for tight lateral anchorage of the sperm head-to-tail coupling apparatus rather than its initial assembly [PMID:26417726, PMID:26621829, PMID:29663073]; the Drosophila ortholog performs an analogous role attaching the centriole/basal body to the spermatid nucleus via a Yuri Gagarin/dynein-dynactin pathway independent of KASH proteins [PMID:20647369]. Beyond the germline, SPAG4 is reactivated in cancers, where hypoxia drives its expression through a HIF-1/VHL-dependent mechanism and it promotes migration and invasion [PMID:23818324]; mechanistically it activates PI3K/Akt/mTOR signaling with elevated HIF-1α to drive aerobic glycolysis, engages a c-MYC/SULT2B1 axis to sustain glycolytic metabolism, and activates MAPK/ERK signaling to drive EMT and drug resistance [PMID:39410830, PMID:40287810, PMID:42126986]. An oncogenic SPAG4-L splice isoform, generated when the tRF-3005a/RALY axis suppresses exon 8 skipping, activates GRB14/PI3K/AKT signaling to promote tumor progression [PMID:41872130].","teleology":[{"year":1999,"claim":"Established the first molecular partner of SPAG4, linking it physically to the sperm cytoskeleton and outer dense fibers and defining the leucine zipper as the binding interface.","evidence":"Yeast two-hybrid, co-IP, leucine zipper mutagenesis and immunofluorescence in spermatids","pmids":["10373309","9691178"],"confidence":"High","gaps":["Did not define nuclear membrane topology","Functional consequence of the Odf1 interaction in vivo not tested"]},{"year":2010,"claim":"Showed the SUN ortholog mediates centriole/basal body attachment to the spermatid nucleus, placing it upstream of dynein-dynactin and Yuri Gagarin and outside the KASH-protein axis.","evidence":"Drosophila genetic mutant, epistasis/double-mutant analysis and immunolocalization","pmids":["20647369"],"confidence":"Medium","gaps":["Ortholog-based; mammalian centriole-attachment role not directly tested","Direct binding partners at the nucleus not identified"]},{"year":2013,"claim":"Revealed cancer reactivation of SPAG4 and placed its expression under hypoxic HIF-1/VHL control while demonstrating a pro-invasive role.","evidence":"siRNA knockdown, overexpression, invasion/scratch assays in renal clear cell carcinoma","pmids":["23818324"],"confidence":"Medium","gaps":["Downstream effector pathway not defined","Direct HIF-1 binding to SPAG4 regulatory region not mapped"]},{"year":2015,"claim":"Defined SPAG4 as an inner nuclear membrane LINC component essential for manchette-to-nucleus coupling and nuclear elongation, with a knockout phenotype of globozoospermia.","evidence":"Two independent knockout mouse models with immunofluorescence and LINC-component mislocalization analysis","pmids":["26417726","26621829"],"confidence":"High","gaps":["Did not resolve membrane topology of the protein","Order of LINC assembly relative to SPAG4 not established"]},{"year":2015,"claim":"Identified a germ-cell nuclear-envelope complex of SPAG4 with SEPT12 and lamin, linking it to a human infertility mutation.","evidence":"Yeast two-hybrid, reciprocal co-IP and co-localization in male germ cells","pmids":["25775403"],"confidence":"Medium","gaps":["Single lab; reciprocal validation across systems limited","Stoichiometry and direct vs indirect contacts within the complex unresolved"]},{"year":2018,"claim":"Distinguished SPAG4's role as anchoring rather than building the head-to-tail coupling apparatus, and extended its interactome to Nesprin3 in a cancer migration context.","evidence":"KO mouse EM ultrastructure; co-IP and BiFC with migration assays in lung cancer cells","pmids":["29663073","29901114"],"confidence":"Medium","gaps":["Molecular basis of basal-plate anchorage not defined","Whether Nesprin3 interaction reflects germline LINC biology untested"]},{"year":2023,"claim":"Determined SPAG4's classical SUN topology and its nucleoplasmic engagement of lamin B3 plus SUN3 heteromer formation, providing the structural logic for LINC bridging.","evidence":"Protease protection/membrane fractionation topology, co-IP, immunofluorescence and Western blot","pmids":["36825599"],"confidence":"High","gaps":["High-resolution structure of the SUN domain assembly not solved","Direct