{"gene":"MAEL","run_date":"2026-04-28T18:30:27","timeline":{"discoveries":[{"year":2009,"finding":"The human MAEL gene promoter contains a CpG island (-295 to +148) and is regulated by DNA methylation; treatment with the demethylating agent 5'-Aza-2-Deoxycytidine significantly upregulated MAEL expression, establishing epigenetic silencing as a regulatory mechanism.","method":"Luciferase reporter assay (promoter mapping), 5'-Aza-2-Deoxycytidine treatment with RT-PCR","journal":"Molecular biology reports","confidence":"Medium","confidence_rationale":"Tier 2 — direct promoter functional assay with demethylation rescue, single lab","pmids":["19693694"],"is_preprint":false},{"year":2013,"finding":"MAEL localizes to nuage compartments (intermitochondrial cement, perinuclear granules, satellite bodies, chromatoid bodies) and to non-nuage structures (mitochondria-associated granules, reticulated body, granulated body) in rat spermatogenic cells, and co-localizes with MIWI in both nuage and non-nuage compartments, suggesting functional interaction.","method":"Immunofluorescence and immunoelectron microscopy (IEM) in rat testis","journal":"Histochemistry and cell biology","confidence":"Medium","confidence_rationale":"Tier 2 — direct localization by IEM with co-localization data, single lab","pmids":["23412502"],"is_preprint":false},{"year":2013,"finding":"MAEL interacts with stress granule (SG) components in cancer cells, including PABPC1, YBX1, KHSRP, SYNCRIP, DDX39, ELAV1, EIF4A1, and EIF3F, and co-localizes with the SG marker PABPC1 during oxidative stress, suggesting a role in SG-associated miRNA-mediated gene silencing in somatic cells.","method":"Immunoprecipitation and Nano-LC-MS/MS proteomics, anti-tag co-IP confirmation, immunofluorescence co-localization","journal":"Oncology reports","confidence":"Medium","confidence_rationale":"Tier 2 — reciprocal IP with MS discovery and orthogonal immunofluorescence, single lab","pmids":["24189637"],"is_preprint":false},{"year":2016,"finding":"MAEL interacts with Snail and inhibits E-cadherin promoter activity, thereby inducing epithelial-mesenchymal transition and stemness characteristics in colon cancer cells.","method":"Immunoprecipitation, confocal immunofluorescence, luciferase reporter assay for E-cadherin promoter activity, in vitro and in vivo functional studies","journal":"International journal of cancer","confidence":"Medium","confidence_rationale":"Tier 2 — IP plus orthogonal promoter reporter assay, single lab","pmids":["27537253"],"is_preprint":false},{"year":2017,"finding":"MAEL promotes lysosome-dependent degradation of the protein phosphatase ILKAP in gastric cancer, leading to increased phosphorylation of ILKAP substrates p38, CHK1, and RSK2, and driving oncogenic progression; adenovirus-mediated ILKAP overexpression reversed MAEL oncogenic effects in vitro and in vivo.","method":"siRNA knockdown, overexpression, western blot for phosphosubstrates, lysosome inhibitor assays, in vivo xenograft, adenoviral rescue","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal approaches including genetic rescue, single lab","pmids":["29371914"],"is_preprint":false},{"year":2017,"finding":"Mael depletion in cancer cells induces ATM-dependent DNA damage, apoptosis, and senescence accompanied by increased reactive oxygen species; Mael represses retrotransposon activity in cancer cells and is essential for Myc/Ras-induced transformation, as its overexpression inhibited Ras-induced senescence.","method":"siRNA knockdown, ATM inhibitor epistasis, ROS assays, apoptosis/senescence assays, retrotransposon activity assay, Myc/Ras transformation assay","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 — epistasis with ATM plus multiple functional readouts, single lab","pmids":["27926513"],"is_preprint":false},{"year":2017,"finding":"Hypermethylation of the MAEL promoter region (-131 to +177) suppresses MAEL expression and de-represses LINE-1 (L1) transposable element activity, establishing a direct mechanistic link between MAEL promoter methylation, MAEL silencing, and loss of transposon control.","method":"Targeted DNA methylation of MAEL promoter, luciferase reporter assay, quantitative RT-PCR for MAEL and L1 expression in human cells","journal":"Human reproduction","confidence":"Medium","confidence_rationale":"Tier 1 — targeted methylation with direct functional readout in vitro, single lab","pmids":["29095993"],"is_preprint":false},{"year":2022,"finding":"MAEL transactivates PTGS2 expression in hepatocellular carcinoma cells, leading to IL-8 secretion and activation of AKT/NF-κB/STAT3 signaling; PTGS2 overexpression rescued the suppression of tumor aggressiveness