{"gene":"TDRD7","run_date":"2026-06-10T10:51:54","timeline":{"discoveries":[{"year":2011,"finding":"TDRD7 is a Tudor domain RNA-binding protein expressed in lens fiber cells that localizes to distinct cytoplasmic RNA granules (TDRD7-RGs) and interacts with STAU1-ribonucleoproteins (RNPs), as demonstrated by co-immunoprecipitation. TDRD7 co-immunoprecipitates with specific lens mRNAs and is required for their posttranscriptional control, which is critical for normal lens development.","method":"Co-immunoprecipitation (co-IP) of TDRD7 with STAU1-RNPs and specific lens mRNAs; Tdrd7 null mouse model with defined cataract and spermatogenesis arrest phenotypes; immunofluorescence localization","journal":"Science","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, loss-of-function mouse model with defined molecular phenotype, replicated in human mutations and mouse nullizygosity","pmids":["21436445"],"is_preprint":false},{"year":2011,"finding":"TDRD7 is essential for dynamic RNP remodeling of chromatoid bodies during spermatogenesis, including initial establishment, subsequent RNP fusion with processing bodies/GW bodies, and later structural maintenance. TDRD7 suppresses LINE1 retrotransposons independently of the piRNA biogenesis pathway (in which TDRD1 and TDRD9 operate), defining a distinct TDRD pathway against retrotransposons in the male germline.","method":"Single and double Tdrd7/Tdrd6 knockout mice with detailed phenotypic analysis; genetic epistasis with Tdrd1, Tdrd6, and Tdrd9; retrotransposon expression assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — loss-of-function genetics with genetic epistasis across multiple TDRD family members, single and double KO comparison, defined cellular phenotype","pmids":["21670278"],"is_preprint":false},{"year":2006,"finding":"TDRD7/TRAP, along with TDRD1 and TDRD6, localizes specifically to nuage (chromatoid bodies) in male germ cells and forms a ribonucleoprotein complex together with TDRD1/MTR-1. Localization to nuage depends on a single Tudor domain as the structural unit, requires MVH/DDX4 (mouse vasa homologue) activity upstream, and the repeated Tudor domain architecture is functionally essential for germ cell differentiation.","method":"Immunofluorescence co-localization; co-immunoprecipitation of complex; in vivo overexpression of full-length and truncated (dominant negative) forms; analysis in Mvh/Ddx4 mutant mice","journal":"Developmental biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-localization and co-IP, dominant-negative overexpression, epistasis in Mvh mutant, multiple orthogonal methods","pmids":["17141210"],"is_preprint":false},{"year":2018,"finding":"TDRD7, induced by interferon as an ISG, inhibits paramyxovirus (Sendai virus, hPIV3, RSV) replication by inhibiting autophagy. Mechanistically, TDRD7 interferes with the activation of AMPK, an enzyme required for initiating autophagy and for efficient replication of paramyxoviruses.","method":"High-throughput shRNA screen of ISG library; genetic ablation (knockdown/knockout) and ectopic overexpression of TDRD7 in multiple cell types; AMPK activity assays; genetic ablation of AMPK; chemical inhibition of AMPK","journal":"PLoS pathogens","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple cell types, genetic ablation plus ectopic expression rescue, AMPK activity assays, chemical inhibitor epistasis, multiple orthogonal methods","pmids":["29381763"],"is_preprint":false},{"year":2020,"finding":"TDRD7 inhibits AMPK activation to restrict HSV-1 replication independently of the autophagy pathway. HSV-1 replication depends on AMPK activity after viral entry but does not require AMPK's role in autophagy, and TDRD7's antiviral function is dependent on its ability to inhibit AMPK.","method":"Knockdown, knockout, and ectopic expression of TDRD7 in multiple human and mouse cell lines; AMPK genetic ablation; chemical inhibition of AMPK; epistasis experiments","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple cell types, genetic and pharmacological epistasis, loss-of-function and gain-of-function, multiple orthogonal methods in one study","pmids":["32273341"],"is_preprint":false},{"year":2023,"finding":"TDRD7 physically interacts with AMPK and inhibits its activation. A specific AMPK-interacting domain was identified in TDRD7; deletion of this domain abolished both anti-AMPK and antiviral activities of TDRD7. TDRD7-deficient primary mouse cells and knockout mice showed enhanced AMPK activation and increased susceptibility to respiratory virus infection.","method":"Co-immunoprecipitation of TDRD7 with AMPK; domain deletion mutagenesis; primary mouse cells from TDRD7 KO; in vivo mouse infection model; antiviral activity assays","journal":"mBio","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct protein interaction by Co-IP, mutagenesis of interaction domain, in vivo mouse model, multiple orthogonal methods","pmids":["37712680"],"is_preprint":false},{"year":2020,"finding":"TDRD7 is required for normal HSPB1 (HSP27) expression in lens fiber cells. RNA immunoprecipitation demonstrated that TDRD7 directly binds Hspb1 mRNA in lens lysates, and single-molecule RNA imaging showed co-localization of TDRD7 protein with cytoplasmic Hspb1 mRNA in differentiating fiber cells. Loss of TDRD7 results in reduced HSPB1, abnormal F-actin cytoskeletal organization, and abnormal