{"gene":"MAEL","run_date":"2026-06-10T02:59:50","timeline":{"discoveries":[{"year":2023,"finding":"MAEL promotes degradation of citrate synthase (CS) and fumarate hydratase (FH) via chaperone-mediated autophagy (CMA): MAEL interacts with CS/FH through its MAEL domain and with HSPA8 through its HMG domain, thereby enhancing the binding affinity of CS/FH with HSPA8 and facilitating their transport to the lysosome for degradation. This degradation was suppressed by lysosome inhibitors (leupeptin, NH4Cl) but not by macroautophagy inhibitor 3-MA or proteasome inhibitor MG132, confirming CMA as the mechanism.","method":"Co-immunoprecipitation, domain-mapping, lysosomal inhibitor assays (leupeptin, NH4Cl, 3-MA, MG132), overexpression/knockdown in breast cancer cells","journal":"The FEBS journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP with domain mapping and orthogonal inhibitor assays, single lab","pmids":["36866961"],"is_preprint":false},{"year":2017,"finding":"MAEL promotes lysosome-dependent degradation of the protein phosphatase ILKAP in gastric cancer cells, leading to increased phosphorylation of ILKAP substrates p38, CHK1, and RSK2, thereby driving oncogenic signaling.","method":"Knockdown/overexpression in GC cell lines, xenograft tumor assays, immunoprecipitation, adenovirus-mediated ILKAP overexpression rescue experiments","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis rescue experiment plus biochemical pathway readout, single lab","pmids":["29371914"],"is_preprint":false},{"year":2016,"finding":"MAEL interacts with the transcription factor Snail and inhibits E-cadherin promoter activity in colorectal cancer cells, promoting epithelial-mesenchymal transition.","method":"Immunoprecipitation, confocal immunofluorescence co-localization, luciferase reporter assay for E-cadherin promoter activity","journal":"International journal of cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP plus luciferase reporter, single lab","pmids":["27537253"],"is_preprint":false},{"year":2013,"finding":"MAEL interacts with multiple stress granule (SG) components in cancer cells (PABPC1, YBX1, KHSRP, SYNCRIP, DDX39, ELAV1, EIF4A1, EIF3F confirmed by co-immunoprecipitation) and co-localizes with the SG marker PABPC1 in stress granules during oxidative stress.","method":"Immunoprecipitation followed by Nano-LC-MS/MS proteomics, anti-tag immunoprecipitation confirmation, immunofluorescence co-localization","journal":"Oncology reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MS-based interactome validated by reciprocal co-IP and co-localization, single lab","pmids":["24189637"],"is_preprint":false},{"year":2017,"finding":"MAEL knockdown in cancer cells induces ATM-dependent DNA damage response, leading to cancer-specific apoptosis and senescence accompanied by increased reactive oxygen species. MAEL also represses retrotransposon activity in cancer cells and its overexpression inhibits Ras-induced senescence, indicating oncogenic function via protection of genetic integrity.","method":"siRNA knockdown in multiple cancer cell lines, ATM-dependency assays, ROS measurement, DNA damage markers, Myc/Ras transformation assays, retrotransposon activity reporter","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis (ATM dependency) plus multiple orthogonal cellular phenotype readouts, single lab","pmids":["27926513"],"is_preprint":false},{"year":2022,"finding":"MAEL transcriptionally activates PTGS2, which in turn stimulates IL-8 secretion and activation of AKT/NF-κB/STAT3 signaling to promote cancer stemness and sorafenib resistance in hepatocellular carcinoma cells. The suppressive effect of MAEL knockout was rescued by PTGS2 overexpression.","method":"MAEL knockout HCC cells, transcriptional profiling, PTGS2 overexpression rescue, signaling pathway western blots (AKT, NF-κB, STAT3), IL-8 ELISA","journal":"Cancers","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic rescue epistasis plus pathway readouts, single lab","pmids":["35740546"],"is_preprint":false},{"year":2013,"finding":"MAEL protein localizes in nuage structures (intermitochondrial cement, perinuclear granules, satellite bodies) and chromatoid bodies in rat spermatogenic cells, and co-localizes with MIWI in both nuage and non-nuage compartments, suggesting a functional interaction with MIWI during spermatogenesis.","method":"Immunofluorescence and immunoelectron microscopy in rat testis sections; co-localization with DDX4, DDX25, and MIWI","journal":"Histochemistry and cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct subcellular localization by immunoelectron microscopy with co-localization data, single lab","pmids":["23412502"],"is_preprint":false},{"year":2023,"finding":"MAEL protein localizes to the mitochondria of ejaculated human spermatozoa. MAEL knockdown impairs mitochondrial function and reduces ATP production. MAEL directly binds to GPX4 and UBL4B, whose expression levels are positively correlated with MAEL in sperm and reduced in asthenozoospermic men.","method":"Immunohistochemistry, immunogold staining in human testis/sperm, siRNA knockdown in H358 cells, mitochondrial function assay, ATP measurement, co-immunoprecipitation (MAEL with GPX4 and UBL4B)","journal":"Andrology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization by immunogold plus functional KD assay plus co-IP, single lab","pmids":["36779514"],"is_preprint":false},{"year":2009,"finding":"The human MAEL gene is regulated by DNA methylation: its promoter contains a CpG island (-295 to +148), and treatment with the demethylating agent 5'-Aza-2-Deoxycytidine significantly upregulates MAEL expression in cancer cell lines.","method":"Digital differential display cloning, 5'-Aza-2-Deoxycytidine treatment, RT-PCR, promoter mapping","journal":"Molecular