{"gene":"DAZAP2","run_date":"2026-06-09T22:57:19","timeline":{"discoveries":[{"year":2009,"finding":"DAZAP2 interacts with TCF-4 (and all Tcf/Lef family members) via a short region proximal to the TCF-4 HMG box, and modulates TCF-4 affinity for its DNA-recognition motif; knockdown of DAZAP2 reduces Wnt/β-catenin transcriptional reporter activity and alters expression of Wnt target genes.","method":"Co-immunoprecipitation, deletion mapping, chromatin immunoprecipitation, siRNA knockdown with reporter assays","journal":"Nucleic Acids Research","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal interaction mapping, ChIP, and functional reporter assays in a single focused study with multiple orthogonal methods","pmids":["19304756"],"is_preprint":false},{"year":2015,"finding":"DAZAP2 acts as an inhibitory adaptor of the IL-25 receptor (IL-17RB): upon IL-25 stimulation, TRAF4 is recruited to IL-25R and in turn recruits the E3 ubiquitin ligase SMURF2, which mediates proteasomal degradation of DAZAP2, thereby permitting ACT1/IL-25R interaction and downstream signaling. Silencing DAZAP2 increases ACT1/IL-25R interaction and IL-25 responsiveness, while loss of TRAF4 blocks DAZAP2 degradation and blunts IL-25 responses in vivo.","method":"Genetic knockout mice (Traf4−/−), co-immunoprecipitation, siRNA knockdown, in vivo IL-25 challenge, airway inflammation readouts","journal":"Journal of Immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo knockout model combined with co-IP and silencing experiments across multiple orthogonal methods, independently supported by earlier yeast two-hybrid and co-IP data (PMID:22070932)","pmids":["25681341","22070932"],"is_preprint":false},{"year":2011,"finding":"DAZAP2 binds IL-17RB (IL-25R) through two SH2-binding domains; the IL-17RB binding domain maps to residues 329–347 in the cytoplasmic region. Stimulation of IL-17RB with IL-17E/IL-25 induces accumulation of DAZAP2 in the cytoplasm. SMURF2 (E3 ubiquitin ligase) interacts with DAZAP2 and promotes its proteasome-dependent degradation.","method":"Yeast two-hybrid screening, co-immunoprecipitation, domain deletion/point mutagenesis (Tyr→Ala), confocal microscopy, proteasome inhibitor assays","journal":"Immunobiology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — yeast two-hybrid plus co-IP plus mutagenesis plus localization in a single focused study with multiple orthogonal methods","pmids":["22070932"],"is_preprint":false},{"year":2021,"finding":"In unstressed cells, DAZAP2 promotes HIPK2 polyubiquitination and proteasomal degradation by interacting with the E3 ubiquitin ligase SIAH1. Upon DNA damage, HIPK2 site-specifically phosphorylates DAZAP2, which terminates DAZAP2's HIPK2-degrading function and triggers DAZAP2 relocalization to the nucleus. Nuclear DAZAP2 then interacts with p53 and co-occupies p53 response elements to modulate a defined subset of p53 target genes, thereby specifying cell fate after DNA damage. Knockdown or genetic deletion of DAZAP2 potentiates cancer cell chemosensitivity in vitro and in vivo.","method":"siRNA knockdown, CRISPR knockout, co-immunoprecipitation, phosphorylation assays, ubiquitination assays, chromatin immunoprecipitation, mouse xenograft model, site-specific mutagenesis","journal":"Nucleic Acids Research","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (co-IP, ChIP, ubiquitination assay, phosphorylation site mutagenesis, in vivo xenograft) in a single focused study","pmids":["33591310"],"is_preprint":false},{"year":2015,"finding":"Maternal Dazap2 (MDazap2) in zebrafish binds to Bucky ball (an essential regulator of oocyte polarity and germ plasm assembly), colocalizes with germ plasm in oocytes and primordial germ cells, and is required for germ-granule maintenance. Molecular epistasis analysis shows MDazap2 is epistatic to Tdrd7 and counteracts Dynein activity to maintain germ granules in the embryonic germline.","method":"Genetic mutant analysis, co-immunoprecipitation (Dazap2–Bucky ball interaction), epistasis with dynein and Tdrd7, confocal localization","journal":"Cell Reports","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genetic epistasis in zebrafish mutants combined with co-IP and colocalization, multiple orthogonal approaches in one study","pmids":["26119733"],"is_preprint":false},{"year":2009,"finding":"In Xenopus embryos, Dazap2 is required downstream of FGF receptor activation for posterior neural patterning (hoxb9 expression); this function is independent of canonical Wnt signaling and Cdx activity. Loss of Dazap2 reduces hoxb9 and increases anterior marker otx2; overexpression of Dazap2 induces posterior neural markers and overcomes anteriorizing effects of noggin.","method":"Morpholino knockdown, mRNA overexpression, in situ hybridization, epistasis with FGF receptor, Wnt pathway inhibition, and Cdx loss-of-function in Xenopus embryos","journal":"Developmental Biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — clean loss- and gain-of-function in vivo with genetic epistasis using multiple pathway inhibitors","pmids":["19555680"],"is_preprint":false},{"year":2019,"finding":"DAZAP2 is a downstream effector of the p38/MAPK/CREB signaling