fiber cell morphology preceding cataract.","method":"RNA immunoprecipitation (RIP) of TDRD7 with Hspb1 mRNA; single-molecule RNA imaging (co-localization); RNA-seq and 2D-DIGE/mass spectrometry; scanning electron microscopy; phalloidin/WGA staining; Hspb1 knockdown in Xenopus","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 / Moderate — RIP and single-molecule imaging for TDRD7-Hspb1 mRNA interaction, independent RNA-seq and proteomics confirmation, functional Xenopus validation","pmids":["32420594"],"is_preprint":false},{"year":2021,"finding":"TDRD7 mediates autophagosome maturation by directly binding Tbc1d20 mRNA and downregulating TBC1D20 expression (a key regulator of autophagosome-lysosome fusion). Loss of TDRD7 causes accumulation of autophagosomes due to failure of autophagosome fusion with lysosomes, disrupting autophagic flux. This mechanism is required for lens transparency (removal of damaged proteins/organelles from fiber cells) and for acrosome biogenesis in spermatids.","method":"Transcriptome analysis; biochemical binding assays of TDRD7 with Tbc1d20 mRNA; autophagosome-lysosome fusion assays in tdrd7-deficient MEFs; transmission electron microscopy; LC3/LAMP1 flux assays; CTSD processing assays","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — biochemical mRNA binding assay plus cellular autophagic flux assays and TEM, single lab but multiple orthogonal methods","pmids":["33618632"],"is_preprint":false},{"year":2021,"finding":"In zebrafish, Tdrd7 regulates disaggregated perinuclear relocalization of germ plasm during primordial germ cell (PGC) migration, and Tdrd7-dependent reconfiguration of chromatin accessibility is required for elaboration of PGC fate (transcriptome divergence from somatic cells) but not for PGC migration.","method":"Zebrafish Tdrd7 loss-of-function; ATAC-seq (chromatin accessibility); RNA-seq transcriptome analysis; live imaging of germ plasm relocalization","journal":"Developmental cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic loss-of-function with ATAC-seq and RNA-seq in zebrafish, single lab, two orthogonal genome-wide methods","pmids":["33651978"],"is_preprint":false},{"year":2014,"finding":"In Drosophila, the TDRD7 ortholog Tapas (Tap) localizes to the nuage and physically interacts with piRNA pathway components Aubergine, Argonaute3, and RNA helicases Spindle-E and Vasa. Tap loss leads to mild increases in transposon expression and decreases in germline piRNAs. Together with Tejas (Tej/TDRD5 ortholog), Tap is required for localization of piRNA pathway components at the nuage and for piRNA production in germline cells.","method":"Co-immunoprecipitation of Tap with Aub, Ago3, Spi-E, Vasa; genetic loss-of-function single and double mutants; immunofluorescence localization; piRNA sequencing; transposon expression assays","journal":"BMC biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, genetic epistasis with double mutants, single lab but multiple orthogonal methods in Drosophila ortholog","pmids":["25287931"],"is_preprint":false},{"year":2012,"finding":"TDRD7 contains three LOTUS (OST-HTH) domains that are RNA-binding domains. NMR resonance assignments for all three LOTUS domains of mouse TDRD7 were obtained, establishing the structural basis for their RNA-binding function and enabling future three-dimensional structure determination and RNA interaction mapping.","method":"NMR spectroscopy (1H, 13C, 15N resonance assignments) of recombinant mouse TDRD7 LOTUS domains","journal":"Biomolecular NMR assignments","confidence":"Low","confidence_rationale":"Tier 1 / Weak — NMR resonance assignments only (no 3D structure or functional RNA-binding validation reported in this abstract), single lab","pmids":["22481467"],"is_preprint":false},{"year":2008,"finding":"TDRD7 was identified as a scaffold protein found in complexes with proteins that regulate cytoskeleton dynamics and centrosomal movements, mRNA transport, and the protein translation apparatus.","method":"Immunoprecipitation used to identify protein complexes; monoclonal antibody characterization by ELISA, Western blot, immunoprecipitation, and immunocytochemistry","journal":"Hybridoma","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single IP method, complex membership stated without detailed mechanistic follow-up","pmids":["18582216"],"is_preprint":false}],"current_model":"TDRD7 is a Tudor/LOTUS domain RNA-binding scaffold protein that operates in cytoplasmic RNA granules to posttranscriptionally regulate specific target mRNAs (including Hspb1 and Tbc1d20), controls autophagosome maturation by suppressing TBC1D20 expression, localizes to nuage/chromatoid bodies in germ cells where it remodels RNP composition and suppresses LINE1 retrotransposons independently of the piRNA pathway, and functions as an interferon-stimulated antiviral factor by directly binding and inhibiting AMPK activation to block autophagy-dependent and autophagy-independent viral replication."