caused by MAEL knockout.","method":"MAEL knockout, transcriptional profiling, PTGS2 overexpression rescue, signaling pathway analysis by western blot, functional assays","journal":"Cancers","confidence":"Medium","confidence_rationale":"Tier 2 — genetic rescue with transcriptional profiling and pathway validation, single lab","pmids":["35740546"],"is_preprint":false},{"year":2022,"finding":"Morphine upregulates MAEL expression in lung cancer cells via the Nrf2/PTEN pathway; MAEL silencing reversed morphine-induced changes in immune factors (PD-L1, TGF-β, IL-10, IL-2) and CD8+ T cell percentages, placing MAEL downstream of Nrf2/PTEN in morphine-mediated immunosuppression.","method":"siRNA knockdown, PTEN overexpression, western blot, RT-qPCR, flow cytometry, ELISA","journal":"BMC pharmacology & toxicology","confidence":"Low","confidence_rationale":"Tier 3 — epistasis inference from overexpression/knockdown without direct binding evidence, single lab","pmids":["36476246"],"is_preprint":false},{"year":2023,"finding":"MAEL interacts with citrate synthase (CS) and fumarate hydratase (FH) via its MAEL domain, and with HSPA8 via its HMG domain, enhancing the binding of CS/FH to HSPA8 and facilitating their transport to the lysosome for chaperone-mediated autophagy (CMA)-dependent degradation; this promotes aerobic glycolysis and breast cancer progression.","method":"Co-immunoprecipitation (MAEL domain and HMG domain mapping), lysosome inhibitor assays (leupeptin, NH4Cl), macroautophagy inhibitor (3-MA) and proteasome inhibitor (MG132) controls, CS/FH overexpression rescue, functional metabolic assays","journal":"The FEBS journal","confidence":"High","confidence_rationale":"Tier 1-2 — domain-resolved binding, multiple inhibitor controls distinguishing CMA from other degradation pathways, genetic rescue; moderate evidence from single lab with orthogonal methods","pmids":["36866961"],"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 in human H358 cells; MAEL directly binds GPX4 and UBL4B, and MAEL levels correlate with GPX4 and UBL4B protein levels in sperm.","method":"Immunohistochemistry, immunogold staining (subcellular localization), siRNA knockdown with mitochondria function and ATP assays, co-IP (MAEL–GPX4, MAEL–UBL4B binding)","journal":"Andrology","confidence":"Medium","confidence_rationale":"Tier 2 — direct localization by immunogold, functional KD with defined readout, and co-IP of binding partners, single lab","pmids":["36779514"],"is_preprint":false},{"year":2013,"finding":"Mael is required for early oogenesis in mice; RNAi-mediated downregulation of Mael in fetal ovary explants disrupted fetal oocyte growth and differentiation, and reduced expression of germ-cell markers during embryonic stem cell differentiation into germ cells in vitro.","method":"siRNA knockdown in fetal ovary explants, germ-cell marker expression analysis, embryonic stem cell differentiation assay","journal":"Zygote","confidence":"Medium","confidence_rationale":"Tier 2 — loss-of-function with defined cellular phenotype in two orthogonal systems, single lab","pmids":["23410657"],"is_preprint":false}],"current_model":"MAEL is a multifunctional protein that, in germ cells, localizes to nuage compartments and mitochondria where it participates in piRNA biogenesis, transposable element silencing, and mitochondrial function (via binding partners MIWI, GPX4, UBL4B); its promoter is regulated by DNA methylation, which controls transposon repression. In cancer cells, MAEL promotes oncogenesis through multiple mechanisms: it scaffolds a chaperone-mediated autophagy complex (via its MAEL and HMG domains interacting with metabolic enzymes CS/FH and HSPA8) to degrade Krebs cycle enzymes and drive aerobic glycolysis; it promotes lysosomal degradation of ILKAP to hyperactivate downstream kinase signaling; it interacts with Snail to repress E-cadherin and drive EMT; it transactivates PTGS2 to activate AKT/NF-κB/STAT3; and it associates with stress granule components to potentially regulate miRNA-mediated silencing."