cascade: p38/MAPK phosphorylates CREB, which binds the DAZAP2 promoter CpG island 2 to drive DAZAP2 expression. Hypermethylation of the CREB binding motif in the DAZAP2 promoter blocks CREB binding and silences DAZAP2 in multiple myeloma cells; demethylation with 5-aza-2'-deoxycytidine restores CREB binding and DAZAP2 expression.","method":"Bisulfite genomic sequencing, luciferase promoter assays, chromatin immunoprecipitation, 5-aza-2'-deoxycytidine treatment, p38 inhibitor experiments","journal":"Cellular Signalling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus promoter luciferase assays plus pharmacological inhibition, single lab study","pmids":["31034872"],"is_preprint":false},{"year":2004,"finding":"DAZAP2 protein is predominantly localized in the cytoplasm with a discrete punctuated distribution pattern, as determined by confocal microscopy of transfected cells.","method":"Confocal microscopy of pEGFP-DAZAP2 fusion protein expressed in COS7 cells","journal":"Genomics, Proteomics & Bioinformatics","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single localization experiment in transfected cells, single lab, no functional consequence linked","pmids":["15629043"],"is_preprint":false},{"year":2025,"finding":"DAZAP2 functions as a pan-coronavirus restriction factor: it inhibits SARS-CoV-2 and other coronaviruses by (1) blocking virion fusion with both endolysosomal and plasma membranes, and (2) suppressing viral genomic RNA replication without affecting primary translation of viral replicases. Knockout of DAZAP2 enhances SARS-CoV-2 infection in mouse models and human primary airway epithelial cells. The antiviral mechanism appears indirect, potentially through regulation of host gene expression, consistent with its primary nuclear localization.","method":"Genome-wide CRISPR knockout screen, DAZAP2 KO mouse models, primary human airway epithelial cell infection assays, viral entry/fusion assays, RNA replication assays","journal":"mBio","confidence":"High","confidence_rationale":"Tier 2 / Strong — CRISPR screen plus in vivo knockout mouse plus primary cell validation plus mechanistic dissection of entry vs. replication steps across multiple coronavirus genera","pmids":["40833112"],"is_preprint":false},{"year":2026,"finding":"miR-378a post-transcriptionally suppresses DAZAP2; loss of DAZAP2 leads to enhanced nuclear translocation of phosphorylated SMAD1/5/9 and activation of canonical BMP signaling, promoting osteogenic differentiation. Rescue experiments confirmed the miR-378a–DAZAP2–SMAD axis.","method":"miRNA overexpression, microarray/RNA-seq target identification, luciferase 3'UTR reporter assay (implied), rescue overexpression of DAZAP2, Western blot for p-SMAD1/5/9 nuclear translocation","journal":"Biochemical and Biophysical Research Communications","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — functional assays with rescue experiments across two orthogonal readouts (target suppression + SMAD pathway), single lab","pmids":["42185189"],"is_preprint":false}],"current_model":"DAZAP2 is a multifunctional scaffold/adaptor protein that operates in several signaling contexts: it interacts with TCF/LEF transcription factors to modulate Wnt/β-catenin target gene expression via effects on TCF-4 DNA binding; it acts as an inhibitory component of the IL-25 receptor complex that is relieved by TRAF4–SMURF2-mediated proteasomal degradation; in the DNA damage response it promotes HIPK2 degradation through SIAH1-dependent ubiquitination until HIPK2 phosphorylates DAZAP2, causing its nuclear relocalization where it co-occupies p53 response elements to specify p53 target gene output; in zebrafish it binds Bucky ball and counteracts Dynein to maintain germ granules in primordial germ cells; in Xenopus it acts downstream of FGF receptor activation to specify posterior neural identity independently of Wnt and Cdx; its expression is regulated by p38/MAPK-driven CREB binding to its promoter, which is silenced by CpG hypermethylation in multiple myeloma; and it functions as a pan-coronavirus restriction factor by blocking virion membrane fusion and suppressing viral RNA replication, likely through indirect regulation of host gene expression from its nuclear compartment."},"narrative":{"mechanistic_narrative":"DAZAP2 is a small multifunctional scaffold/adaptor protein that tunes the output of several signaling and transcriptional pathways, predominantly by modulating the activity, stability, or nuclear access of partner factors [PMID:19304756, PMID:33591310]. In Wnt signaling it binds TCF/LEF transcription factors at a region adjacent to the TCF-4 HMG box and adjusts TCF-4 affinity for DNA, with its loss reducing β-catenin-dependent transcription and altering Wnt target gene expression [PMID:19304756]. In IL-25 (IL-17E) signaling DAZAP2 binds the IL-25 receptor IL-17RB and acts as an inhibitory adaptor; IL-25 stimulation recruits TRAF4, which engages the E3 ligase SMURF2 to drive DAZAP2 proteasomal degradation, relieving the block on ACT1/IL-25R coupling and permitting downstream signaling [PMID:25681341, PMID:22070932]. In the DNA damage response, DAZAP2 normally promotes SIAH1-dependent