},"narrative":{"mechanistic_narrative":"TDRD7 is a Tudor/LOTUS-domain RNA-binding scaffold protein that assembles into cytoplasmic RNA granules to exert posttranscriptional control over specific target mRNAs during cell differentiation [PMID:21436445]. In lens fiber cells it localizes to distinct TDRD7-containing RNA granules, associates with STAU1-ribonucleoproteins, and directly binds and regulates target transcripts including Hspb1, whose proper expression is needed for normal F-actin organization and fiber cell morphology [PMID:21436445, PMID:32420594]. TDRD7 also governs autophagosome maturation by directly binding Tbc1d20 mRNA and suppressing TBC1D20, thereby permitting autophagosome–lysosome fusion; loss of this control blocks autophagic flux and is required for both lens transparency and acrosome biogenesis [PMID:33618632]. In the germline, TDRD7 localizes to nuage/chromatoid bodies in a Tudor-domain- and MVH/DDX4-dependent manner, where it drives dynamic remodeling and fusion of these RNP granules and suppresses LINE1 retrotransposons through a pathway distinct from the TDRD1/TDRD9 piRNA route [PMID:21670278, PMID:17141210]. Separately, TDRD7 acts as an interferon-stimulated antiviral effector that physically interacts with AMPK through a defined AMPK-binding domain and inhibits its activation, restricting paramyxovirus replication via blockade of autophagy and restricting HSV-1 replication through an autophagy-independent requirement for AMPK [PMID:29381763, PMID:32273341, PMID:37712680].","teleology":[{"year":2006,"claim":"Establishing where TDRD7 acts and what builds the complex: TDRD7 was shown to occupy germ-cell nuage as part of a Tudor-domain RNP, defining its subcellular platform and its dependence on the RNA helicase MVH/DDX4.","evidence":"Immunofluorescence co-localization, co-IP, dominant-negative truncations, and analysis in Mvh/Ddx4 mutant mice","pmids":["17141210"],"confidence":"High","gaps":["Did not identify the RNA cargo bound in nuage","Did not connect nuage localization to a specific posttranscriptional outcome"]},{"year":2008,"claim":"An early survey placed TDRD7 in complexes linked to cytoskeleton, mRNA transport, and translation machinery, hinting at a scaffolding role before specific partners were defined.","evidence":"Immunoprecipitation and monoclonal antibody characterization to identify associated protein complexes","pmids":["18582216"],"confidence":"Low","gaps":["Single IP method without reciprocal validation","Named complex members not mechanistically followed up","No functional consequence established"]},{"year":2011,"claim":"TDRD7 was defined as an RNA-granule scaffold controlling specific mRNAs in lens development, linking its molecular activity to a clear loss-of-function phenotype and human disease.","evidence":"Co-IP of TDRD7 with STAU1-RNPs and lens mRNAs, Tdrd7-null mouse with cataract and spermatogenesis arrest, immunofluorescence","pmids":["21436445"],"confidence":"High","gaps":["Did not resolve which individual mRNAs drive the cataract phenotype","Mechanism of granule assembly not defined"]},{"year":2011,"claim":"Genetic dissection showed TDRD7 remodels chromatoid-body RNPs and restrains LINE1 retrotransposons through a pathway separate from the piRNA-producing TDRDs, distinguishing its germline role.","evidence":"Single and double Tdrd7/Tdrd6 knockout mice, epistasis with Tdrd1/Tdrd6/Tdrd9, retrotransposon expression assays","pmids":["21670278"],"confidence":"High","gaps":["Molecular mechanism of LINE1 suppression independent of piRNA not defined","Direct RNA targets in chromatoid bodies not identified"]},{"year":2014,"claim":"The Drosophila ortholog Tapas tied TDRD7 to piRNA-pathway components at the nuage, providing a comparative framework for its transposon-related germline function.","evidence":"Co-IP of Tap with Aub, Ago3, Spindle-E, Vasa; single and double mutants with Tej; piRNA sequencing and transposon assays","pmids":["25287931"],"confidence":"Medium","gaps":["Ortholog couples to piRNA pathway, whereas mouse TDRD7 acts piRNA-independently — reconciliation unresolved","Direct RNA targets of Tap not mapped"]},{"year":2018,"claim":"An ISG screen reframed TDRD7 as an antiviral effector, showing it blocks paramyxovirus replication by interfering with AMPK-dependent autophagy.","evidence":"shRNA ISG screen, knockdown/knockout and overexpression across cell types, AMPK activity assays, AMPK ablation and chemical inhibition","pmids":["29381763"],"confidence":"High","gaps":["Did not establish whether TDRD7 contacts AMPK directly","Did not separate autophagy-dependent from autophagy-independent effects"]},{"year":2020,"claim":"TDRD7 was shown to restrict HSV-1 via AMPK inhibition independent of autophagy, demonstrating the antiviral effect operates through AMPK itself rather than solely through autophagy.","evidence":"Knockdown/knockout/ectopic expression in human and mouse lines, AMPK genetic ablation, chemical inhibition, epistasis","pmids":["32273341"],"confidence":"High","gaps":["Did not define the physical basis of AMPK inhibition","Step in viral life cycle requiring AMPK not fully resolved"]},{"year":2020,"claim":"TDRD7's direct mRNA target in lens was pinned to Hspb1, connecting its granule-localized binding to cytoskeletal and morphological control preceding cataract.","evidence":"RIP of TDRD7 with Hspb1 mRNA, single-molecule RNA imaging, RNA-seq/proteomics, SEM, phalloidin staining, Hspb1 knockdown in Xenopus","pmids":["32420594"],"confidence":"High","gaps":["Whether TDRD7 stabilizes, transports, or translationally regulates Hspb1 mRNA not resolved","Full target mRNA repertoire not defined"]},{"year":2021,"claim":"TDRD7 was linked to autophagosome maturation by binding Tbc1d20 mRNA and suppressing TBC1D20, explaining how it clears organelles