biology reports","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — demethylation drug experiment directly linking CpG methylation to MAEL expression, single lab","pmids":["19693694"],"is_preprint":false},{"year":2017,"finding":"Experimental hypermethylation of the MAEL promoter region (-131 to +177) suppresses MAEL expression and de-represses LINE-1 (L1) retrotransposon activity in vitro, establishing that MAEL promoter methylation controls transposon silencing.","method":"Targeted DNA methylation of MAEL promoter in human NCI-H358 cells, luciferase reporter assay, RT-qPCR of MAEL and LINE-1 expression","journal":"Human reproduction","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — targeted methylation experiment plus functional reporter and downstream transposon readout, single lab","pmids":["29095993"],"is_preprint":false},{"year":2022,"finding":"In lung cancer cells, morphine upregulates MAEL expression via the Nrf2/PTEN pathway (morphine up-regulates Nrf2 and down-regulates PTEN; PTEN reversal abolishes morphine-induced MAEL upregulation). MAEL silencing reverses morphine-induced upregulation of immune checkpoint molecules PD-L1, TGF-β, and IL-10, and partially restores CD8+ T cell killing activity.","method":"Western blot, RT-qPCR, ELISA, flow cytometry, siRNA knockdown of MAEL, PTEN overexpression, LDH release cytotoxicity assay","journal":"BMC pharmacology & toxicology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — pathway placed by siRNA/overexpression but mechanistic link is indirect (expression correlation with pathway components), single lab","pmids":["36476246"],"is_preprint":false},{"year":2022,"finding":"MAEL knockdown reduces expression of drug efflux transporters MRP and LRP in drug-resistant T-ALL cells, and MAEL overexpression enhances resistance to the Notch inhibitor LY411575, identifying MAEL as a promoter of drug resistance via regulation of MRP/LRP.","method":"RNA interference knockdown, MAEL overexpression, western blot for MRP and LRP, drug sensitivity assays in T-iPSC model","journal":"Cancer medicine","confidence":"Low","confidence_rationale":"Tier 3 / Weak — siRNA knockdown plus overexpression with defined molecular readout, single lab, single method type","pmids":["35488386"],"is_preprint":false},{"year":2013,"finding":"Mael knockdown by siRNA during early oogenesis disrupts fetal oocyte growth and differentiation in mouse fetal ovary explants, and also impairs germ-cell marker expression during embryonic stem cell differentiation into germ cells in vitro, indicating a functional role for Mael in oogenesis.","method":"siRNA knockdown in mouse fetal ovary explants and ESC differentiation assays, expression analysis of germ cell markers","journal":"Zygote","confidence":"Low","confidence_rationale":"Tier 3 / Weak — siRNA loss-of-function with cellular phenotype, single lab, single method","pmids":["23410657"],"is_preprint":false}],"current_model":"MAEL is a multifunctional protein that in germ cells localizes to nuage structures and mitochondria where it silences retrotransposons (via the piRNA pathway), binds MIWI, and supports mitochondrial function (binding GPX4/UBL4B); in cancer cells MAEL acts as an oncogene by promoting chaperone-mediated autophagy-dependent degradation of metabolic enzymes (CS, FH) and the phosphatase ILKAP, interacting with Snail to repress E-cadherin transcription, activating PTGS2/AKT/STAT3 stemness signaling, suppressing ATM-dependent DNA damage responses, and binding stress granule components—with its own expression controlled by CpG promoter methylation."},"narrative":{"mechanistic_narrative":"MAEL is a germ-cell and cancer-associated protein that links transposon silencing and nuage/mitochondrial biology to oncogenic protein turnover and signaling [PMID:23412502, PMID:27926513, PMID:36866961]. In spermatogenic cells it localizes to nuage structures (intermitochondrial cement, perinuclear granules, chromatoid bodies) and co-localizes with MIWI, and in human spermatozoa it localizes to mitochondria where it binds GPX4 and UBL4B to support mitochondrial function and ATP production [PMID:23412502, PMID:36779514]. MAEL restrains retrotransposon activity in both germ cells and cancer cells, and its own expression is controlled by CpG-island promoter methylation: demethylation upregulates MAEL while targeted promoter hypermethylation suppresses it and de-represses LINE-1 [PMID:19693694, PMID:29095993, PMID:27926513]. In cancer, MAEL acts as an oncogene by promoting chaperone-mediated autophagy-dependent degradation of target proteins—it bridges the metabolic enzymes citrate synthase and fumarate hydratase to HSPA8 via its MAEL and HMG domains for lysosomal degradation, and similarly drives lysosomal degradation of the phosphatase ILKAP to amplify p38/CHK1/RSK2 phosphorylation [PMID:36866961, PMID:29371914]. MAEL further interacts with Snail to repress the E-cadherin promoter and promote EMT, transcriptionally activates PTGS2 to engage IL-8/AKT/NF-κB/STAT3 stemness and drug-resistance signaling, and protects genomic integrity such that its knockdown triggers ATM-dependent DNA damage responses, ROS accumulation, apoptosis, and senescence [PMID:27537253, PMID:35740546, PMID:27926513]. MAEL also associates with stress granule components including PABPC1 under oxidative stress [PMID:24189637].","teleology":[{"year":2009,"claim":"Established that MAEL expression is epigenetically silenced in somatic/cancer cells, explaining its normally germline-restricted pattern and its re-expression in tumors.","evidence":"Promoter CpG-island mapping and 5'-Aza-2-Deoxycytidine demethylation with RT-PCR in cancer cell lines","pmids":["19693694"],"confidence":"Medium","gaps":["Does not identify the methyltransferases or demethylation context in vivo","Does