},"narrative":{"teleology":[{"year":2009,"claim":"Establishing that MAEL expression is epigenetically regulated resolved how a germline gene becomes silenced or activated in somatic/cancer contexts, revealing CpG island methylation as the principal on/off switch.","evidence":"Luciferase reporter mapping of the MAEL promoter CpG island and 5-Aza-dC demethylation rescue in human cells","pmids":["19693694"],"confidence":"Medium","gaps":["Factors that establish or maintain MAEL promoter methylation in vivo are not identified","Whether methylation-dependent regulation operates equivalently in germ cells versus cancer cells is untested"]},{"year":2013,"claim":"Subcellular mapping of MAEL to nuage and non-nuage compartments in spermatocytes, together with MIWI co-localization, positioned MAEL as a component of the piRNA/transposon-silencing machinery in mammalian male germ cells.","evidence":"Immunofluorescence and immunoelectron microscopy in rat testis sections","pmids":["23412502"],"confidence":"Medium","gaps":["Direct biochemical interaction between MAEL and MIWI was not demonstrated","Whether MAEL functions in piRNA biogenesis versus downstream effector silencing remains unresolved"]},{"year":2013,"claim":"Demonstrating that MAEL is required for early oogenesis extended its functional role beyond spermatogenesis to female germ-cell development.","evidence":"siRNA knockdown in mouse fetal ovary explants and embryonic stem cell-to-germ-cell differentiation assay","pmids":["23410657"],"confidence":"Medium","gaps":["The molecular targets of MAEL during oocyte differentiation are unknown","No conditional knockout confirms this phenotype in vivo"]},{"year":2013,"claim":"Identification of MAEL interactions with stress granule components (PABPC1, YBX1, KHSRP, EIF4A1, and others) in cancer cells revealed a potential somatic role in mRNA regulation and miRNA-mediated silencing beyond the germline piRNA pathway.","evidence":"Anti-tag co-IP followed by nano-LC-MS/MS and immunofluorescence co-localization with PABPC1 under oxidative stress in cancer cells","pmids":["24189637"],"confidence":"Medium","gaps":["Functional consequence of MAEL–stress granule association for mRNA fate is not established","RNA-binding activity of MAEL itself was not tested"]},{"year":2016,"claim":"The finding that MAEL interacts with Snail to repress the E-cadherin promoter provided the first direct mechanistic link between MAEL and epithelial-mesenchymal transition in cancer.","evidence":"Co-immunoprecipitation, confocal co-localization, and E-cadherin promoter luciferase reporter assay in colon cancer cells, with in vivo xenograft validation","pmids":["27537253"],"confidence":"Medium","gaps":["Whether MAEL binds DNA directly at the E-cadherin promoter or acts solely through Snail scaffolding is unknown","Structural basis of the MAEL–Snail interaction is not defined"]},{"year":2017,"claim":"Two studies converged to show that MAEL controls transposable element activity in both somatic and cancer contexts: targeted promoter methylation de-repressed LINE-1, and MAEL depletion in cancer cells activated retrotransposons and ATM-dependent DNA damage, establishing transposon silencing as a core MAEL function outside the germline.","evidence":"Targeted MAEL promoter methylation with L1 expression readout; siRNA knockdown with retrotransposon assay, ATM inhibitor epistasis, ROS/apoptosis/senescence assays, Myc/Ras transformation assay","pmids":["29095993","27926513"],"confidence":"Medium","gaps":["The molecular mechanism by which MAEL silences transposons in somatic cells (piRNA-dependent or independent) is not resolved","Whether retrotransposon de-repression is the primary cause of ATM activation upon MAEL loss or a parallel effect is unclear"]},{"year":2017,"claim":"Showing that MAEL drives lysosomal degradation of the phosphatase ILKAP, with consequent hyperphosphorylation of p38, CHK1, and RSK2, established a protein-degradation-based oncogenic mechanism distinct from transposon silencing.","evidence":"siRNA/overexpression, lysosome inhibitor rescue, phospho-substrate western blots, adenoviral ILKAP rescue in gastric cancer xenografts","pmids":["29371914"],"confidence":"Medium","gaps":["How MAEL targets ILKAP specifically to lysosomes is unknown","Whether the MAEL–ILKAP axis operates through chaperone-mediated autophagy (as later shown for CS/FH) has not been tested"]},{"year":2022,"claim":"Identifying PTGS2 as a transcriptional target of MAEL that activates AKT/NF-κB/STAT3 signaling added a transcription-level oncogenic axis to MAEL's repertoire in hepatocellular carcinoma.","evidence":"MAEL knockout, transcriptional profiling, PTGS2 overexpression rescue, and western blot pathway analysis in HCC cells","pmids":["35740546"],"confidence":"Medium","gaps":["Whether MAEL directly binds the PTGS2 promoter or acts through an intermediary transcription factor is not determined","Generalizability to other cancer types is untested"]},{"year":2023,"claim":"Domain-resolved mapping revealed that MAEL scaffolds chaperone-mediated autophagy of Krebs cycle enzymes: the MAEL domain binds CS and FH while the HMG domain binds HSPA8, bridging substrates to the CMA machinery for lysosomal degradation, thereby rewiring cancer cell metabolism toward aerobic glycolysis.","evidence":"Domain-truncation