KASH-domain partner spanning the perinuclear space not identified here"]},{"year":2024,"claim":"Connected SPAG4 to oncogenic metabolic reprogramming via PI3K/Akt/mTOR activation and HIF-1α elevation driving aerobic glycolysis.","evidence":"Gain/loss-of-function, extracellular flux analysis and PI3K pharmacological rescue in colorectal cancer cells","pmids":["39410830"],"confidence":"Medium","gaps":["How a SUN-domain INM protein activates cytoplasmic PI3K is unexplained","Direct molecular link between SPAG4 and pathway components not shown"]},{"year":2025,"claim":"Defined a c-MYC/SULT2B1 transcriptional-metabolic axis through which SPAG4 sustains glycolysis and proliferation.","evidence":"Knockdown/overexpression with SULT2B1 rescue and multiple metabolic readouts in HT29 cells","pmids":["40287810"],"confidence":"Medium","gaps":["Mechanism by which SPAG4 regulates c-MYC not established","Single cell-line context"]},{"year":2026,"claim":"Showed SPAG4 drives EMT and lenvatinib resistance via MAPK/ERK signaling under DEHP exposure, and that an alternatively spliced SPAG4-L isoform generated by the tRF-3005a/RALY axis activates GRB14/PI3K/AKT to promote tumor progression.","evidence":"Genetic/pharmacological rescue with EMT and invasion readouts; RNA-seq, RNA-protein interaction and splicing analysis with co-IP","pmids":["42126986","41872130"],"confidence":"Medium","gaps":["Isoform-specific functions of SPAG4-L vs canonical SPAG4 incompletely separated","Direct RALY-SPAG4 mRNA binding site not mapped"]},{"year":null,"claim":"How a single inner-nuclear-membrane LINC protein mechanistically activates cytoplasmic PI3K/Akt and MAPK/ERK signaling cascades in cancer remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No direct molecular bridge between SPAG4 and PI3K/MAPK components identified","Relationship between germline LINC function and oncogenic signaling unknown","No structure of SPAG4-containing complexes"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[1,2,6]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[0,1]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[9,11,12]}],"localization":[{"term_id":"GO:0005635","term_label":"nuclear envelope","supporting_discovery_ids":[1,2,6]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-1474165","term_label":"Reproduction","supporting_discovery_ids":[1,2,4]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[9,11,12]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[9,10]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[8,11]}],"complexes":["LINC complex"],"partners":["ODF1","SUN3","SEPT12","LMNB3","NESP1","NESP3","RALY"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9NPE6","full_name":"Sperm-associated antigen 4 protein","aliases":["Outer dense fiber-associated protein SPAG4","SUN domain-containing protein 4"],"length_aa":437,"mass_kda":48.2,"function":"Involved in spermatogenesis. Required for sperm head formation but not required to establish and maintain general polarity of the sperm head. Required for anchoring and organization of the manchette. Required for targeting of SUN3 and probably SYNE1 through a probable SUN1:SYNE3 LINC complex to the nuclear envelope and involved in accurate posterior sperm head localization of the complex. May anchor SUN3 the nuclear envelope. Involved in maintenance of the nuclear envelope integrity. May assist the organization and assembly of outer dense fibers (ODFs), a specific structure of the sperm tail","subcellular_location":"Membrane; Cytoplasm, cytoskeleton; Cytoplasm, cytoskeleton, flagellum axoneme; Nucleus envelope; Nucleus inner membrane","url":"https://www.uniprot.org/uniprotkb/Q9NPE6/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SPAG4","classification":"Not Classified","n_dependent_lines":15,"n_total_lines":1208,"dependency_fraction":0.012417218543046357},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/SPAG4","total_profiled":1310},"omim":[{"mim_id":"618984","title":"SAD1 AND UNC84 DOMAIN-CONTAINING PROTEIN 3; SUN3","url":"https://www.omim.org/entry/618984"},{"mim_id":"613942","title":"SAD1 AND UNC84 DOMAIN-CONTAINING PROTEIN 5; SUN5","url":"https://www.omim.org/entry/613942"},{"mim_id":"603038","title":"SPERM-ASSOCIATED