not link methylation status to specific tumor types or outcomes"]},{"year":2013,"claim":"Defined MAEL's germline subcellular niche, placing it in nuage and chromatoid bodies alongside MIWI, the structural basis for a piRNA-pathway role.","evidence":"Immunofluorescence and immunoelectron microscopy with MIWI/DDX4/DDX25 co-localization in rat testis","pmids":["23412502"],"confidence":"Medium","gaps":["Co-localization does not demonstrate direct biochemical interaction with MIWI","Functional contribution to piRNA biogenesis not tested here"]},{"year":2013,"claim":"Showed MAEL is functionally required in the female germline, extending its role beyond spermatogenesis to oogenesis.","evidence":"siRNA knockdown in mouse fetal ovary explants and ESC-to-germ-cell differentiation assays","pmids":["23410657"],"confidence":"Low","gaps":["Single loss-of-function method without rescue","Molecular mechanism of oocyte differentiation defect undefined"]},{"year":2013,"claim":"Identified a stress-granule association for MAEL in cancer cells, suggesting RNP/RNA-regulatory engagement outside germ cells.","evidence":"Co-IP/Nano-LC-MS/MS interactome with reciprocal anti-tag co-IP and PABPC1 co-localization under oxidative stress","pmids":["24189637"],"confidence":"Medium","gaps":["Functional consequence of SG localization not established","Direct versus indirect (RNA-bridged) nature of interactions unresolved"]},{"year":2016,"claim":"Connected MAEL to EMT by showing it cooperates with Snail to repress E-cadherin, providing a transcriptional mechanism for its pro-metastatic activity.","evidence":"Co-IP, immunofluorescence co-localization, and E-cadherin promoter luciferase reporter in colorectal cancer cells","pmids":["27537253"],"confidence":"Medium","gaps":["MAEL's molecular role at the promoter (cofactor vs adaptor) unclear","Direct DNA-binding versus Snail-dependent recruitment not distinguished"]},{"year":2017,"claim":"Reframed MAEL as a guardian of genome integrity in cancer, with knockdown unleashing ATM-dependent damage responses and overexpression repressing retrotransposons and senescence.","evidence":"siRNA across cancer lines, ATM-dependency epistasis, ROS/DNA-damage markers, Myc/Ras transformation and retrotransposon reporter assays","pmids":["27926513"],"confidence":"Medium","gaps":["Molecular mechanism by which MAEL suppresses transposons/ROS not resolved","Link between transposon silencing and DNA-damage suppression inferred, not directly demonstrated"]},{"year":2017,"claim":"Identified ILKAP as a degradation target of MAEL, providing a phosphatase-loss mechanism for downstream oncogenic kinase signaling.","evidence":"Knockdown/overexpression, xenografts, IP, and adenoviral ILKAP rescue in gastric cancer cells","pmids":["29371914"],"confidence":"Medium","gaps":["Degradation route (CMA vs other lysosomal) not dissected here","Direct binding interface not mapped"]},{"year":2017,"claim":"Demonstrated causally that MAEL promoter methylation controls transposon silencing, tying the epigenetic regulation of MAEL to its biological function.","evidence":"Targeted promoter methylation in NCI-H358 cells with luciferase reporter and LINE-1 RT-qPCR","pmids":["29095993"],"confidence":"Medium","gaps":["Mechanism by which MAEL protein represses LINE-1 not addressed","In vivo relevance to germ cells not tested"]},{"year":2022,"claim":"Defined a PTGS2-centered stemness/drug-resistance axis downstream of MAEL, linking it to IL-8/AKT/NF-κB/STAT3 signaling.","evidence":"MAEL knockout HCC cells with PTGS2 rescue, signaling western blots, and IL-8 ELISA","pmids":["35740546"],"confidence":"Medium","gaps":["How MAEL transcriptionally activates PTGS2 mechanistically is unknown","Direct versus indirect transcriptional control not established"]},{"year":2022,"claim":"Linked MAEL to drug-efflux-mediated resistance, broadening its oncogenic repertoire to chemoresistance.","evidence":"RNAi/overexpression with MRP/LRP westerns and LY411575 sensitivity in T-ALL/T-iPSC model","pmids":["35488386"],"confidence":"Low","gaps":["Single method type without rescue","Mechanism connecting MAEL to MRP/LRP regulation unknown"]},{"year":2022,"claim":"Placed MAEL in an immune-evasion pathway, regulated by morphine via Nrf2/PTEN and controlling checkpoint molecule expression.","evidence":"Western/RT-qPCR/ELISA/flow cytometry with siRNA and PTEN overexpression and LDH cytotoxicity in lung cancer cells","pmids":["36476246"],"confidence":"Low","gaps":["Mechanistic link is correlative across pathway components","Direct MAEL targets in immune checkpoint regulation not identified"]},{"year":2023,"claim":"Established the molecular logic of MAEL-driven chaperone-mediated autophagy, showing it bridges metabolic enzyme substrates to HSPA8 via distinct domains for lysosomal degradation.","evidence":"Reciprocal co-IP, domain mapping, and lysosomal/macroautophagy/proteasome inhibitor panel in breast cancer cells","pmids":["36866961"],"confidence":"Medium","gaps":["Substrate selectivity rules beyond CS/FH not defined","No structural model of the MAEL–HSPA8–substrate ternary complex"]},{"year":2023,"claim":"Defined a mitochondrial function for MAEL in sperm, binding GPX4 and UBL4B, linking it to ATP production and asthenozoospermia.","evidence":"Immunogold localization, siRNA knockdown with mitochondrial/ATP assays, and co-IP in human sperm/cells","pmids":["36779514"],"confidence":"Medium","gaps":["Whether GPX4/UBL4B binding is regulatory or structural is unresolved","Causal contribution to clinical asthenozoospermia not proven"]},{"year":null,"claim":"How MAEL's germline nuage/piRNA functions mechanistically connect to its cancer-cell roles in CMA-mediated degradation, transcriptional regulation, and signaling remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural data on MAEL or HMG domain function across contexts","No unifying model linking transposon silencing to oncogenic protein degradation","Direct piRNA-pathway biochemistry for human MAEL not established in the corpus"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,1]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[2,5]}],"localization":[{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[7,6]},{"term_id":"GO:0005764","term_label":"lysosome","supporting_discovery_ids":[0,1]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[3]}],"pathway":[{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[0]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[5,1]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[4]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[4,5]}],"complexes":[],"partners":["HSPA8","SNAIL","ILKAP","MIWI","GPX4","UBL4B","PABPC1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q96JY0","full_name":"Protein maelstrom homolog","aliases":[],"length_aa":434,"mass_kda":49.2,"function":"Plays a central role during spermatogenesis by repressing transposable elements and preventing their mobilization, which is essential for the germline integrity. Acts via the piRNA metabolic process, which mediates the repression of transposable elements during meiosis by forming complexes composed of piRNAs and Piwi proteins and governs the methylation and subsequent repression of transposons. Its association with piP-bodies suggests a participation in the secondary piRNAs metabolic process. Required for the localization of germ-cell factors to the meiotic nuage (By similarity)","subcellular_location":"Cytoplasm; Nucleus","url":"https://www.uniprot.org/uniprotkb/Q96JY0/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/MAEL","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/MAEL","total_profiled":1310},"omim":[{"mim_id":"611368","title":"MAELSTROM SPERMATOGENIC TRANSPOSON SILENCER; MAEL","url":"https://www.omim.org/entry/611368"},{"mim_id":"608487","title":"TRIPARTITE MOTIF-CONTAINING PROTEIN 5; TRIM5","url":"https://www.omim.org/entry/608487"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"testis","ntpm":148.8}],"url":"https://www.proteinatlas.org/search/MAEL"},"hgnc":{"alias_symbol":["FLJ14904","CT128","SPATA35"],"prev_symbol":[]},"alphafold":{"accession":"Q96JY0","domains":[{"cath_id":"1.10.30.10","chopping":"9-64","consensus_level":"high","plddt":90.5027,"start":9,"end":64},{"cath_id":"3.30.420.10","chopping":"104-313","consensus_level":"high","plddt":90.6522,"start":104,"end":313}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96JY0","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q96JY0-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q96JY0-F1-predicted_aligned_error_v6.png","plddt_mean":72.25},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MAEL","jax_strain_url":"https://www.jax.org/strain/search?query=MAEL"},"sequence":{"accession":"Q96JY0","fasta_url":"https://rest.uniprot.org/uniprotkb/Q96JY0.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q96JY0/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96JY0"}},"corpus_meta":[{"pmid":"36866961","id":"PMC_36866961","title":"MAEL facilitates metabolic reprogramming and breast cancer progression by promoting the degradation of citrate synthase and fumarate hydratase via chaperone-mediated autophagy.","date":"2023","source":"The FEBS journal","url":"https://pubmed.ncbi.nlm.nih.gov/36866961","citation_count":42,"is_preprint":false},{"pmid":"19693694","id":"PMC_19693694","title":"Identification of a novel human cancer/testis gene MAEL that is regulated by DNA methylation.","date":"2009","source":"Molecular biology reports","url":"https://pubmed.ncbi.nlm.nih.gov/19693694","citation_count":34,"is_preprint":false},{"pmid":"23412502","id":"PMC_23412502","title":"Expression of MAEL in nuage and non-nuage compartments of rat spermatogenic cells and colocalization with DDX4, DDX25 and MIWI.","date":"2013","source":"Histochemistry and cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/23412502","citation_count":24,"is_preprint":false},{"pmid":"24189637","id":"PMC_24189637","title":"Proteomic analysis reveals that MAEL, a component of nuage, interacts with stress granule proteins in cancer cells.","date":"2013","source":"Oncology reports","url":"https://pubmed.ncbi.nlm.nih.gov/24189637","citation_count":20,"is_preprint":false},{"pmid":"29371914","id":"PMC_29371914","title":"MAEL contributes to gastric cancer progression by promoting ILKAP degradation.","date":"2017","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/29371914","citation_count":20,"is_preprint":false},{"pmid":"27537253","id":"PMC_27537253","title":"MAEL expression links epithelial-mesenchymal transition and stem cell properties in colorectal cancer.","date":"2016","source":"International journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/27537253","citation_count":18,"is_preprint":false},{"pmid":"20388553","id":"PMC_20388553","title":"Temporal expression and steroidal regulation of piRNA pathway genes (mael, piwi, vasa) during Silurana (Xenopus) tropicalis embryogenesis and early larval development.","date":"2010","source":"Comparative biochemistry and physiology. Toxicology & pharmacology : CBP","url":"https://pubmed.ncbi.nlm.nih.gov/20388553","citation_count":18,"is_preprint":false},{"pmid":"36476246","id":"PMC_36476246","title":"Morphine suppresses the immune function of lung cancer by up-regulating MAEL expression.","date":"2022","source":"BMC pharmacology & toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/36476246","citation_count":16,"is_preprint":false},{"pmid":"29095993","id":"PMC_29095993","title":"MAEL promoter hypermethylation is associated with de-repression of LINE-1 in human hypospermatogenesis.","date":"2017","source":"Human