co-IP, lysosome/macroautophagy/proteasome inhibitor epistasis, CS/FH overexpression rescue, and metabolic flux assays in breast cancer cells","pmids":["36866961"],"confidence":"High","gaps":["Whether LAMP2A (the CMA receptor) interaction is direct has not been shown","Structural basis for MAEL domain selectivity toward CS/FH over other mitochondrial enzymes is unknown","Single-lab finding awaits independent replication"]},{"year":2023,"claim":"Demonstrating that MAEL localizes to sperm mitochondria and directly binds GPX4 and UBL4B, and that MAEL knockdown impairs mitochondrial function and ATP production, established a non-nuage mitochondrial role for MAEL in human spermatozoa.","evidence":"Immunogold staining of ejaculated human sperm, co-IP for GPX4 and UBL4B, siRNA knockdown with mitochondrial function and ATP assays in H358 cells","pmids":["36779514"],"confidence":"Medium","gaps":["The functional consequence of MAEL–GPX4 binding (e.g., GPX4 stabilization or redox regulation) is not defined","Mitochondrial function assays were performed in a lung cancer cell line, not primary spermatozoa"]},{"year":null,"claim":"A unifying structural and mechanistic model explaining how MAEL's dual domains (MAEL and HMG) coordinate its diverse functions — transposon silencing, CMA scaffolding, Snail interaction, and mitochondrial roles — remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No crystal or cryo-EM structure of MAEL exists","Whether MAEL's germline piRNA function and its somatic CMA/degradation functions share a common biochemical mechanism is unknown","In vivo conditional knockout models confirming cancer-specific MAEL functions are lacking"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[9]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[3,7]}],"localization":[{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[1,10]},{"term_id":"GO:0005764","term_label":"lysosome","supporting_discovery_ids":[4,9]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[2]}],"pathway":[{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[9]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[4,5,7,9]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[9]}],"complexes":[],"partners":["SNAI1","HSPA8","CS","FH","GPX4","UBL4B","ILKAP","PABPC1"],"other_free_text":[]},"mechanistic_narrative":"MAEL is a germ-cell-enriched protein that functions in transposable element silencing, piRNA pathway biology, and gametogenesis, while also serving as an oncogenic effector in multiple cancer types. In germ cells, MAEL localizes to nuage compartments and mitochondria, co-localizes with the piRNA pathway effector MIWI, directly binds GPX4 and UBL4B, and is required for mitochondrial function, ATP production, and early oogenesis [PMID:23412502, PMID:36779514, PMID:23410657]. MAEL expression is controlled by promoter CpG island methylation, and its silencing de-represses LINE-1 retrotransposons, linking MAEL to transposon control in both germ cells and cancer [PMID:29095993, PMID:27926513]. In cancer cells, MAEL scaffolds chaperone-mediated autophagy of Krebs cycle enzymes citrate synthase and fumarate hydratase (via its MAEL and HMG domains bridging these substrates to HSPA8) to promote aerobic glycolysis, drives lysosomal degradation of the phosphatase ILKAP to hyperactivate p38/CHK1/RSK2 signaling, interacts with Snail to repress E-cadherin and induce EMT, and transactivates PTGS2 to activate AKT/NF-κB/STAT3 signaling [PMID:36866961, PMID:29371914, PMID:27537253, PMID:35740546]."},"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":"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":"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":33,"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":19,"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":14,"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":"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":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":"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":"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":1,"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":10848,"output_tokens":2940,"usd":0.038322},"stage2":{"model":"claude-opus-4-6","input_tokens":6298,"output_tokens":3022,"usd":0.16056},"total_usd":0.198882,"stage1_batch_id":"msgbatch_01Mgbec4vM6c9vXht7JVJzss","stage2_batch_id":"msgbatch_01JkuuH5RB2BdJNsgnhjbC6s","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2009,\n      \"finding\": \"The human MAEL gene promoter contains a CpG island (-295 to +148) and is regulated by DNA methylation; treatment with the demethylating agent 5'-Aza-2-Deoxycytidine significantly upregulated MAEL expression, establishing epigenetic silencing as a regulatory mechanism.