ANTIGEN 4; SPAG4","url":"https://www.omim.org/entry/603038"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Group enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"pancreas","ntpm":85.0},{"tissue":"testis","ntpm":30.4}],"url":"https://www.proteinatlas.org/search/SPAG4"},"hgnc":{"alias_symbol":["SUN4","CT127"],"prev_symbol":[]},"alphafold":{"accession":"Q9NPE6","domains":[{"cath_id":"2.60.120.260","chopping":"261-423","consensus_level":"high","plddt":88.6583,"start":261,"end":423}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NPE6","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NPE6-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NPE6-F1-predicted_aligned_error_v6.png","plddt_mean":70.94},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SPAG4","jax_strain_url":"https://www.jax.org/strain/search?query=SPAG4"},"sequence":{"accession":"Q9NPE6","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9NPE6.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9NPE6/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NPE6"}},"corpus_meta":[{"pmid":"10373309","id":"PMC_10373309","title":"Spag4, a novel sperm protein, binds outer dense-fiber protein Odf1 and localizes to microtubules of manchette and axoneme.","date":"1999","source":"Developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/10373309","citation_count":134,"is_preprint":false},{"pmid":"26417726","id":"PMC_26417726","title":"SUN4 is essential for nuclear remodeling during mammalian spermiogenesis.","date":"2015","source":"Developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/26417726","citation_count":63,"is_preprint":false},{"pmid":"26621829","id":"PMC_26621829","title":"The LINC complex component Sun4 plays a crucial role in sperm head formation and fertility.","date":"2015","source":"Biology open","url":"https://pubmed.ncbi.nlm.nih.gov/26621829","citation_count":60,"is_preprint":false},{"pmid":"20647369","id":"PMC_20647369","title":"The Drosophila SUN protein Spag4 cooperates with the coiled-coil protein Yuri Gagarin to maintain association of the basal body and spermatid nucleus.","date":"2010","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/20647369","citation_count":57,"is_preprint":false},{"pmid":"10870102","id":"PMC_10870102","title":"The 'SUN' family: yeast SUN4/SCW3 is involved in cell septation.","date":"2000","source":"Yeast (Chichester, England)","url":"https://pubmed.ncbi.nlm.nih.gov/10870102","citation_count":50,"is_preprint":false},{"pmid":"25775403","id":"PMC_25775403","title":"SEPT12/SPAG4/LAMINB1 complexes are required for maintaining the integrity of the nuclear envelope in postmeiotic male germ cells.","date":"2015","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/25775403","citation_count":48,"is_preprint":false},{"pmid":"29663073","id":"PMC_29663073","title":"Ultra-structure of the sperm head-to-tail linkage complex in the absence of the spermatid-specific LINC component SPAG4.","date":"2018","source":"Histochemistry and cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/29663073","citation_count":32,"is_preprint":false},{"pmid":"14614621","id":"PMC_14614621","title":"Human sperm associated antigen 4 (SPAG4) is a potential cancer marker.","date":"2003","source":"Cell and tissue research","url":"https://pubmed.ncbi.nlm.nih.gov/14614621","citation_count":29,"is_preprint":false},{"pmid":"29901114","id":"PMC_29901114","title":"Sperm‑associated antigen 4 (SPAG4) as a new cancer marker interacts with Nesprin3 to regulate cell migration in lung carcinoma.","date":"2018","source":"Oncology reports","url":"https://pubmed.ncbi.nlm.nih.gov/29901114","citation_count":29,"is_preprint":false},{"pmid":"23818324","id":"PMC_23818324","title":"Hypoxia regulates the sperm associated antigen 4 (SPAG4) via HIF, which is expressed in renal clear cell carcinoma and promotes migration and invasion in vitro.","date":"2013","source":"Molecular carcinogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/23818324","citation_count":26,"is_preprint":false},{"pmid":"9691178","id":"PMC_9691178","title":"A novel testis-specific gene, SPAG4, whose product interacts specifically with outer dense