reproduction (Oxford, England)","url":"https://pubmed.ncbi.nlm.nih.gov/29095993","citation_count":15,"is_preprint":false},{"pmid":"36711243","id":"PMC_36711243","title":"MAEL gene contributes to bovine testicular development through the m5C-mediated splicing.","date":"2023","source":"iScience","url":"https://pubmed.ncbi.nlm.nih.gov/36711243","citation_count":13,"is_preprint":false},{"pmid":"27926513","id":"PMC_27926513","title":"Mael is essential for cancer cell survival and tumorigenesis through protection of genetic integrity.","date":"2017","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/27926513","citation_count":12,"is_preprint":false},{"pmid":"35740546","id":"PMC_35740546","title":"MAEL Augments Cancer Stemness Properties and Resistance to Sorafenib in Hepatocellular Carcinoma through the PTGS2/AKT/STAT3 Axis.","date":"2022","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/35740546","citation_count":11,"is_preprint":false},{"pmid":"30488287","id":"PMC_30488287","title":"MAEL Cancer-Testis Antigen as a Diagnostic Marker in Primary Stages of Gastric Cancer with Helicobacter pylori Infection.","date":"2020","source":"Journal of gastrointestinal cancer","url":"https://pubmed.ncbi.nlm.nih.gov/30488287","citation_count":6,"is_preprint":false},{"pmid":"23410657","id":"PMC_23410657","title":"Role of Mael in early oogenesis and during germ-cell differentiation from embryonic stem cells in mice in vitro.","date":"2013","source":"Zygote (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/23410657","citation_count":5,"is_preprint":false},{"pmid":"35488386","id":"PMC_35488386","title":"Identification of MAEL as a promoter for the drug resistance model of iPSCs derived from T-ALL.","date":"2022","source":"Cancer medicine","url":"https://pubmed.ncbi.nlm.nih.gov/35488386","citation_count":4,"is_preprint":false},{"pmid":"36779514","id":"PMC_36779514","title":"The MAEL expression in mitochondria of human spermatozoa and the association with asthenozoospermia.","date":"2023","source":"Andrology","url":"https://pubmed.ncbi.nlm.nih.gov/36779514","citation_count":2,"is_preprint":false},{"pmid":"33902648","id":"PMC_33902648","title":"MAEL as a diagnostic marker for the early detection of esophageal squamous cell carcinoma.","date":"2021","source":"Diagnostic pathology","url":"https://pubmed.ncbi.nlm.nih.gov/33902648","citation_count":2,"is_preprint":false},{"pmid":"9680313","id":"PMC_9680313","title":"Physical mapping of a collection of Mael-generating amber mutations in the beta gene of Escherichia coli RNA polymerase and the functional effect of internal deletions constructed through their manipulation.","date":"1997","source":"Genes and function","url":"https://pubmed.ncbi.nlm.nih.gov/9680313","citation_count":2,"is_preprint":false},{"pmid":"42156581","id":"PMC_42156581","title":"Vorinostat unmasks MAEL to enhance DC vaccine-induced CTL killing in hepatocellular carcinoma, potentiated by TIGIT checkpoint inhibition.","date":"2026","source":"Cancer immunology, immunotherapy : CII","url":"https://pubmed.ncbi.nlm.nih.gov/42156581","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.09.01.25334358","title":"Integrative genomics elucidates the evolutionary, temporal, and developmental origins of a hydrocephalus risk gene","date":"2025-09-02","source":"bioRxiv","url":"https://doi.org/10.1101/2025.09.01.25334358","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":12185,"output_tokens":3175,"usd":0.04209,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10625,"output_tokens":4130,"usd":0.078187,"stage2_stop_reason":"end_turn"},"total_usd":0.120277,"stage1_batch_id":"msgbatch_01BbTCMyrRPyhtEq6b1MdwCN","stage2_batch_id":"msgbatch_011dEed5bbxYvTAaQWKJevxu","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2023,\n      \"finding\": \"MAEL promotes degradation of citrate synthase (CS) and fumarate hydratase (FH) via chaperone-mediated autophagy (CMA): MAEL interacts with CS/FH through its MAEL domain and with HSPA8 through its HMG domain, thereby enhancing the binding affinity of CS/FH with HSPA8 and facilitating their transport to the lysosome for degradation. This degradation was suppressed by lysosome inhibitors (leupeptin, NH4Cl) but not by macroautophagy inhibitor 3-MA or proteasome inhibitor MG132, confirming CMA as the mechanism.\",\n      \"method\": \"Co-immunoprecipitation, domain-mapping, lysosomal inhibitor assays (leupeptin, NH4Cl, 3-MA, MG132), overexpression/knockdown in breast cancer cells\",\n      \"journal\": \"The FEBS journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP with domain mapping and orthogonal inhibitor assays, single lab\",\n      \"pmids\": [\"36866961\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"MAEL promotes lysosome-dependent degradation of the protein phosphatase ILKAP in gastric cancer cells, leading to increased phosphorylation of ILKAP substrates p38, CHK1, and RSK2, thereby driving oncogenic signaling.\",\n      \"method\": \"Knockdown/overexpression in GC cell lines, xenograft tumor assays, immunoprecipitation, adenovirus-mediated ILKAP overexpression rescue experiments\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis rescue experiment plus biochemical pathway readout, single lab\",\n      \"pmids\": [\"29371914\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"MAEL interacts with the transcription factor Snail and inhibits E-cadherin promoter activity in colorectal cancer cells, promoting epithelial-mesenchymal transition.