polyubiquitination and degradation of HIPK2; HIPK2 in turn site-specifically phosphorylates DAZAP2, terminating this activity and triggering DAZAP2 relocalization to the nucleus where it interacts with p53 and co-occupies p53 response elements to shape a defined subset of p53 target genes and cell fate, such that DAZAP2 loss potentiates chemosensitivity [PMID:33591310]. DAZAP2 also acts in developmental and germline contexts—maintaining germ granules by binding Bucky ball and counteracting Dynein in zebrafish primordial germ cells [PMID:26119733], and specifying posterior neural identity downstream of FGF receptor activation independently of Wnt and Cdx in Xenopus [PMID:19555680]—and functions as a pan-coronavirus restriction factor that blocks virion membrane fusion and suppresses viral RNA replication, an effect attributed to indirect regulation of host gene expression from its nuclear compartment [PMID:40833112]. Its expression is itself controlled by p38/MAPK/CREB-driven transcription that is silenced by promoter CpG hypermethylation in multiple myeloma [PMID:31034872].","teleology":[{"year":2004,"claim":"Established the baseline subcellular distribution of DAZAP2, the first step toward asking where it acts.","evidence":"Confocal microscopy of EGFP-DAZAP2 fusion in transfected COS7 cells","pmids":["15629043"],"confidence":"Low","gaps":["Single localization experiment with no functional consequence linked","Overexpressed fusion in a heterologous cell line may not reflect endogenous distribution","Does not address the nuclear pools later implicated in p53 and antiviral functions"]},{"year":2009,"claim":"Defined the first transcriptional role for DAZAP2 by showing it binds TCF/LEF factors and tunes Wnt/β-catenin target gene output, answering whether DAZAP2 directly influences a named transcription factor.","evidence":"Co-IP, deletion mapping, ChIP, and siRNA knockdown with Wnt reporter assays","pmids":["19304756"],"confidence":"High","gaps":["Mechanism by which DAZAP2 alters TCF-4 DNA affinity at the molecular level is undefined","Does not establish whether the effect is direct on DNA binding or via additional cofactors"]},{"year":2009,"claim":"Placed DAZAP2 in vertebrate axial patterning, showing it acts downstream of FGF receptor signaling to specify posterior neural identity and distinguishing this from Wnt and Cdx inputs.","evidence":"Morpholino knockdown, mRNA overexpression, in situ hybridization, and pathway epistasis in Xenopus embryos","pmids":["19555680"],"confidence":"High","gaps":["Molecular effector linking DAZAP2 to hoxb9 induction is unknown","Relationship between this developmental role and its biochemical activities is unresolved"]},{"year":2011,"claim":"Identified DAZAP2 as a direct IL-17RB-binding adaptor and mapped the interaction and its SMURF2-driven degradation, answering how DAZAP2 engages the IL-25 receptor.","evidence":"Yeast two-hybrid, co-IP, domain/point mutagenesis, confocal microscopy, and proteasome inhibitor assays","pmids":["22070932"],"confidence":"High","gaps":["Functional consequence of binding for IL-25 signaling not yet established in this study","Trigger for SMURF2-mediated degradation not defined"]},{"year":2015,"claim":"Resolved DAZAP2's role as an inhibitory brake on IL-25 signaling that is released by TRAF4/SMURF2-mediated degradation, establishing a regulated derepression switch in vivo.","evidence":"Traf4-/- knockout mice, co-IP, siRNA, and in vivo IL-25 airway inflammation challenge","pmids":["25681341","22070932"],"confidence":"High","gaps":["How DAZAP2 sterically or biochemically blocks ACT1/IL-25R coupling is not detailed","Whether this brake operates in other IL-17 family receptors is untested"]},{"year":2015,"claim":"Extended DAZAP2 function to germline development, showing it maintains germ granules by binding Bucky ball and antagonizing Dynein, the first cytoskeletal/RNP-related role.","evidence":"Zebrafish genetic mutants, co-IP, epistasis with Tdrd7 and dynein, and confocal colocalization","pmids":["26119733"],"confidence":"High","gaps":["Mechanism of Dynein antagonism is not defined","Whether mammalian DAZAP2 retains a germ-granule function is unaddressed"]},{"year":2019,"claim":"Defined how DAZAP2 expression is controlled, showing p38/MAPK/CREB drives its transcription and that promoter CpG hypermethylation silences it in multiple myeloma.","evidence":"Bisulfite sequencing, luciferase promoter assays, ChIP, demethylation (5-aza), and p38 inhibition","pmids":["31034872"],"confidence":"Medium","gaps":["Single-lab study not independently replicated","Functional consequence of DAZAP2 silencing for myeloma biology is not established"]},{"year":2021,"claim":"Established a phosphorylation-gated switch in which DAZAP2 controls HIPK2 stability until HIPK2 phosphorylates it, relocalizing DAZAP2 to the nucleus to shape p53 target gene output and chemosensitivity.","evidence":"siRNA, CRISPR KO, co-IP, ubiquitination and phosphorylation assays, ChIP, site-specific mutagenesis, and mouse xenografts","pmids":["33591310"],"confidence":"High","gaps":["The basis for selectivity of which p53 response elements are co-occupied is unclear","How nuclear DAZAP2 