fiber protein ODF27, maps to human chromosome 20q11.2.","date":"1998","source":"Cytogenetics and cell genetics","url":"https://pubmed.ncbi.nlm.nih.gov/9691178","citation_count":22,"is_preprint":false},{"pmid":"36825599","id":"PMC_36825599","title":"SUN4 is a spermatid type II inner nuclear membrane protein that forms heteromeric assemblies with SUN3 and interacts with lamin B3.","date":"2023","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/36825599","citation_count":9,"is_preprint":false},{"pmid":"39410830","id":"PMC_39410830","title":"SPAG4 enhances mitochondrial respiration and aerobic glycolysis in colorectal cancer cells by activating the PI3K/Akt signaling pathway.","date":"2024","source":"Journal of biochemical and molecular toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/39410830","citation_count":4,"is_preprint":false},{"pmid":"35180817","id":"PMC_35180817","title":"The impact of glutamine deprivation on the expression of MEIS3, SPAG4, LHX1, LHX2, and LHX6 genes in ERN1 knockdown U87 glioma cells.","date":"2022","source":"Endocrine regulations","url":"https://pubmed.ncbi.nlm.nih.gov/35180817","citation_count":4,"is_preprint":false},{"pmid":"39539547","id":"PMC_39539547","title":"Integrated multi-level omics profiling of disulfidptosis identifis SPAG4 as an innovative immunotherapeutic target in glioblastoma.","date":"2024","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/39539547","citation_count":1,"is_preprint":false},{"pmid":"40287810","id":"PMC_40287810","title":"SPAG4 Regulates Glycolytic Metabolism in HT29 Cells as a Target via the c-MYC/SULT2B1 Pathway.","date":"2025","source":"Discovery medicine","url":"https://pubmed.ncbi.nlm.nih.gov/40287810","citation_count":0,"is_preprint":false},{"pmid":"41872130","id":"PMC_41872130","title":"tRF-3005a regulates exon skipping of SPAG4 by interacting with RALY to drive gastric cancer progression.","date":"2026","source":"Cell death discovery","url":"https://pubmed.ncbi.nlm.nih.gov/41872130","citation_count":0,"is_preprint":false},{"pmid":"42126986","id":"PMC_42126986","title":"Di-2-ethylhexyl Phthalate Reprograms Epithelial-Mesenchymal Transition and Lenvatinib Responsiveness in Hepatoma Cells via SPAG4-Dependent MAPK/ERK Signaling.","date":"2026","source":"Chemical research in toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/42126986","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":10634,"output_tokens":3218,"usd":0.040086,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10705,"output_tokens":3634,"usd":0.072188,"stage2_stop_reason":"end_turn"},"total_usd":0.112274,"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\": 1999,\n      \"finding\": \"SPAG4 (Spag4) protein specifically interacts with the outer dense fiber protein Odf1 (ODF27), but not Odf2, via a leucine zipper motif. SPAG4 also self-associates. The protein localizes to microtubules of the manchette and axoneme in elongating spermatids and epididymal sperm.\",\n      \"method\": \"Yeast two-hybrid interaction screen, co-immunoprecipitation, leucine zipper mutagenesis, immunofluorescence localization\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal interaction demonstrated, leucine zipper-mediated binding confirmed, replicated by independent human SPAG4 paper (PMID:9691178), localization directly demonstrated\",\n      \"pmids\": [\"10373309\", \"9691178\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"SUN4/SPAG4 is an inner nuclear membrane protein essential for coupling the manchette to the nuclear periphery during spermiogenesis. In SUN4-null mice, manchette microtubules are highly disorganized, the nucleus fails to elongate, and mice display globozoospermia and infertility.\",\n      \"method\": \"Knockout mouse model, immunofluorescence, nuclear morphology analysis\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean KO mouse with defined cellular phenotype (globozoospermia), replicated independently in two separate labs (PMID:26417726, PMID:26621829)\",\n      \"pmids\": [\"26417726\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Sun4/SPAG4 localizes to the posterior nuclear envelope of spermatids, likely interacting with Sun3/Nesprin1 LINC components. Sun4 deficiency causes mislocalization of other LINC components and failure of manchette formation, resulting in a globozoospermia-like phenotype.