\",\n      \"method\": \"Immunoprecipitation, confocal immunofluorescence co-localization, luciferase reporter assay for E-cadherin promoter activity\",\n      \"journal\": \"International journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP plus luciferase reporter, single lab\",\n      \"pmids\": [\"27537253\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"MAEL interacts with multiple stress granule (SG) components in cancer cells (PABPC1, YBX1, KHSRP, SYNCRIP, DDX39, ELAV1, EIF4A1, EIF3F confirmed by co-immunoprecipitation) and co-localizes with the SG marker PABPC1 in stress granules during oxidative stress.\",\n      \"method\": \"Immunoprecipitation followed by Nano-LC-MS/MS proteomics, anti-tag immunoprecipitation confirmation, immunofluorescence co-localization\",\n      \"journal\": \"Oncology reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MS-based interactome validated by reciprocal co-IP and co-localization, single lab\",\n      \"pmids\": [\"24189637\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"MAEL knockdown in cancer cells induces ATM-dependent DNA damage response, leading to cancer-specific apoptosis and senescence accompanied by increased reactive oxygen species. MAEL also represses retrotransposon activity in cancer cells and its overexpression inhibits Ras-induced senescence, indicating oncogenic function via protection of genetic integrity.\",\n      \"method\": \"siRNA knockdown in multiple cancer cell lines, ATM-dependency assays, ROS measurement, DNA damage markers, Myc/Ras transformation assays, retrotransposon activity reporter\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis (ATM dependency) plus multiple orthogonal cellular phenotype readouts, single lab\",\n      \"pmids\": [\"27926513\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"MAEL transcriptionally activates PTGS2, which in turn stimulates IL-8 secretion and activation of AKT/NF-κB/STAT3 signaling to promote cancer stemness and sorafenib resistance in hepatocellular carcinoma cells. The suppressive effect of MAEL knockout was rescued by PTGS2 overexpression.\",\n      \"method\": \"MAEL knockout HCC cells, transcriptional profiling, PTGS2 overexpression rescue, signaling pathway western blots (AKT, NF-κB, STAT3), IL-8 ELISA\",\n      \"journal\": \"Cancers\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic rescue epistasis plus pathway readouts, single lab\",\n      \"pmids\": [\"35740546\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"MAEL protein localizes in nuage structures (intermitochondrial cement, perinuclear granules, satellite bodies) and chromatoid bodies in rat spermatogenic cells, and co-localizes with MIWI in both nuage and non-nuage compartments, suggesting a functional interaction with MIWI during spermatogenesis.\",\n      \"method\": \"Immunofluorescence and immunoelectron microscopy in rat testis sections; co-localization with DDX4, DDX25, and MIWI\",\n      \"journal\": \"Histochemistry and cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct subcellular localization by immunoelectron microscopy with co-localization data, single lab\",\n      \"pmids\": [\"23412502\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"MAEL protein localizes to the mitochondria of ejaculated human spermatozoa. MAEL knockdown impairs mitochondrial function and reduces ATP production. MAEL directly binds to GPX4 and UBL4B, whose expression levels are positively correlated with MAEL in sperm and reduced in asthenozoospermic men.\",\n      \"method\": \"Immunohistochemistry, immunogold staining in human testis/sperm, siRNA knockdown in H358 cells, mitochondrial function assay, ATP measurement, co-immunoprecipitation (MAEL with GPX4 and UBL4B)\",\n      \"journal\": \"Andrology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization by immunogold plus functional KD assay plus co-IP, single lab\",\n      \"pmids\": [\"36779514\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"The human MAEL gene is regulated by DNA methylation: its promoter contains a CpG island (-295 to +148), and treatment with the demethylating agent 5'-Aza-2-Deoxycytidine significantly upregulates MAEL expression in cancer cell lines.\",\n      \"method\": \"Digital differential display cloning, 5'-Aza-2-Deoxycytidine treatment, RT-PCR, promoter mapping\",\n      \"journal\": \"Molecular biology reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — demethylation drug experiment directly linking CpG methylation to MAEL expression, single lab\",\n      \"pmids\": [\"19693694\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Experimental hypermethylation of the MAEL promoter region (-131 to +177) suppresses MAEL expression and de-represses LINE-1 (L1) retrotransposon activity in vitro, establishing that MAEL promoter methylation controls transposon silencing.\",\n      \"method\": \"Targeted DNA methylation of MAEL promoter in human NCI-H358 cells, luciferase reporter assay, RT-qPCR of MAEL and LINE-1 expression\",\n      \"journal\": \"Human reproduction\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — targeted methylation experiment plus functional reporter and downstream transposon readout, single lab\",\n      \"pmids\": [\"29095993\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"In lung cancer cells, morphine upregulates MAEL expression via the Nrf2/PTEN pathway (morphine up-regulates Nrf2 and down-regulates PTEN; PTEN reversal abolishes morphine-induced MAEL upregulation). MAEL silencing reverses morphine-induced upregulation of immune checkpoint molecules PD-L1, TGF-β, and IL-10, and partially restores CD8+ T cell killing activity.\",\n      \"method\": \"Western blot, RT-qPCR, ELISA, flow cytometry, siRNA knockdown of MAEL, PTEN overexpression, LDH release cytotoxicity assay\",\n      \"journal\": \"BMC pharmacology & toxicology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — pathway placed by siRNA/overexpression but mechanistic link is indirect (expression correlation with pathway components), single lab\",\n      \"pmids\": [\"36476246\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"MAEL knockdown reduces expression of drug efflux transporters MRP and LRP in drug-resistant T-ALL cells, and MAEL overexpression enhances resistance to the Notch inhibitor LY411575, identifying MAEL as a promoter of drug resistance via regulation of MRP/LRP.