for lens transparency and acrosome biogenesis.","evidence":"Transcriptome analysis, TDRD7–Tbc1d20 mRNA binding assays, autophagosome-lysosome fusion and LC3/LAMP1 flux assays, TEM, CTSD processing in tdrd7-deficient MEFs","pmids":["33618632"],"confidence":"Medium","gaps":["Mechanism of TDRD7-mediated TBC1D20 mRNA downregulation not defined","Relationship between this autophagy role and AMPK-mediated antiviral autophagy control unclear"]},{"year":2021,"claim":"In zebrafish, TDRD7 was shown to relocalize germ plasm and reconfigure chromatin accessibility to elaborate germ-cell fate, separating its role in fate from migration.","evidence":"Zebrafish loss-of-function with ATAC-seq, RNA-seq, and live imaging of germ plasm","pmids":["33651978"],"confidence":"Medium","gaps":["Mechanism linking a cytoplasmic RNA-granule protein to chromatin accessibility unresolved","Direct molecular targets in PGCs not identified"]},{"year":2023,"claim":"The antiviral mechanism was resolved to a direct TDRD7–AMPK interaction via a defined domain, with in vivo confirmation that loss of TDRD7 raises AMPK activity and viral susceptibility.","evidence":"Co-IP of TDRD7 with AMPK, domain deletion mutagenesis, TDRD7-KO primary cells and mice, in vivo respiratory virus infection","pmids":["37712680"],"confidence":"High","gaps":["Structural basis of the TDRD7–AMPK contact not determined","Whether the AMPK-binding domain overlaps with RNA-binding domains unclear"]},{"year":null,"claim":"How TDRD7's RNA-binding/scaffold activity and its AMPK-inhibitory activity are mechanistically integrated within one protein — and whether they operate in the same or distinct cellular pools — remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structure of full-length TDRD7 or its complexes","Domain map linking RNA binding, granule assembly, and AMPK inhibition not established","Comprehensive target mRNA set not defined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[0,6,7]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[3,4,5]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0,6]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[0,2]}],"pathway":[{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[3,7]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[3,4,5]},{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[0,6]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[0,1,8]}],"complexes":["chromatoid body / nuage RNP","STAU1-ribonucleoprotein","TDRD7-RNA granule"],"partners":["STAU1","AMPK","TDRD1","DDX4","TDRD6"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8NHU6","full_name":"Tudor domain-containing protein 7","aliases":["PCTAIRE2-binding protein","Tudor repeat associator with PCTAIRE-2","Trap"],"length_aa":1098,"mass_kda":123.6,"function":"Component of specific cytoplasmic RNA granules involved in post-transcriptional regulation of specific genes: probably acts by binding to specific mRNAs and regulating their translation. Required for lens transparency during lens development, by regulating translation of genes such as CRYBB3 and HSPB1 in the developing lens. Also required during spermatogenesis","subcellular_location":"Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q8NHU6/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TDRD7","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/TDRD7","total_profiled":1310},"omim":[{"mim_id":"620253","title":"CATARACT 50 WITH OR WITHOUT GLAUCOMA; CTRCT50","url":"https://www.omim.org/entry/620253"},{"mim_id":"614593","title":"MEIOSIS REGULATOR AND mRNA STABILITY FACTOR 1; MARF1","url":"https://www.omim.org/entry/614593"},{"mim_id":"613887","title":"CATARACT 36; CTRCT36","url":"https://www.omim.org/entry/613887"},{"mim_id":"611258","title":"TUDOR DOMAIN-CONTAINING PROTEIN 7; TDRD7","url":"https://www.omim.org/entry/611258"},{"mim_id":"601637","title":"CYTOCHROME P450, FAMILY 51, SUBFAMILY A, POLYPEPTIDE 1; CYP51A1","url":"https://www.omim.org/entry/601637"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Cytoplasmic bodies","reliability":"Supported"},{"location":"Nucleoplasm","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"retina","ntpm":58.4}],"url":"https://www.proteinatlas.org/search/TDRD7"},"hgnc":{"alias_symbol":["PCTAIRE2BP"],"prev_symbol":[]},"alphafold":{"accession":"Q8NHU6","domains":[{"cath_id":"3.30.420.610","chopping":"4-90","consensus_level":"high","plddt":86.482,"start":4,"end":90},{"cath_id":"3.30.420.610","chopping":"352-404","consensus_level":"high","plddt":80.1596,"start":352,"end":404},{"cath_id":"2.30.30.140","chopping":"467-584","consensus_level":"medium","plddt":90.8369,"start":467,"end":584},{"cath_id":"2.30.30.140","chopping":"629-841","consensus_level":"medium","plddt":87.4849,"start":629,"end":841},{"cath_id":"2.30.30.140","chopping":"913-1096","consensus_level":"medium","plddt":87.2161,"start":913,"end":1096}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8NHU6","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8NHU6-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8NHU6-F1-predicted_aligned_error_v6.png","plddt_mean":73.12},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TDRD7","jax_strain_url":"https://www.jax.org/strain/search?query=TDRD7"},"sequence":{"accession":"Q8NHU6","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8NHU6.