mechanistically biases p53 output is undefined"]},{"year":2025,"claim":"Identified DAZAP2 as a pan-coronavirus restriction factor acting at both viral entry/fusion and RNA replication steps, defining an antiviral function distinct from its other roles.","evidence":"Genome-wide CRISPR KO screen, DAZAP2 KO mice, primary human airway epithelial infection, and entry/fusion vs. replication assays","pmids":["40833112"],"confidence":"High","gaps":["The proposed indirect mechanism via host gene expression is not molecularly resolved","How a nuclear protein blocks membrane fusion is unexplained"]},{"year":2026,"claim":"Connected DAZAP2 to BMP/SMAD signaling, showing miR-378a suppression of DAZAP2 enhances nuclear p-SMAD1/5/9 and osteogenic differentiation.","evidence":"miRNA overexpression, target identification, 3'UTR reporter, DAZAP2 rescue, and Western blot for nuclear p-SMAD","pmids":["42185189"],"confidence":"Medium","gaps":["Single-lab study with implied (not shown) reporter validation","Direct molecular link between DAZAP2 and SMAD nuclear translocation is not defined"]},{"year":null,"claim":"A unifying biochemical activity that explains how one small adaptor influences Wnt, IL-25, p53, BMP, developmental patterning, and antiviral pathways remains undefined.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model or defined domain-level activity ties the disparate functions together","Whether a common partner-binding mode underlies all roles is unknown","The relationship between cytoplasmic and nuclear pools across contexts is unresolved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[1,2]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,3]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[2,7]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[3,8]}],"pathway":[],"complexes":[],"partners":["TCF7L2","IL17RB","TRAF4","SMURF2","HIPK2","SIAH1","TP53"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q15038","full_name":"DAZ-associated protein 2","aliases":["Deleted in azoospermia-associated protein 2","Proline-rich transcript in brain protein"],"length_aa":168,"mass_kda":17.3,"function":"In unstressed cells, promotes SIAH1-mediated polyubiquitination and degradation of the serine/threonine-protein kinase HIPK2, probably by acting as a loading factor that potentiates complex formation between HIPK2 and ubiquitin ligase SIAH1 (PubMed:33591310). In response to DNA damage, localizes to the nucleus following phosphorylation by HIPK2 and modulates the expression of a subset of TP53/p53 target genes by binding to TP53 at target gene promoters (PubMed:33591310). This limits the expression of a number of cell death-mediating TP53 target genes, reducing DNA damage-induced cell death (PubMed:33591310). Enhances the binding of transcription factor TCF7L2/TCF4, a Wnt signaling pathway effector, to the promoters of target genes (By similarity). Plays a role in stress granule formation (PubMed:17984221)","subcellular_location":"Cytoplasm; Nucleus; Nucleus speckle; Nucleus, nuclear body; Cytoplasm, Stress granule","url":"https://www.uniprot.org/uniprotkb/Q15038/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/DAZAP2","classification":"Not Classified","n_dependent_lines":5,"n_total_lines":1208,"dependency_fraction":0.0041390728476821195},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/DAZAP2","total_profiled":1310},"omim":[{"mim_id":"607431","title":"DAZ-ASSOCIATED PROTEIN 2; DAZAP2","url":"https://www.omim.org/entry/607431"},{"mim_id":"607430","title":"DAZ-ASSOCIATED PROTEIN 1; DAZAP1","url":"https://www.omim.org/entry/607430"},{"mim_id":"601486","title":"DELETED IN AZOOSPERMIA-LIKE; DAZL","url":"https://www.omim.org/entry/601486"},{"mim_id":"400003","title":"DELETED IN AZOOSPERMIA 1; DAZ1","url":"https://www.omim.org/entry/400003"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nuclear speckles","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/DAZAP2"},"hgnc":{"alias_symbol":["KIAA0058"],"prev_symbol":[]},"alphafold":{"accession":"Q15038","domains":[{"cath_id":"-","chopping":"92-155","consensus_level":"medium","plddt":72.0495,"start":92,"end":155}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q15038","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q15038-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q15038-F1-predicted_aligned_error_v6.png","plddt_mean":58.59},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=DAZAP2","jax_strain_url":"https://www.jax.org/strain/search?query=DAZAP2"},"sequence":{"accession":"Q15038","fasta_url":"https://rest.uniprot.org/uniprotkb/Q15038.