\",\n      \"method\": \"RNA interference knockdown, MAEL overexpression, western blot for MRP and LRP, drug sensitivity assays in T-iPSC model\",\n      \"journal\": \"Cancer medicine\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — siRNA knockdown plus overexpression with defined molecular readout, single lab, single method type\",\n      \"pmids\": [\"35488386\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Mael knockdown by siRNA during early oogenesis disrupts fetal oocyte growth and differentiation in mouse fetal ovary explants, and also impairs germ-cell marker expression during embryonic stem cell differentiation into germ cells in vitro, indicating a functional role for Mael in oogenesis.\",\n      \"method\": \"siRNA knockdown in mouse fetal ovary explants and ESC differentiation assays, expression analysis of germ cell markers\",\n      \"journal\": \"Zygote\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — siRNA loss-of-function with cellular phenotype, single lab, single method\",\n      \"pmids\": [\"23410657\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MAEL is a multifunctional protein that in germ cells localizes to nuage structures and mitochondria where it silences retrotransposons (via the piRNA pathway), binds MIWI, and supports mitochondrial function (binding GPX4/UBL4B); in cancer cells MAEL acts as an oncogene by promoting chaperone-mediated autophagy-dependent degradation of metabolic enzymes (CS, FH) and the phosphatase ILKAP, interacting with Snail to repress E-cadherin transcription, activating PTGS2/AKT/STAT3 stemness signaling, suppressing ATM-dependent DNA damage responses, and binding stress granule components—with its own expression controlled by CpG promoter methylation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"MAEL is a germ-cell and cancer-associated protein that links transposon silencing and nuage/mitochondrial biology to oncogenic protein turnover and signaling [#6, #4, #0]. In spermatogenic cells it localizes to nuage structures (intermitochondrial cement, perinuclear granules, chromatoid bodies) and co-localizes with MIWI, and in human spermatozoa it localizes to mitochondria where it binds GPX4 and UBL4B to support mitochondrial function and ATP production [#6, #7]. MAEL restrains retrotransposon activity in both germ cells and cancer cells, and its own expression is controlled by CpG-island promoter methylation: demethylation upregulates MAEL while targeted promoter hypermethylation suppresses it and de-represses LINE-1 [#8, #9, #4]. In cancer, MAEL acts as an oncogene by promoting chaperone-mediated autophagy-dependent degradation of target proteins—it bridges the metabolic enzymes citrate synthase and fumarate hydratase to HSPA8 via its MAEL and HMG domains for lysosomal degradation, and similarly drives lysosomal degradation of the phosphatase ILKAP to amplify p38/CHK1/RSK2 phosphorylation [#0, #1]. MAEL further interacts with Snail to repress the E-cadherin promoter and promote EMT, transcriptionally activates PTGS2 to engage IL-8/AKT/NF-\\u03baB/STAT3 stemness and drug-resistance signaling, and protects genomic integrity such that its knockdown triggers ATM-dependent DNA damage responses, ROS accumulation, apoptosis, and senescence [#2, #5, #4]. MAEL also associates with stress granule components including PABPC1 under oxidative stress [#3].\"\n,\n  \"teleology\": [\n    {\n      \"year\": 2009,\n      \"claim\": \"Established that MAEL expression is epigenetically silenced in somatic/cancer cells, explaining its normally germline-restricted pattern and its re-expression in tumors.\",\n      \"evidence\": \"Promoter CpG-island mapping and 5'-Aza-2-Deoxycytidine demethylation with RT-PCR in cancer cell lines\",\n      \"pmids\": [\"19693694\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not identify the methyltransferases or demethylation context in vivo\", \"Does not link methylation status to specific tumor types or outcomes\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Defined MAEL's germline subcellular niche, placing it in nuage and chromatoid bodies alongside MIWI, the structural basis for a piRNA-pathway role.\",\n      \"evidence\": \"Immunofluorescence and immunoelectron microscopy with MIWI/DDX4/DDX25 co-localization in rat testis\",\n      \"pmids\": [\"23412502\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Co-localization does not demonstrate direct biochemical interaction with MIWI\", \"Functional contribution to piRNA biogenesis not tested here\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Showed MAEL is functionally required in the female germline, extending its role beyond spermatogenesis to oogenesis.\",\n      \"evidence\": \"siRNA knockdown in mouse fetal ovary explants and ESC-to-germ-cell differentiation assays\",\n      \"pmids\": [\"23410657\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single loss-of-function method without rescue\", \"Molecular mechanism of oocyte differentiation defect undefined\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identified a stress-granule association for MAEL in cancer cells, suggesting RNP/RNA-regulatory engagement outside germ cells.\",\n      \"evidence\": \"Co-IP/Nano-LC-MS/MS interactome with reciprocal anti-tag co-IP and PABPC1 co-localization under oxidative stress\",\n      \"pmids\": [\"24189637\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of SG localization not established\", \"Direct versus indirect (RNA-bridged) nature of interactions unresolved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Connected MAEL to EMT by showing it cooperates with Snail to repress E-cadherin, providing a transcriptional mechanism for its pro-metastatic activity.