\",\n      \"method\": \"Luciferase reporter assay (promoter mapping), 5'-Aza-2-Deoxycytidine treatment with RT-PCR\",\n      \"journal\": \"Molecular biology reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct promoter functional assay with demethylation rescue, single lab\",\n      \"pmids\": [\"19693694\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"MAEL localizes to nuage compartments (intermitochondrial cement, perinuclear granules, satellite bodies, chromatoid bodies) and to non-nuage structures (mitochondria-associated granules, reticulated body, granulated body) in rat spermatogenic cells, and co-localizes with MIWI in both nuage and non-nuage compartments, suggesting functional interaction.\",\n      \"method\": \"Immunofluorescence and immunoelectron microscopy (IEM) in rat testis\",\n      \"journal\": \"Histochemistry and cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct localization by IEM with co-localization data, single lab\",\n      \"pmids\": [\"23412502\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"MAEL interacts with stress granule (SG) components in cancer cells, including PABPC1, YBX1, KHSRP, SYNCRIP, DDX39, ELAV1, EIF4A1, and EIF3F, and co-localizes with the SG marker PABPC1 during oxidative stress, suggesting a role in SG-associated miRNA-mediated gene silencing in somatic cells.\",\n      \"method\": \"Immunoprecipitation and Nano-LC-MS/MS proteomics, anti-tag co-IP confirmation, immunofluorescence co-localization\",\n      \"journal\": \"Oncology reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal IP with MS discovery and orthogonal immunofluorescence, single lab\",\n      \"pmids\": [\"24189637\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"MAEL interacts with Snail and inhibits E-cadherin promoter activity, thereby inducing epithelial-mesenchymal transition and stemness characteristics in colon cancer cells.\",\n      \"method\": \"Immunoprecipitation, confocal immunofluorescence, luciferase reporter assay for E-cadherin promoter activity, in vitro and in vivo functional studies\",\n      \"journal\": \"International journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — IP plus orthogonal promoter reporter assay, single lab\",\n      \"pmids\": [\"27537253\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"MAEL promotes lysosome-dependent degradation of the protein phosphatase ILKAP in gastric cancer, leading to increased phosphorylation of ILKAP substrates p38, CHK1, and RSK2, and driving oncogenic progression; adenovirus-mediated ILKAP overexpression reversed MAEL oncogenic effects in vitro and in vivo.\",\n      \"method\": \"siRNA knockdown, overexpression, western blot for phosphosubstrates, lysosome inhibitor assays, in vivo xenograft, adenoviral rescue\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal approaches including genetic rescue, single lab\",\n      \"pmids\": [\"29371914\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Mael depletion in cancer cells induces ATM-dependent DNA damage, apoptosis, and senescence accompanied by increased reactive oxygen species; Mael represses retrotransposon activity in cancer cells and is essential for Myc/Ras-induced transformation, as its overexpression inhibited Ras-induced senescence.\",\n      \"method\": \"siRNA knockdown, ATM inhibitor epistasis, ROS assays, apoptosis/senescence assays, retrotransposon activity assay, Myc/Ras transformation assay\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — epistasis with ATM plus multiple functional readouts, single lab\",\n      \"pmids\": [\"27926513\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Hypermethylation of the MAEL promoter region (-131 to +177) suppresses MAEL expression and de-represses LINE-1 (L1) transposable element activity, establishing a direct mechanistic link between MAEL promoter methylation, MAEL silencing, and loss of transposon control.\",\n      \"method\": \"Targeted DNA methylation of MAEL promoter, luciferase reporter assay, quantitative RT-PCR for MAEL and L1 expression in human cells\",\n      \"journal\": \"Human reproduction\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 — targeted methylation with direct functional readout in vitro, single lab\",\n      \"pmids\": [\"29095993\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"MAEL transactivates PTGS2 expression in hepatocellular carcinoma cells, leading to IL-8 secretion and activation of AKT/NF-κB/STAT3 signaling; PTGS2 overexpression rescued the suppression of tumor aggressiveness caused by MAEL knockout.