\",\n      \"method\": \"Knockout mouse model, immunofluorescence, co-localization studies\",\n      \"journal\": \"Biology open\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO mouse with defined phenotype, LINC component mislocalization shown, independently corroborates PMID:26417726\",\n      \"pmids\": [\"26621829\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"SPAG4 (SUN4) interacts with SEPT12 in male germ cells, and SEPT12/SPAG4/LAMINB1 form a complex at the nuclear periphery of round spermatids. A SEPT12 mutation from an infertile man disrupts the integration of this nuclear envelope complex.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, co-localization by immunofluorescence\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP shown, Y2H interaction, single lab with two orthogonal methods\",\n      \"pmids\": [\"25775403\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"SPAG4-deficient sperm develop the head-to-tail coupling apparatus (HTCA) structurally, but the lateral attachment of the basal plate to the implantation fossa is diminished, indicating SPAG4 is required for tight anchorage of the sperm head-to-tail linkage rather than HTCA formation per se.\",\n      \"method\": \"Knockout mouse model, electron microscopy ultrastructural analysis\",\n      \"journal\": \"Histochemistry and cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse with ultrastructural analysis by EM, single lab\",\n      \"pmids\": [\"29663073\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Drosophila Spag4 (SUN protein ortholog) is required for centriole/basal body attachment to the spermatid nucleus. In spag4 mutants, nuclei and centrioles dissociate after meiosis. Epistasis studies placed Yuri Gagarin and dynein-dynactin activities downstream of spag4 in this centriole attachment pathway. This function does not involve either Drosophila KASH protein (Klarsicht or MSP-300).\",\n      \"method\": \"Genetic mutant analysis, immunofluorescence localization, epistasis/double-mutant analysis\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis in Drosophila ortholog, localization and mutant phenotype, single lab\",\n      \"pmids\": [\"20647369\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"SUN4/SPAG4 is an inner nuclear membrane protein with a classical SUN domain protein topology: the C-terminal SUN domain localizes to the perinuclear space and the N-terminus is directed to the nucleoplasm where it interacts with the spermiogenesis-specific lamin B3. SUN4 also forms heteromeric assemblies with SUN3 in vivo and regulates SUN3 expression.\",\n      \"method\": \"Topology analysis by protease protection/membrane fractionation, co-immunoprecipitation, immunofluorescence, Western blot\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — direct topology determination, co-IP for lamin B3 and SUN3 interactions, multiple orthogonal methods in single study\",\n      \"pmids\": [\"36825599\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"SPAG4 interacts with Nesprin3 in lung cancer cells, as determined by co-immunoprecipitation and bimolecular fluorescence complementation. SPAG4 knockdown reduces migration of A549 lung cancer cells, and SPAG4 acts as a positive regulator of Nesprin3 localization and expression. Silencing Nesprin3 also reduces cell migration.\",\n      \"method\": \"Co-immunoprecipitation, bimolecular fluorescence complementation (BiFC), RNAi knockdown, scratch migration assay, immunofluorescence\",\n      \"journal\": \"Oncology reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — reciprocal Co-IP plus BiFC for interaction, functional KD phenotype, single lab\",\n      \"pmids\": [\"29901114\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"SPAG4 expression is regulated by hypoxia via a HIF-1 and VHL-dependent mechanism. SPAG4 knockdown reduces invasion capability of renal clear cell carcinoma (RCC) cells in vitro, while overexpression enhances tumor cell migration.