\",\n      \"evidence\": \"Co-IP, immunofluorescence co-localization, and E-cadherin promoter luciferase reporter in colorectal cancer cells\",\n      \"pmids\": [\"27537253\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"MAEL's molecular role at the promoter (cofactor vs adaptor) unclear\", \"Direct DNA-binding versus Snail-dependent recruitment not distinguished\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Reframed MAEL as a guardian of genome integrity in cancer, with knockdown unleashing ATM-dependent damage responses and overexpression repressing retrotransposons and senescence.\",\n      \"evidence\": \"siRNA across cancer lines, ATM-dependency epistasis, ROS/DNA-damage markers, Myc/Ras transformation and retrotransposon reporter assays\",\n      \"pmids\": [\"27926513\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular mechanism by which MAEL suppresses transposons/ROS not resolved\", \"Link between transposon silencing and DNA-damage suppression inferred, not directly demonstrated\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identified ILKAP as a degradation target of MAEL, providing a phosphatase-loss mechanism for downstream oncogenic kinase signaling.\",\n      \"evidence\": \"Knockdown/overexpression, xenografts, IP, and adenoviral ILKAP rescue in gastric cancer cells\",\n      \"pmids\": [\"29371914\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Degradation route (CMA vs other lysosomal) not dissected here\", \"Direct binding interface not mapped\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Demonstrated causally that MAEL promoter methylation controls transposon silencing, tying the epigenetic regulation of MAEL to its biological function.\",\n      \"evidence\": \"Targeted promoter methylation in NCI-H358 cells with luciferase reporter and LINE-1 RT-qPCR\",\n      \"pmids\": [\"29095993\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which MAEL protein represses LINE-1 not addressed\", \"In vivo relevance to germ cells not tested\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Defined a PTGS2-centered stemness/drug-resistance axis downstream of MAEL, linking it to IL-8/AKT/NF-\\u03baB/STAT3 signaling.\",\n      \"evidence\": \"MAEL knockout HCC cells with PTGS2 rescue, signaling western blots, and IL-8 ELISA\",\n      \"pmids\": [\"35740546\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How MAEL transcriptionally activates PTGS2 mechanistically is unknown\", \"Direct versus indirect transcriptional control not established\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Linked MAEL to drug-efflux-mediated resistance, broadening its oncogenic repertoire to chemoresistance.\",\n      \"evidence\": \"RNAi/overexpression with MRP/LRP westerns and LY411575 sensitivity in T-ALL/T-iPSC model\",\n      \"pmids\": [\"35488386\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single method type without rescue\", \"Mechanism connecting MAEL to MRP/LRP regulation unknown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Placed MAEL in an immune-evasion pathway, regulated by morphine via Nrf2/PTEN and controlling checkpoint molecule expression.\",\n      \"evidence\": \"Western/RT-qPCR/ELISA/flow cytometry with siRNA and PTEN overexpression and LDH cytotoxicity in lung cancer cells\",\n      \"pmids\": [\"36476246\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Mechanistic link is correlative across pathway components\", \"Direct MAEL targets in immune checkpoint regulation not identified\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Established the molecular logic of MAEL-driven chaperone-mediated autophagy, showing it bridges metabolic enzyme substrates to HSPA8 via distinct domains for lysosomal degradation.\",\n      \"evidence\": \"Reciprocal co-IP, domain mapping, and lysosomal/macroautophagy/proteasome inhibitor panel in breast cancer cells\",\n      \"pmids\": [\"36866961\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Substrate selectivity rules beyond CS/FH not defined\", \"No structural model of the MAEL–HSPA8–substrate ternary complex\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Defined a mitochondrial function for MAEL in sperm, binding GPX4 and UBL4B, linking it to ATP production and asthenozoospermia.\",\n      \"evidence\": \"Immunogold localization, siRNA knockdown with mitochondrial/ATP assays, and co-IP in human sperm/cells\",\n      \"pmids\": [\"36779514\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether GPX4/UBL4B binding is regulatory or structural is unresolved\", \"Causal contribution to clinical asthenozoospermia not proven\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How MAEL's germline nuage/piRNA functions mechanistically connect to its cancer-cell roles in CMA-mediated degradation, transcriptional regulation, and signaling remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural data on MAEL or HMG domain function across contexts\", \"No unifying model linking transposon silencing to oncogenic protein degradation\", \"Direct piRNA-pathway biochemistry for human MAEL not established in the corpus\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [2, 5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [7, 6]},\n      {\"term_id\": \"GO:0005764\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [5, 1]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [4, 5]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"HSPA8\", \"Snail\", \"ILKAP\", \"MIWI\", \"GPX4\", \"UBL4B\", \"PABPC1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}