\",\n      \"method\": \"MAEL knockout, transcriptional profiling, PTGS2 overexpression rescue, signaling pathway analysis by western blot, functional assays\",\n      \"journal\": \"Cancers\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic rescue with transcriptional profiling and pathway validation, single lab\",\n      \"pmids\": [\"35740546\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Morphine upregulates MAEL expression in lung cancer cells via the Nrf2/PTEN pathway; MAEL silencing reversed morphine-induced changes in immune factors (PD-L1, TGF-β, IL-10, IL-2) and CD8+ T cell percentages, placing MAEL downstream of Nrf2/PTEN in morphine-mediated immunosuppression.\",\n      \"method\": \"siRNA knockdown, PTEN overexpression, western blot, RT-qPCR, flow cytometry, ELISA\",\n      \"journal\": \"BMC pharmacology & toxicology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — epistasis inference from overexpression/knockdown without direct binding evidence, single lab\",\n      \"pmids\": [\"36476246\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"MAEL interacts with citrate synthase (CS) and fumarate hydratase (FH) via its MAEL domain, and with HSPA8 via its HMG domain, enhancing the binding of CS/FH to HSPA8 and facilitating their transport to the lysosome for chaperone-mediated autophagy (CMA)-dependent degradation; this promotes aerobic glycolysis and breast cancer progression.\",\n      \"method\": \"Co-immunoprecipitation (MAEL domain and HMG domain mapping), lysosome inhibitor assays (leupeptin, NH4Cl), macroautophagy inhibitor (3-MA) and proteasome inhibitor (MG132) controls, CS/FH overexpression rescue, functional metabolic assays\",\n      \"journal\": \"The FEBS journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — domain-resolved binding, multiple inhibitor controls distinguishing CMA from other degradation pathways, genetic rescue; moderate evidence from single lab with orthogonal methods\",\n      \"pmids\": [\"36866961\"],\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 in human H358 cells; MAEL directly binds GPX4 and UBL4B, and MAEL levels correlate with GPX4 and UBL4B protein levels in sperm.\",\n      \"method\": \"Immunohistochemistry, immunogold staining (subcellular localization), siRNA knockdown with mitochondria function and ATP assays, co-IP (MAEL–GPX4, MAEL–UBL4B binding)\",\n      \"journal\": \"Andrology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct localization by immunogold, functional KD with defined readout, and co-IP of binding partners, single lab\",\n      \"pmids\": [\"36779514\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Mael is required for early oogenesis in mice; RNAi-mediated downregulation of Mael in fetal ovary explants disrupted fetal oocyte growth and differentiation, and reduced expression of germ-cell markers during embryonic stem cell differentiation into germ cells in vitro.\",\n      \"method\": \"siRNA knockdown in fetal ovary explants, germ-cell marker expression analysis, embryonic stem cell differentiation assay\",\n      \"journal\": \"Zygote\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function with defined cellular phenotype in two orthogonal systems, single lab\",\n      \"pmids\": [\"23410657\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MAEL is a multifunctional protein that, in germ cells, localizes to nuage compartments and mitochondria where it participates in piRNA biogenesis, transposable element silencing, and mitochondrial function (via binding partners MIWI, GPX4, UBL4B); its promoter is regulated by DNA methylation, which controls transposon repression. In cancer cells, MAEL promotes oncogenesis through multiple mechanisms: it scaffolds a chaperone-mediated autophagy complex (via its MAEL and HMG domains interacting with metabolic enzymes CS/FH and HSPA8) to degrade Krebs cycle enzymes and drive aerobic glycolysis; it promotes lysosomal degradation of ILKAP to hyperactivate downstream kinase signaling; it interacts with Snail to repress E-cadherin and drive EMT; it transactivates PTGS2 to activate AKT/NF-κB/STAT3; and it associates with stress granule components to potentially regulate miRNA-mediated silencing.