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8NHU6/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8NHU6"}},"corpus_meta":[{"pmid":"21436445","id":"PMC_21436445","title":"Mutations in the RNA granule component TDRD7 cause cataract and glaucoma.","date":"2011","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/21436445","citation_count":167,"is_preprint":false},{"pmid":"21670278","id":"PMC_21670278","title":"Tudor domain containing 7 (Tdrd7) is essential for dynamic ribonucleoprotein (RNP) remodeling of chromatoid bodies during spermatogenesis.","date":"2011","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/21670278","citation_count":129,"is_preprint":false},{"pmid":"17141210","id":"PMC_17141210","title":"Tudor-related proteins TDRD1/MTR-1, TDRD6 and TDRD7/TRAP: domain composition, intracellular localization, and function in male germ cells in mice.","date":"2006","source":"Developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/17141210","citation_count":127,"is_preprint":false},{"pmid":"31048812","id":"PMC_31048812","title":"Loss-of-function mutations in TDRD7 lead to a rare novel syndrome combining congenital cataract and nonobstructive azoospermia in humans.","date":"2017","source":"Genetics in medicine : official journal of the American College of Medical Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/31048812","citation_count":85,"is_preprint":false},{"pmid":"29381763","id":"PMC_29381763","title":"A new mechanism of interferon's antiviral action: Induction of autophagy, essential for paramyxovirus replication, is inhibited by the interferon stimulated gene, TDRD7.","date":"2018","source":"PLoS pathogens","url":"https://pubmed.ncbi.nlm.nih.gov/29381763","citation_count":57,"is_preprint":false},{"pmid":"25287931","id":"PMC_25287931","title":"The Tudor domain protein Tapas, a homolog of the vertebrate Tdrd7, functions in the piRNA pathway to regulate retrotransposons in germline of Drosophila melanogaster.","date":"2014","source":"BMC 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TDRD7 co-immunoprecipitates with specific lens mRNAs and is required for their posttranscriptional control, which is critical for normal lens development.\",\n      \"method\": \"Co-immunoprecipitation (co-IP) of TDRD7 with STAU1-RNPs and specific lens mRNAs; Tdrd7 null mouse model with defined cataract and spermatogenesis arrest phenotypes; immunofluorescence localization\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, loss-of-function mouse model with defined molecular phenotype, replicated in human mutations and mouse nullizygosity\",\n      \"pmids\": [\"21436445\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"TDRD7 is essential for dynamic RNP remodeling of chromatoid bodies during spermatogenesis, including initial establishment, subsequent RNP fusion with processing bodies/GW bodies, and later structural maintenance. TDRD7 suppresses LINE1 retrotransposons independently of the piRNA biogenesis pathway (in which TDRD1 and TDRD9 operate), defining a distinct TDRD pathway against retrotransposons in the male germline.\",\n      \"method\": \"Single and double Tdrd7/Tdrd6 knockout mice with detailed phenotypic analysis; genetic epistasis with Tdrd1, Tdrd6, and Tdrd9; retrotransposon expression assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — loss-of-function genetics with genetic epistasis across multiple TDRD family members, single and double KO comparison, defined cellular phenotype\",\n      \"pmids\": [\"21670278\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"TDRD7/TRAP, along with TDRD1 and TDRD6, localizes specifically to nuage (chromatoid bodies) in male germ cells and forms a ribonucleoprotein complex together with TDRD1/MTR-1. Localization to nuage depends on a single Tudor domain as the structural unit, requires MVH/DDX4 (mouse vasa homologue) activity upstream, and the repeated Tudor domain architecture is functionally essential for germ cell differentiation.\",\n      \"method\": \"Immunofluorescence co-localization; co-immunoprecipitation of complex; in vivo overexpression of full-length and truncated (dominant negative) forms; analysis in Mvh/Ddx4 mutant mice\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-localization and co-IP, dominant-negative overexpression, epistasis in Mvh mutant, multiple orthogonal methods\",\n      \"pmids\": [\"17141210\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"TDRD7, induced by interferon as an ISG, inhibits paramyxovirus (Sendai virus, hPIV3, RSV) replication by inhibiting autophagy. Mechanistically, TDRD7 interferes with the activation of AMPK, an enzyme required for initiating autophagy and for efficient replication of paramyxoviruses.\",\n      \"method\": \"High-throughput shRNA screen of ISG library; genetic ablation (knockdown/knockout) and ectopic overexpression of TDRD7 in multiple cell types; AMPK activity assays; genetic ablation of AMPK; chemical inhibition of AMPK\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple cell types, genetic ablation plus ectopic expression rescue, AMPK activity assays, chemical inhibitor epistasis, multiple orthogonal methods\",\n      \"pmids\": [\"29381763\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"TDRD7 inhibits AMPK activation to restrict HSV-1 replication independently of the autophagy pathway. HSV-1 replication depends on AMPK activity after viral entry but does not require AMPK's role in autophagy, and TDRD7's antiviral function is dependent on its ability to inhibit AMPK.