\",\n      \"method\": \"siRNA knockdown, transient overexpression, scratch assay, invasion assay, immunofluorescence, RNase protection assay\",\n      \"journal\": \"Molecular carcinogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — HIF/VHL regulation shown mechanistically, functional KD and OE with defined phenotypic readout, single lab\",\n      \"pmids\": [\"23818324\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SPAG4 overexpression activates the PI3K/Akt/mTOR signaling pathway and elevates HIF-1α in colorectal cancer cells, promoting mitochondrial respiration and aerobic glycolysis. Pharmacological inhibition of PI3K (LY294002) reverses SPAG4 overexpression-induced effects on proliferation, migration, invasion, and glycolysis.\",\n      \"method\": \"siRNA knockdown, overexpression, XF24 extracellular flux analysis, CCK-8, Transwell assay, Western blot, pharmacological inhibition\",\n      \"journal\": \"Journal of biochemical and molecular toxicology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — gain- and loss-of-function with pharmacological rescue, multiple metabolic readouts, single lab\",\n      \"pmids\": [\"39410830\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SPAG4 promotes glycolytic metabolism in HT29 colorectal cancer cells through a c-MYC/SULT2B1 axis: SPAG4 knockdown reduces c-MYC expression, which decreases SULT2B1 expression, suppressing glycolysis and cell proliferation. Elevated SULT2B1 counteracts the glycolytic reduction induced by SPAG4 or c-MYC silencing.\",\n      \"method\": \"siRNA knockdown, overexpression, CCK-8, colony formation, glucose uptake, lactate production, ATP/ADP ratio, Western blot, qRT-PCR, 2-DG rescue\",\n      \"journal\": \"Discovery medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — epistasis-like rescue experiment with SULT2B1 OE, multiple metabolic readouts, single lab\",\n      \"pmids\": [\"40287810\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"DEHP-induced upregulation of SPAG4 activates the MAPK/ERK signaling pathway, driving epithelial-mesenchymal transition (EMT) and reduced lenvatinib responsiveness in hepatocellular carcinoma cells. Genetic silencing of SPAG4 or pharmacological MAPK/ERK inhibition reverses DEHP-induced EMT and drug resistance.\",\n      \"method\": \"siRNA knockdown, overexpression, pharmacological inhibition, EMT marker analysis, migration/invasion assays, Western blot\",\n      \"journal\": \"Chemical research in toxicology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — genetic and pharmacological rescue experiments, multiple orthogonal functional readouts, single lab\",\n      \"pmids\": [\"42126986\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"tRF-3005a binds RALY, enhancing its interaction with SPAG4 mRNA and suppressing exon 8 skipping of SPAG4, leading to increased production of the oncogenic SPAG4-L isoform that activates GRB14/PI3K/AKT signaling to promote gastric cancer progression.\",\n      \"method\": \"RNA sequencing, RNA-protein interaction assays, alternative splicing analysis, co-immunoprecipitation, Western blot, functional cell assays\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — mechanistic splicing regulation with RALY interaction shown, isoform-specific downstream pathway identified, single lab\",\n      \"pmids\": [\"41872130\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SPAG4/SUN4 is a testis-specific (and cancer-reactivated) inner nuclear membrane SUN-domain protein that forms LINC complexes by localizing its N-terminus to the nucleoplasm—where it interacts with lamin B3 and SEPT12—and its C-terminal SUN domain to the perinuclear space; in spermatids it couples the manchette microtubule structure to the nuclear periphery (interacting with SUN3/Nesprin1 and Odf1 via leucine zipper), is essential for nuclear elongation and sperm head-to-tail anchorage, and in cancer contexts activates PI3K/Akt/mTOR and MAPK/ERK signaling to promote glycolysis, migration, and invasion, with its expression regulated by HIF-1/VHL-dependent hypoxia and by alternative splicing controlled by the tRF-3005a/RALY axis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SPAG4 (SUN4) is a testis-enriched SUN-domain protein of the inner