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"MAEL is a germ-cell-enriched protein that functions in transposable element silencing, piRNA pathway biology, and gametogenesis, while also serving as an oncogenic effector in multiple cancer types. In germ cells, MAEL localizes to nuage compartments and mitochondria, co-localizes with the piRNA pathway effector MIWI, directly binds GPX4 and UBL4B, and is required for mitochondrial function, ATP production, and early oogenesis [PMID:23412502, PMID:36779514, PMID:23410657]. MAEL expression is controlled by promoter CpG island methylation, and its silencing de-represses LINE-1 retrotransposons, linking MAEL to transposon control in both germ cells and cancer [PMID:29095993, PMID:27926513]. In cancer cells, MAEL scaffolds chaperone-mediated autophagy of Krebs cycle enzymes citrate synthase and fumarate hydratase (via its MAEL and HMG domains bridging these substrates to HSPA8) to promote aerobic glycolysis, drives lysosomal degradation of the phosphatase ILKAP to hyperactivate p38/CHK1/RSK2 signaling, interacts with Snail to repress E-cadherin and induce EMT, and transactivates PTGS2 to activate AKT/NF-κB/STAT3 signaling [PMID:36866961, PMID:29371914, PMID:27537253, PMID:35740546].\",\n  \"teleology\": [\n    {\n      \"year\": 2009,\n      \"claim\": \"Establishing that MAEL expression is epigenetically regulated resolved how a germline gene becomes silenced or activated in somatic/cancer contexts, revealing CpG island methylation as the principal on/off switch.\",\n      \"evidence\": \"Luciferase reporter mapping of the MAEL promoter CpG island and 5-Aza-dC demethylation rescue in human cells\",\n      \"pmids\": [\"19693694\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Factors that establish or maintain MAEL promoter methylation in vivo are not identified\",\n        \"Whether methylation-dependent regulation operates equivalently in germ cells versus cancer cells is untested\"\n      ]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Subcellular mapping of MAEL to nuage and non-nuage compartments in spermatocytes, together with MIWI co-localization, positioned MAEL as a component of the piRNA/transposon-silencing machinery in mammalian male germ cells.\",\n      \"evidence\": \"Immunofluorescence and immunoelectron microscopy in rat testis sections\",\n      \"pmids\": [\"23412502\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct biochemical interaction between MAEL and MIWI was not demonstrated\",\n        \"Whether MAEL functions in piRNA biogenesis versus downstream effector silencing remains unresolved\"\n      ]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Demonstrating that MAEL is required for early oogenesis extended its functional role beyond spermatogenesis to female germ-cell development.\",\n      \"evidence\": \"siRNA knockdown in mouse fetal ovary explants and embryonic stem cell-to-germ-cell differentiation assay\",\n      \"pmids\": [\"23410657\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"The molecular targets of MAEL during oocyte differentiation are unknown\",\n        \"No conditional knockout confirms this phenotype in vivo\"\n      ]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identification of MAEL interactions with stress granule components (PABPC1, YBX1, KHSRP, EIF4A1, and others) in cancer cells revealed a potential somatic role in mRNA regulation and miRNA-mediated silencing beyond the germline piRNA pathway.\",\n      \"evidence\": \"Anti-tag co-IP followed by nano-LC-MS/MS and immunofluorescence co-localization with PABPC1 under oxidative stress in cancer cells\",\n      \"pmids\": [\"24189637\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Functional consequence of MAEL–stress granule association for mRNA fate is not established\",\n        \"RNA-binding activity of MAEL itself was not tested\"\n      ]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"The finding that MAEL interacts with Snail to repress the E-cadherin promoter provided the first direct mechanistic link between MAEL and epithelial-mesenchymal transition in cancer.\",\n      \"evidence\": \"Co-immunoprecipitation, confocal co-localization, and E-cadherin promoter luciferase reporter assay in colon cancer cells, with in vivo xenograft validation\",\n      \"pmids\": [\"27537253\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether MAEL binds DNA directly at the E-cadherin promoter or acts solely through Snail scaffolding is unknown\",\n        \"Structural basis of the MAEL–Snail interaction is not defined\"\n      ]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Two studies converged to show that MAEL controls transposable element activity in both somatic and cancer contexts: targeted promoter methylation de-repressed LINE-1, and MAEL depletion in cancer cells activated retrotransposons and ATM-dependent DNA damage, establishing transposon silencing as a core MAEL function outside the germline.