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q15038/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q15038"}},"corpus_meta":[{"pmid":"19304756","id":"PMC_19304756","title":"Dazap2 modulates transcription driven by the Wnt effector TCF-4.","date":"2009","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/19304756","citation_count":32,"is_preprint":false},{"pmid":"25681341","id":"PMC_25681341","title":"TRAF4-SMURF2-mediated DAZAP2 degradation is critical for IL-25 signaling and allergic airway inflammation.","date":"2015","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/25681341","citation_count":30,"is_preprint":false},{"pmid":"33591310","id":"PMC_33591310","title":"DAZAP2 acts as specifier of the p53 response to DNA damage.","date":"2021","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/33591310","citation_count":15,"is_preprint":false},{"pmid":"22070932","id":"PMC_22070932","title":"Smurf2 regulates IL17RB by proteasomal degradation of its novel binding partner DAZAP2.","date":"2011","source":"Immunobiology","url":"https://pubmed.ncbi.nlm.nih.gov/22070932","citation_count":15,"is_preprint":false},{"pmid":"32490061","id":"PMC_32490061","title":"The hsa-miR-302 cluster controls ectodermal differentiation of human pluripotent stem cell via repression of DAZAP2.","date":"2020","source":"Regenerative therapy","url":"https://pubmed.ncbi.nlm.nih.gov/32490061","citation_count":14,"is_preprint":false},{"pmid":"15629043","id":"PMC_15629043","title":"The structure, expression and function prediction of DAZAP2, a down-regulated gene in multiple myeloma.","date":"2004","source":"Genomics, proteomics & bioinformatics","url":"https://pubmed.ncbi.nlm.nih.gov/15629043","citation_count":12,"is_preprint":false},{"pmid":"17935665","id":"PMC_17935665","title":"Molecular features and expression of DAZAP2 in human multiple myeloma.","date":"2007","source":"Chinese medical journal","url":"https://pubmed.ncbi.nlm.nih.gov/17935665","citation_count":8,"is_preprint":false},{"pmid":"31034872","id":"PMC_31034872","title":"Promoter methylation induced epigenetic silencing of DAZAP2, a downstream effector of p38/MAPK pathway, in multiple myeloma cells.","date":"2019","source":"Cellular signalling","url":"https://pubmed.ncbi.nlm.nih.gov/31034872","citation_count":8,"is_preprint":false},{"pmid":"26119733","id":"PMC_26119733","title":"Maternal dazap2 Regulates Germ Granules by Counteracting Dynein in Zebrafish Primordial Germ Cells.","date":"2015","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/26119733","citation_count":8,"is_preprint":false},{"pmid":"22792345","id":"PMC_22792345","title":"The effects of promoter methylation on downregulation of DAZAP2 in multiple myeloma cell lines.","date":"2012","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/22792345","citation_count":7,"is_preprint":false},{"pmid":"19555680","id":"PMC_19555680","title":"Dazap2 is required for FGF-mediated posterior neural patterning, independent of Wnt and Cdx function.","date":"2009","source":"Developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/19555680","citation_count":6,"is_preprint":false},{"pmid":"40833112","id":"PMC_40833112","title":"DAZAP2 functions as a pan-coronavirus restriction factor by inhibiting viral entry and genomic replication.","date":"2025","source":"mBio","url":"https://pubmed.ncbi.nlm.nih.gov/40833112","citation_count":3,"is_preprint":false},{"pmid":"42185189","id":"PMC_42185189","title":"Periodontal ligament stem cell-derived exosomal miR-378a programs osteogenic commitment via DAZAP2/SMAD signaling.","date":"2026","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/42185189","citation_count":0,"is_preprint":false},{"pmid":"42027905","id":"PMC_42027905","title":"Comprehensive analysis of the critical transcript function of the DAZAP2 gene in porcine testis.","date":"2026","source":"Archives animal breeding","url":"https://pubmed.ncbi.nlm.nih.gov/42027905","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":9180,"output_tokens":3119,"usd":0.037163,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10529,"output_tokens":3619,"usd":0.07156,"stage2_stop_reason":"end_turn"},"total_usd":0.108723,"stage1_batch_id":"msgbatch_01ACAxJQabDsht39JXeWG22d","stage2_batch_id":"msgbatch_01QEU22A9U5sbPTgsMzTmvSf","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2009,\n      \"finding\": \"DAZAP2 interacts with TCF-4 (and all Tcf/Lef family members) via a short region proximal to the TCF-4 HMG box, and modulates TCF-4 affinity for its DNA-recognition motif; knockdown of DAZAP2 reduces Wnt/β-catenin transcriptional reporter activity and alters expression of Wnt target genes.\",\n      \"method\": \"Co-immunoprecipitation, deletion mapping, chromatin immunoprecipitation, siRNA knockdown with reporter assays\",\n      \"journal\": \"Nucleic Acids Research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal interaction mapping, ChIP, and functional reporter assays in a single focused study with multiple orthogonal methods\",\n      \"pmids\": [\"19304756\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"DAZAP2 acts as an inhibitory adaptor of the IL-25 receptor (IL-17RB): upon IL-25 stimulation, TRAF4 is recruited to IL-25R and in turn recruits the E3 ubiquitin ligase SMURF2, which mediates proteasomal degradation of DAZAP2, thereby permitting ACT1/IL-25R interaction and downstream signaling. Silencing DAZAP2 increases ACT1/IL-25R interaction and IL-25 responsiveness, while loss of TRAF4 blocks DAZAP2 degradation and blunts IL-25 responses in vivo.