\",\n      \"method\": \"Knockdown, knockout, and ectopic expression of TDRD7 in multiple human and mouse cell lines; AMPK genetic ablation; chemical inhibition of AMPK; epistasis experiments\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple cell types, genetic and pharmacological epistasis, loss-of-function and gain-of-function, multiple orthogonal methods in one study\",\n      \"pmids\": [\"32273341\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"TDRD7 physically interacts with AMPK and inhibits its activation. A specific AMPK-interacting domain was identified in TDRD7; deletion of this domain abolished both anti-AMPK and antiviral activities of TDRD7. TDRD7-deficient primary mouse cells and knockout mice showed enhanced AMPK activation and increased susceptibility to respiratory virus infection.\",\n      \"method\": \"Co-immunoprecipitation of TDRD7 with AMPK; domain deletion mutagenesis; primary mouse cells from TDRD7 KO; in vivo mouse infection model; antiviral activity assays\",\n      \"journal\": \"mBio\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct protein interaction by Co-IP, mutagenesis of interaction domain, in vivo mouse model, multiple orthogonal methods\",\n      \"pmids\": [\"37712680\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"TDRD7 is required for normal HSPB1 (HSP27) expression in lens fiber cells. RNA immunoprecipitation demonstrated that TDRD7 directly binds Hspb1 mRNA in lens lysates, and single-molecule RNA imaging showed co-localization of TDRD7 protein with cytoplasmic Hspb1 mRNA in differentiating fiber cells. Loss of TDRD7 results in reduced HSPB1, abnormal F-actin cytoskeletal organization, and abnormal fiber cell morphology preceding cataract.\",\n      \"method\": \"RNA immunoprecipitation (RIP) of TDRD7 with Hspb1 mRNA; single-molecule RNA imaging (co-localization); RNA-seq and 2D-DIGE/mass spectrometry; scanning electron microscopy; phalloidin/WGA staining; Hspb1 knockdown in Xenopus\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIP and single-molecule imaging for TDRD7-Hspb1 mRNA interaction, independent RNA-seq and proteomics confirmation, functional Xenopus validation\",\n      \"pmids\": [\"32420594\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"TDRD7 mediates autophagosome maturation by directly binding Tbc1d20 mRNA and downregulating TBC1D20 expression (a key regulator of autophagosome-lysosome fusion). Loss of TDRD7 causes accumulation of autophagosomes due to failure of autophagosome fusion with lysosomes, disrupting autophagic flux. This mechanism is required for lens transparency (removal of damaged proteins/organelles from fiber cells) and for acrosome biogenesis in spermatids.\",\n      \"method\": \"Transcriptome analysis; biochemical binding assays of TDRD7 with Tbc1d20 mRNA; autophagosome-lysosome fusion assays in tdrd7-deficient MEFs; transmission electron microscopy; LC3/LAMP1 flux assays; CTSD processing assays\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — biochemical mRNA binding assay plus cellular autophagic flux assays and TEM, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"33618632\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"In zebrafish, Tdrd7 regulates disaggregated perinuclear relocalization of germ plasm during primordial germ cell (PGC) migration, and Tdrd7-dependent reconfiguration of chromatin accessibility is required for elaboration of PGC fate (transcriptome divergence from somatic cells) but not for PGC migration.\",\n      \"method\": \"Zebrafish Tdrd7 loss-of-function; ATAC-seq (chromatin accessibility); RNA-seq transcriptome analysis; live imaging of germ plasm relocalization\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic loss-of-function with ATAC-seq and RNA-seq in zebrafish, single lab, two orthogonal genome-wide methods\",\n      \"pmids\": [\"33651978\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"In Drosophila, the TDRD7 ortholog Tapas (Tap) localizes to the nuage and physically interacts with piRNA pathway components Aubergine, Argonaute3, and RNA helicases Spindle-E and Vasa. Tap loss leads to mild increases in transposon expression and decreases in germline piRNAs. Together with Tejas (Tej/TDRD5 ortholog), Tap is required for localization of piRNA pathway components at the nuage and for piRNA production in germline cells.\",\n      \"method\": \"Co-immunoprecipitation of Tap with Aub, Ago3, Spi-E, Vasa; genetic loss-of-function single and double mutants; immunofluorescence localization; piRNA sequencing; transposon expression assays\",\n      \"journal\": \"BMC biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, genetic epistasis with double mutants, single lab but multiple orthogonal methods in Drosophila ortholog\",\n      \"pmids\": [\"25287931\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"TDRD7 contains three LOTUS (OST-HTH) domains that are RNA-binding domains. NMR resonance assignments for all three LOTUS domains of mouse TDRD7 were obtained, establishing the structural basis for their RNA-binding function and enabling future three-dimensional structure determination and RNA interaction mapping.