\",\n      \"evidence\": \"Targeted MAEL promoter methylation with L1 expression readout; siRNA knockdown with retrotransposon assay, ATM inhibitor epistasis, ROS/apoptosis/senescence assays, Myc/Ras transformation assay\",\n      \"pmids\": [\"29095993\", \"27926513\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"The molecular mechanism by which MAEL silences transposons in somatic cells (piRNA-dependent or independent) is not resolved\",\n        \"Whether retrotransposon de-repression is the primary cause of ATM activation upon MAEL loss or a parallel effect is unclear\"\n      ]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Showing that MAEL drives lysosomal degradation of the phosphatase ILKAP, with consequent hyperphosphorylation of p38, CHK1, and RSK2, established a protein-degradation-based oncogenic mechanism distinct from transposon silencing.\",\n      \"evidence\": \"siRNA/overexpression, lysosome inhibitor rescue, phospho-substrate western blots, adenoviral ILKAP rescue in gastric cancer xenografts\",\n      \"pmids\": [\"29371914\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"How MAEL targets ILKAP specifically to lysosomes is unknown\",\n        \"Whether the MAEL–ILKAP axis operates through chaperone-mediated autophagy (as later shown for CS/FH) has not been tested\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identifying PTGS2 as a transcriptional target of MAEL that activates AKT/NF-κB/STAT3 signaling added a transcription-level oncogenic axis to MAEL's repertoire in hepatocellular carcinoma.\",\n      \"evidence\": \"MAEL knockout, transcriptional profiling, PTGS2 overexpression rescue, and western blot pathway analysis in HCC cells\",\n      \"pmids\": [\"35740546\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether MAEL directly binds the PTGS2 promoter or acts through an intermediary transcription factor is not determined\",\n        \"Generalizability to other cancer types is untested\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Domain-resolved mapping revealed that MAEL scaffolds chaperone-mediated autophagy of Krebs cycle enzymes: the MAEL domain binds CS and FH while the HMG domain binds HSPA8, bridging substrates to the CMA machinery for lysosomal degradation, thereby rewiring cancer cell metabolism toward aerobic glycolysis.\",\n      \"evidence\": \"Domain-truncation co-IP, lysosome/macroautophagy/proteasome inhibitor epistasis, CS/FH overexpression rescue, and metabolic flux assays in breast cancer cells\",\n      \"pmids\": [\"36866961\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether LAMP2A (the CMA receptor) interaction is direct has not been shown\",\n        \"Structural basis for MAEL domain selectivity toward CS/FH over other mitochondrial enzymes is unknown\",\n        \"Single-lab finding awaits independent replication\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Demonstrating that MAEL localizes to sperm mitochondria and directly binds GPX4 and UBL4B, and that MAEL knockdown impairs mitochondrial function and ATP production, established a non-nuage mitochondrial role for MAEL in human spermatozoa.\",\n      \"evidence\": \"Immunogold staining of ejaculated human sperm, co-IP for GPX4 and UBL4B, siRNA knockdown with mitochondrial function and ATP assays in H358 cells\",\n      \"pmids\": [\"36779514\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"The functional consequence of MAEL–GPX4 binding (e.g., GPX4 stabilization or redox regulation) is not defined\",\n        \"Mitochondrial function assays were performed in a lung cancer cell line, not primary spermatozoa\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"A unifying structural and mechanistic model explaining how MAEL's dual domains (MAEL and HMG) coordinate its diverse functions — transposon silencing, CMA scaffolding, Snail interaction, and mitochondrial roles — remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No crystal or cryo-EM structure of MAEL exists\",\n        \"Whether MAEL's germline piRNA function and its somatic CMA/degradation functions share a common biochemical mechanism is unknown\",\n        \"In vivo conditional knockout models confirming cancer-specific MAEL functions are lacking\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [9]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [3, 7]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [1, 10]},\n      {\"term_id\": \"GO:0005764\", \"supporting_discovery_ids\": [4, 9]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [9]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [4, 5, 7, 9]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [9]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"SNAI1\",\n      \"HSPA8\",\n      \"CS\",\n      \"FH\",\n      \"GPX4\",\n      \"UBL4B\",\n      \"ILKAP\",\n      \"PABPC1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}