nuclear membrane that builds LINC complexes coupling the spermatid nuclear periphery to the cytoskeletal machinery of sperm head morphogenesis [#1, #6]. It adopts classical SUN-protein topology, projecting its C-terminal SUN domain into the perinuclear space while its N-terminus faces the nucleoplasm, where it engages the spermiogenesis-specific lamin B3, and it forms heteromeric assemblies with SUN3 whose expression it also regulates [#6]. Within germ cells SPAG4 anchors a nuclear-envelope complex with SEPT12 and lamin, partners with SUN3/Nesprin1 LINC components at the posterior nuclear envelope, and binds the outer dense fiber protein Odf1 through a leucine zipper, while also self-associating [#0, #2, #3]. Loss of SPAG4 disorganizes the manchette, prevents nuclear elongation, and produces globozoospermia and infertility, and it is required for tight lateral anchorage of the sperm head-to-tail coupling apparatus rather than its initial assembly [#1, #2, #4]; the Drosophila ortholog performs an analogous role attaching the centriole/basal body to the spermatid nucleus via a Yuri Gagarin/dynein-dynactin pathway independent of KASH proteins [#5]. Beyond the germline, SPAG4 is reactivated in cancers, where hypoxia drives its expression through a HIF-1/VHL-dependent mechanism and it promotes migration and invasion [#8]; mechanistically it activates PI3K/Akt/mTOR signaling with elevated HIF-1\\u03b1 to drive aerobic glycolysis, engages a c-MYC/SULT2B1 axis to sustain glycolytic metabolism, and activates MAPK/ERK signaling to drive EMT and drug resistance [#9, #10, #11]. An oncogenic SPAG4-L splice isoform, generated when the tRF-3005a/RALY axis suppresses exon 8 skipping, activates GRB14/PI3K/AKT signaling to promote tumor progression [#12].\",\n  \"teleology\": [\n    {\n      \"year\": 1999,\n      \"claim\": \"Established the first molecular partner of SPAG4, linking it physically to the sperm cytoskeleton and outer dense fibers and defining the leucine zipper as the binding interface.\",\n      \"evidence\": \"Yeast two-hybrid, co-IP, leucine zipper mutagenesis and immunofluorescence in spermatids\",\n      \"pmids\": [\"10373309\", \"9691178\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define nuclear membrane topology\", \"Functional consequence of the Odf1 interaction in vivo not tested\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Showed the SUN ortholog mediates centriole/basal body attachment to the spermatid nucleus, placing it upstream of dynein-dynactin and Yuri Gagarin and outside the KASH-protein axis.\",\n      \"evidence\": \"Drosophila genetic mutant, epistasis/double-mutant analysis and immunolocalization\",\n      \"pmids\": [\"20647369\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Ortholog-based; mammalian centriole-attachment role not directly tested\", \"Direct binding partners at the nucleus not identified\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Revealed cancer reactivation of SPAG4 and placed its expression under hypoxic HIF-1/VHL control while demonstrating a pro-invasive role.\",\n      \"evidence\": \"siRNA knockdown, overexpression, invasion/scratch assays in renal clear cell carcinoma\",\n      \"pmids\": [\"23818324\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Downstream effector pathway not defined\", \"Direct HIF-1 binding to SPAG4 regulatory region not mapped\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Defined SPAG4 as an inner nuclear membrane LINC component essential for manchette-to-nucleus coupling and nuclear elongation, with a knockout phenotype of globozoospermia.\",\n      \"evidence\": \"Two independent knockout mouse models with immunofluorescence and LINC-component mislocalization analysis\",\n      \"pmids\": [\"26417726\", \"26621829\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve membrane topology of the protein\", \"Order of LINC assembly relative to SPAG4 not established\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identified a germ-cell nuclear-envelope complex of SPAG4 with SEPT12 and lamin, linking it to a human infertility mutation.