\",\n      \"method\": \"NMR spectroscopy (1H, 13C, 15N resonance assignments) of recombinant mouse TDRD7 LOTUS domains\",\n      \"journal\": \"Biomolecular NMR assignments\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 1 / Weak — NMR resonance assignments only (no 3D structure or functional RNA-binding validation reported in this abstract), single lab\",\n      \"pmids\": [\"22481467\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"TDRD7 was identified as a scaffold protein found in complexes with proteins that regulate cytoskeleton dynamics and centrosomal movements, mRNA transport, and the protein translation apparatus.\",\n      \"method\": \"Immunoprecipitation used to identify protein complexes; monoclonal antibody characterization by ELISA, Western blot, immunoprecipitation, and immunocytochemistry\",\n      \"journal\": \"Hybridoma\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single IP method, complex membership stated without detailed mechanistic follow-up\",\n      \"pmids\": [\"18582216\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TDRD7 is a Tudor/LOTUS domain RNA-binding scaffold protein that operates in cytoplasmic RNA granules to posttranscriptionally regulate specific target mRNAs (including Hspb1 and Tbc1d20), controls autophagosome maturation by suppressing TBC1D20 expression, localizes to nuage/chromatoid bodies in germ cells where it remodels RNP composition and suppresses LINE1 retrotransposons independently of the piRNA pathway, and functions as an interferon-stimulated antiviral factor by directly binding and inhibiting AMPK activation to block autophagy-dependent and autophagy-independent viral replication.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TDRD7 is a Tudor/LOTUS-domain RNA-binding scaffold protein that assembles into cytoplasmic RNA granules to exert posttranscriptional control over specific target mRNAs during cell differentiation [#0]. In lens fiber cells it localizes to distinct TDRD7-containing RNA granules, associates with STAU1-ribonucleoproteins, and directly binds and regulates target transcripts including Hspb1, whose proper expression is needed for normal F-actin organization and fiber cell morphology [#0, #6]. TDRD7 also governs autophagosome maturation by directly binding Tbc1d20 mRNA and suppressing TBC1D20, thereby permitting autophagosome–lysosome fusion; loss of this control blocks autophagic flux and is required for both lens transparency and acrosome biogenesis [#7]. In the germline, TDRD7 localizes to nuage/chromatoid bodies in a Tudor-domain- and MVH/DDX4-dependent manner, where it drives dynamic remodeling and fusion of these RNP granules and suppresses LINE1 retrotransposons through a pathway distinct from the TDRD1/TDRD9 piRNA route [#1, #2]. Separately, TDRD7 acts as an interferon-stimulated antiviral effector that physically interacts with AMPK through a defined AMPK-binding domain and inhibits its activation, restricting paramyxovirus replication via blockade of autophagy and restricting HSV-1 replication through an autophagy-independent requirement for AMPK [#3, #4, #5].\",\n  \"teleology\": [\n    {\n      \"year\": 2006,\n      \"claim\": \"Establishing where TDRD7 acts and what builds the complex: TDRD7 was shown to occupy germ-cell nuage as part of a Tudor-domain RNP, defining its subcellular platform and its dependence on the RNA helicase MVH/DDX4.\",\n      \"evidence\": \"Immunofluorescence co-localization, co-IP, dominant-negative truncations, and analysis in Mvh/Ddx4 mutant mice\",\n      \"pmids\": [\"17141210\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not identify the RNA cargo bound in nuage\", \"Did not connect nuage localization to a specific posttranscriptional outcome\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"An early survey placed TDRD7 in complexes linked to cytoskeleton, mRNA transport, and translation machinery, hinting at a scaffolding role before specific partners were defined.\",\n      \"evidence\": \"Immunoprecipitation and monoclonal antibody characterization to identify associated protein complexes\",\n      \"pmids\": [\"18582216\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single IP method without reciprocal validation\", \"Named complex members not mechanistically followed up\", \"No functional consequence established\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"TDRD7 was defined as an RNA-granule scaffold controlling specific mRNAs in lens development, linking its molecular activity to a clear loss-of-function phenotype and human disease.\",\n      \"evidence\": \"Co-IP of TDRD7 with STAU1-RNPs and lens mRNAs, Tdrd7-null mouse with cataract and spermatogenesis arrest, immunofluorescence\",\n      \"pmids\": [\"21436445\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve which individual mRNAs drive the cataract phenotype\", \"Mechanism of granule assembly not defined\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Genetic dissection showed TDRD7 remodels chromatoid-body RNPs and restrains LINE1 retrotransposons through a pathway separate from the piRNA-producing TDRDs, distinguishing its germline role.\",\n      \"evidence\": \"Single and double Tdrd7/Tdrd6 knockout mice, epistasis with Tdrd1/Tdrd6/Tdrd9, retrotransposon expression assays\",\n      \"pmids\": [\"21670278\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism of LINE1 suppression independent of piRNA not defined\", \"Direct RNA targets in chromatoid bodies not identified\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"The Drosophila ortholog Tapas tied TDRD7 to piRNA-pathway components at the nuage, providing a comparative framework for its transposon-related germline function.