\",\n      \"method\": \"Genetic knockout mice (Traf4−/−), co-immunoprecipitation, siRNA knockdown, in vivo IL-25 challenge, airway inflammation readouts\",\n      \"journal\": \"Journal of Immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo knockout model combined with co-IP and silencing experiments across multiple orthogonal methods, independently supported by earlier yeast two-hybrid and co-IP data (PMID:22070932)\",\n      \"pmids\": [\"25681341\", \"22070932\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"DAZAP2 binds IL-17RB (IL-25R) through two SH2-binding domains; the IL-17RB binding domain maps to residues 329–347 in the cytoplasmic region. Stimulation of IL-17RB with IL-17E/IL-25 induces accumulation of DAZAP2 in the cytoplasm. SMURF2 (E3 ubiquitin ligase) interacts with DAZAP2 and promotes its proteasome-dependent degradation.\",\n      \"method\": \"Yeast two-hybrid screening, co-immunoprecipitation, domain deletion/point mutagenesis (Tyr→Ala), confocal microscopy, proteasome inhibitor assays\",\n      \"journal\": \"Immunobiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast two-hybrid plus co-IP plus mutagenesis plus localization in a single focused study with multiple orthogonal methods\",\n      \"pmids\": [\"22070932\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"In unstressed cells, DAZAP2 promotes HIPK2 polyubiquitination and proteasomal degradation by interacting with the E3 ubiquitin ligase SIAH1. Upon DNA damage, HIPK2 site-specifically phosphorylates DAZAP2, which terminates DAZAP2's HIPK2-degrading function and triggers DAZAP2 relocalization to the nucleus. Nuclear DAZAP2 then interacts with p53 and co-occupies p53 response elements to modulate a defined subset of p53 target genes, thereby specifying cell fate after DNA damage. Knockdown or genetic deletion of DAZAP2 potentiates cancer cell chemosensitivity in vitro and in vivo.\",\n      \"method\": \"siRNA knockdown, CRISPR knockout, co-immunoprecipitation, phosphorylation assays, ubiquitination assays, chromatin immunoprecipitation, mouse xenograft model, site-specific mutagenesis\",\n      \"journal\": \"Nucleic Acids Research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (co-IP, ChIP, ubiquitination assay, phosphorylation site mutagenesis, in vivo xenograft) in a single focused study\",\n      \"pmids\": [\"33591310\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Maternal Dazap2 (MDazap2) in zebrafish binds to Bucky ball (an essential regulator of oocyte polarity and germ plasm assembly), colocalizes with germ plasm in oocytes and primordial germ cells, and is required for germ-granule maintenance. Molecular epistasis analysis shows MDazap2 is epistatic to Tdrd7 and counteracts Dynein activity to maintain germ granules in the embryonic germline.\",\n      \"method\": \"Genetic mutant analysis, co-immunoprecipitation (Dazap2–Bucky ball interaction), epistasis with dynein and Tdrd7, confocal localization\",\n      \"journal\": \"Cell Reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis in zebrafish mutants combined with co-IP and colocalization, multiple orthogonal approaches in one study\",\n      \"pmids\": [\"26119733\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"In Xenopus embryos, Dazap2 is required downstream of FGF receptor activation for posterior neural patterning (hoxb9 expression); this function is independent of canonical Wnt signaling and Cdx activity. Loss of Dazap2 reduces hoxb9 and increases anterior marker otx2; overexpression of Dazap2 induces posterior neural markers and overcomes anteriorizing effects of noggin.\",\n      \"method\": \"Morpholino knockdown, mRNA overexpression, in situ hybridization, epistasis with FGF receptor, Wnt pathway inhibition, and Cdx loss-of-function in Xenopus embryos\",\n      \"journal\": \"Developmental Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean loss- and gain-of-function in vivo with genetic epistasis using multiple pathway inhibitors\",\n      \"pmids\": [\"19555680\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"DAZAP2 is a downstream effector of the p38/MAPK/CREB signaling cascade: p38/MAPK phosphorylates CREB, which binds the DAZAP2 promoter CpG island 2 to drive DAZAP2 expression. Hypermethylation of the CREB binding motif in the DAZAP2 promoter blocks CREB binding and silences DAZAP2 in multiple myeloma cells; demethylation with 5-aza-2'-deoxycytidine restores CREB binding and DAZAP2 expression.\",\n      \"method\": \"Bisulfite genomic sequencing, luciferase promoter assays, chromatin immunoprecipitation, 5-aza-2'-deoxycytidine treatment, p38 inhibitor experiments\",\n      \"journal\": \"Cellular Signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus promoter luciferase assays plus pharmacological inhibition, single lab study\",\n      \"pmids\": [\"31034872\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"DAZAP2 protein is predominantly localized in the cytoplasm with a discrete punctuated distribution pattern, as determined by confocal microscopy of transfected cells.