\",\n      \"evidence\": \"Yeast two-hybrid, reciprocal co-IP and co-localization in male germ cells\",\n      \"pmids\": [\"25775403\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab; reciprocal validation across systems limited\", \"Stoichiometry and direct vs indirect contacts within the complex unresolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Distinguished SPAG4's role as anchoring rather than building the head-to-tail coupling apparatus, and extended its interactome to Nesprin3 in a cancer migration context.\",\n      \"evidence\": \"KO mouse EM ultrastructure; co-IP and BiFC with migration assays in lung cancer cells\",\n      \"pmids\": [\"29663073\", \"29901114\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular basis of basal-plate anchorage not defined\", \"Whether Nesprin3 interaction reflects germline LINC biology untested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Determined SPAG4's classical SUN topology and its nucleoplasmic engagement of lamin B3 plus SUN3 heteromer formation, providing the structural logic for LINC bridging.\",\n      \"evidence\": \"Protease protection/membrane fractionation topology, co-IP, immunofluorescence and Western blot\",\n      \"pmids\": [\"36825599\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"High-resolution structure of the SUN domain assembly not solved\", \"Direct KASH-domain partner spanning the perinuclear space not identified here\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Connected SPAG4 to oncogenic metabolic reprogramming via PI3K/Akt/mTOR activation and HIF-1\\u03b1 elevation driving aerobic glycolysis.\",\n      \"evidence\": \"Gain/loss-of-function, extracellular flux analysis and PI3K pharmacological rescue in colorectal cancer cells\",\n      \"pmids\": [\"39410830\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How a SUN-domain INM protein activates cytoplasmic PI3K is unexplained\", \"Direct molecular link between SPAG4 and pathway components not shown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defined a c-MYC/SULT2B1 transcriptional-metabolic axis through which SPAG4 sustains glycolysis and proliferation.\",\n      \"evidence\": \"Knockdown/overexpression with SULT2B1 rescue and multiple metabolic readouts in HT29 cells\",\n      \"pmids\": [\"40287810\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which SPAG4 regulates c-MYC not established\", \"Single cell-line context\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Showed SPAG4 drives EMT and lenvatinib resistance via MAPK/ERK signaling under DEHP exposure, and that an alternatively spliced SPAG4-L isoform generated by the tRF-3005a/RALY axis activates GRB14/PI3K/AKT to promote tumor progression.\",\n      \"evidence\": \"Genetic/pharmacological rescue with EMT and invasion readouts; RNA-seq, RNA-protein interaction and splicing analysis with co-IP\",\n      \"pmids\": [\"42126986\", \"41872130\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Isoform-specific functions of SPAG4-L vs canonical SPAG4 incompletely separated\", \"Direct RALY-SPAG4 mRNA binding site not mapped\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How a single inner-nuclear-membrane LINC protein mechanistically activates cytoplasmic PI3K/Akt and MAPK/ERK signaling cascades in cancer remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No direct molecular bridge between SPAG4 and PI3K/MAPK components identified\", \"Relationship between germline LINC function and oncogenic signaling unknown\", \"No structure of SPAG4-containing complexes\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [1, 2, 6]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [9, 11, 12]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005635\", \"supporting_discovery_ids\": [1, 2, 6]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1474165\", \"supporting_discovery_ids\": [1, 2, 4]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [9, 11, 12]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [9, 10]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [8, 11]}\n    ],\n    \"complexes\": [\"LINC complex\"],\n    \"partners\": [\"ODF1\", \"SUN3\", \"SEPT12\", \"LMNB3\", \"NESP1\", \"NESP3\", \"RALY\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}