\",\n      \"evidence\": \"Co-IP of Tap with Aub, Ago3, Spindle-E, Vasa; single and double mutants with Tej; piRNA sequencing and transposon assays\",\n      \"pmids\": [\"25287931\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Ortholog couples to piRNA pathway, whereas mouse TDRD7 acts piRNA-independently — reconciliation unresolved\", \"Direct RNA targets of Tap not mapped\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"An ISG screen reframed TDRD7 as an antiviral effector, showing it blocks paramyxovirus replication by interfering with AMPK-dependent autophagy.\",\n      \"evidence\": \"shRNA ISG screen, knockdown/knockout and overexpression across cell types, AMPK activity assays, AMPK ablation and chemical inhibition\",\n      \"pmids\": [\"29381763\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish whether TDRD7 contacts AMPK directly\", \"Did not separate autophagy-dependent from autophagy-independent effects\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"TDRD7 was shown to restrict HSV-1 via AMPK inhibition independent of autophagy, demonstrating the antiviral effect operates through AMPK itself rather than solely through autophagy.\",\n      \"evidence\": \"Knockdown/knockout/ectopic expression in human and mouse lines, AMPK genetic ablation, chemical inhibition, epistasis\",\n      \"pmids\": [\"32273341\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the physical basis of AMPK inhibition\", \"Step in viral life cycle requiring AMPK not fully resolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"TDRD7's direct mRNA target in lens was pinned to Hspb1, connecting its granule-localized binding to cytoskeletal and morphological control preceding cataract.\",\n      \"evidence\": \"RIP of TDRD7 with Hspb1 mRNA, single-molecule RNA imaging, RNA-seq/proteomics, SEM, phalloidin staining, Hspb1 knockdown in Xenopus\",\n      \"pmids\": [\"32420594\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether TDRD7 stabilizes, transports, or translationally regulates Hspb1 mRNA not resolved\", \"Full target mRNA repertoire not defined\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"TDRD7 was linked to autophagosome maturation by binding Tbc1d20 mRNA and suppressing TBC1D20, explaining how it clears organelles for lens transparency and acrosome biogenesis.\",\n      \"evidence\": \"Transcriptome analysis, TDRD7–Tbc1d20 mRNA binding assays, autophagosome-lysosome fusion and LC3/LAMP1 flux assays, TEM, CTSD processing in tdrd7-deficient MEFs\",\n      \"pmids\": [\"33618632\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of TDRD7-mediated TBC1D20 mRNA downregulation not defined\", \"Relationship between this autophagy role and AMPK-mediated antiviral autophagy control unclear\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"In zebrafish, TDRD7 was shown to relocalize germ plasm and reconfigure chromatin accessibility to elaborate germ-cell fate, separating its role in fate from migration.\",\n      \"evidence\": \"Zebrafish loss-of-function with ATAC-seq, RNA-seq, and live imaging of germ plasm\",\n      \"pmids\": [\"33651978\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking a cytoplasmic RNA-granule protein to chromatin accessibility unresolved\", \"Direct molecular targets in PGCs not identified\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"The antiviral mechanism was resolved to a direct TDRD7–AMPK interaction via a defined domain, with in vivo confirmation that loss of TDRD7 raises AMPK activity and viral susceptibility.\",\n      \"evidence\": \"Co-IP of TDRD7 with AMPK, domain deletion mutagenesis, TDRD7-KO primary cells and mice, in vivo respiratory virus infection\",\n      \"pmids\": [\"37712680\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of the TDRD7–AMPK contact not determined\", \"Whether the AMPK-binding domain overlaps with RNA-binding domains unclear\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How TDRD7's RNA-binding/scaffold activity and its AMPK-inhibitory activity are mechanistically integrated within one protein — and whether they operate in the same or distinct cellular pools — remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structure of full-length TDRD7 or its complexes\", \"Domain map linking RNA binding, granule assembly, and AMPK inhibition not established\", \"Comprehensive target mRNA set not defined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [0, 6, 7]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [3, 4, 5]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 6]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [0, 2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [3, 7]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [3, 4, 5]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [0, 6]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [0, 1, 8]}\n    ],\n    \"complexes\": [\n      \"chromatoid body / nuage RNP\",\n      \"STAU1-ribonucleoprotein\",\n      \"TDRD7-RNA granule\"\n    ],\n    \"partners\": [\n      \"STAU1\",\n      \"AMPK\",\n      \"TDRD1\",\n      \"DDX4\",\n      \"TDRD6\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}