\",\n      \"method\": \"Confocal microscopy of pEGFP-DAZAP2 fusion protein expressed in COS7 cells\",\n      \"journal\": \"Genomics, Proteomics & Bioinformatics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single localization experiment in transfected cells, single lab, no functional consequence linked\",\n      \"pmids\": [\"15629043\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"DAZAP2 functions as a pan-coronavirus restriction factor: it inhibits SARS-CoV-2 and other coronaviruses by (1) blocking virion fusion with both endolysosomal and plasma membranes, and (2) suppressing viral genomic RNA replication without affecting primary translation of viral replicases. Knockout of DAZAP2 enhances SARS-CoV-2 infection in mouse models and human primary airway epithelial cells. The antiviral mechanism appears indirect, potentially through regulation of host gene expression, consistent with its primary nuclear localization.\",\n      \"method\": \"Genome-wide CRISPR knockout screen, DAZAP2 KO mouse models, primary human airway epithelial cell infection assays, viral entry/fusion assays, RNA replication assays\",\n      \"journal\": \"mBio\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — CRISPR screen plus in vivo knockout mouse plus primary cell validation plus mechanistic dissection of entry vs. replication steps across multiple coronavirus genera\",\n      \"pmids\": [\"40833112\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"miR-378a post-transcriptionally suppresses DAZAP2; loss of DAZAP2 leads to enhanced nuclear translocation of phosphorylated SMAD1/5/9 and activation of canonical BMP signaling, promoting osteogenic differentiation. Rescue experiments confirmed the miR-378a–DAZAP2–SMAD axis.\",\n      \"method\": \"miRNA overexpression, microarray/RNA-seq target identification, luciferase 3'UTR reporter assay (implied), rescue overexpression of DAZAP2, Western blot for p-SMAD1/5/9 nuclear translocation\",\n      \"journal\": \"Biochemical and Biophysical Research Communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — functional assays with rescue experiments across two orthogonal readouts (target suppression + SMAD pathway), single lab\",\n      \"pmids\": [\"42185189\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"DAZAP2 is a multifunctional scaffold/adaptor protein that operates in several signaling contexts: it interacts with TCF/LEF transcription factors to modulate Wnt/β-catenin target gene expression via effects on TCF-4 DNA binding; it acts as an inhibitory component of the IL-25 receptor complex that is relieved by TRAF4–SMURF2-mediated proteasomal degradation; in the DNA damage response it promotes HIPK2 degradation through SIAH1-dependent ubiquitination until HIPK2 phosphorylates DAZAP2, causing its nuclear relocalization where it co-occupies p53 response elements to specify p53 target gene output; in zebrafish it binds Bucky ball and counteracts Dynein to maintain germ granules in primordial germ cells; in Xenopus it acts downstream of FGF receptor activation to specify posterior neural identity independently of Wnt and Cdx; its expression is regulated by p38/MAPK-driven CREB binding to its promoter, which is silenced by CpG hypermethylation in multiple myeloma; and it functions as a pan-coronavirus restriction factor by blocking virion membrane fusion and suppressing viral RNA replication, likely through indirect regulation of host gene expression from its nuclear compartment.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"DAZAP2 is a small multifunctional scaffold/adaptor protein that tunes the output of several signaling and transcriptional pathways, predominantly by modulating the activity, stability, or nuclear access of partner factors [#0, #3]. In Wnt signaling it binds TCF/LEF transcription factors at a region adjacent to the TCF-4 HMG box and adjusts TCF-4 affinity for DNA, with its loss reducing \\u03b2-catenin-dependent transcription and altering Wnt target gene expression [#0]. In IL-25 (IL-17E) signaling DAZAP2 binds the IL-25 receptor IL-17RB and acts as an inhibitory adaptor; IL-25 stimulation recruits TRAF4, which engages the E3 ligase SMURF2 to drive DAZAP2 proteasomal degradation, relieving the block on ACT1/IL-25R coupling and permitting downstream signaling [#1, #2]. In the DNA damage response, DAZAP2 normally promotes SIAH1-dependent polyubiquitination and degradation of HIPK2; HIPK2 in turn site-specifically phosphorylates DAZAP2, terminating this activity and triggering DAZAP2 relocalization to the nucleus where it interacts with p53 and co-occupies p53 response elements to shape a defined subset of p53 target genes and cell fate, such that DAZAP2 loss potentiates chemosensitivity [#3]. DAZAP2 also acts in developmental and germline contexts\\u2014maintaining germ granules by binding Bucky ball and counteracting Dynein in zebrafish primordial germ cells [#4], and specifying posterior neural identity downstream of FGF receptor activation independently of Wnt and Cdx in Xenopus [#5]\\u2014and functions as a pan-coronavirus restriction factor that blocks virion membrane fusion and suppresses viral RNA replication, an effect attributed to indirect regulation of host gene expression from its nuclear compartment [#8]. Its expression is itself controlled by p38/MAPK/CREB-driven transcription that is silenced by promoter CpG hypermethylation in multiple myeloma [#6].\",\n  \"teleology\": [\n    {\n      \"year\": 2004,\n      \"claim\": \"Established the baseline subcellular distribution of DAZAP2, the first step toward asking where it acts.\",\n      \"evidence\": \"Confocal microscopy of EGFP-DAZAP2 fusion in transfected COS7 cells\",\n      \"pmids\": [\"15629043\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single localization experiment with no functional consequence linked\", \"Overexpressed fusion in a heterologous cell line may not reflect endogenous distribution\", \"Does not address the nuclear pools later implicated in p53 and antiviral functions\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Defined the first transcriptional role for DAZAP2 by showing it binds TCF/LEF factors and tunes Wnt/\\u03b2-catenin target gene output, answering whether DAZAP2 directly influences a named transcription factor.\",\n      \"evidence\": \"Co-IP, deletion mapping, ChIP, and siRNA knockdown with Wnt reporter assays\",\n      \"pmids\": [\"19304756\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which DAZAP2 alters TCF-4 DNA affinity at the molecular level is undefined\", \"Does not establish whether the effect is direct on DNA binding or via additional cofactors\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Placed DAZAP2 in vertebrate axial patterning, showing it acts downstream of FGF receptor signaling to specify posterior neural identity and distinguishing this from Wnt and Cdx inputs.\",\n      \"evidence\": \"Morpholino knockdown, mRNA overexpression, in situ hybridization, and pathway epistasis in Xenopus embryos\",\n      \"pmids\": [\"19555680\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular effector linking DAZAP2 to hoxb9 induction is unknown\", \"Relationship between this developmental role and its biochemical activities is unresolved\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Identified DAZAP2 as a direct IL-17RB-binding adaptor and mapped the interaction and its SMURF2-driven degradation, answering how DAZAP2 engages the IL-25 receptor.\",\n      \"evidence\": \"Yeast two-hybrid, co-IP, domain/point mutagenesis, confocal microscopy, and proteasome inhibitor assays\",\n      \"pmids\": [\"22070932\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of binding for IL-25 signaling not yet established in this study\", \"Trigger for SMURF2-mediated degradation not defined\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Resolved DAZAP2's role as an inhibitory brake on IL-25 signaling that is released by TRAF4/SMURF2-mediated degradation, establishing a regulated derepression switch in vivo.\",\n      \"evidence\": \"Traf4-/- knockout mice, co-IP, siRNA, and in vivo IL-25 airway inflammation challenge\",\n      \"pmids\": [\"25681341\", \"22070932\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How DAZAP2 sterically or biochemically blocks ACT1/IL-25R coupling is not detailed\", \"Whether this brake operates in other IL-17 family receptors is untested\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Extended DAZAP2 function to germline development, showing it maintains germ granules by binding Bucky ball and antagonizing Dynein, the first cytoskeletal/RNP-related role.\",\n      \"evidence\": \"Zebrafish genetic mutants, co-IP, epistasis with Tdrd7 and dynein, and confocal colocalization\",\n      \"pmids\": [\"26119733\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of Dynein antagonism is not defined\", \"Whether mammalian DAZAP2 retains a germ-granule function is unaddressed\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defined how DAZAP2 expression is controlled, showing p38/MAPK/CREB drives its transcription and that promoter CpG hypermethylation silences it in multiple myeloma.\",\n      \"evidence\": \"Bisulfite sequencing, luciferase promoter assays, ChIP, demethylation (5-aza), and p38 inhibition\",\n      \"pmids\": [\"31034872\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab study not independently replicated\", \"Functional consequence of DAZAP2 silencing for myeloma biology is not established\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Established a phosphorylation-gated switch in which DAZAP2 controls HIPK2 stability until HIPK2 phosphorylates it, relocalizing DAZAP2 to the nucleus to shape p53 target gene output and chemosensitivity.\",\n      \"evidence\": \"siRNA, CRISPR KO, co-IP, ubiquitination and phosphorylation assays, ChIP, site-specific mutagenesis, and mouse xenografts\",\n      \"pmids\": [\"33591310\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The basis for selectivity of which p53 response elements are co-occupied is unclear\", \"How nuclear DAZAP2 mechanistically biases p53 output is undefined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified DAZAP2 as a pan-coronavirus restriction factor acting at both viral entry/fusion and RNA replication steps, defining an antiviral function distinct from its other roles.\",\n      \"evidence\": \"Genome-wide CRISPR KO screen, DAZAP2 KO mice, primary human airway epithelial infection, and entry/fusion vs. replication assays\",\n      \"pmids\": [\"40833112\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The proposed indirect mechanism via host gene expression is not molecularly resolved\", \"How a nuclear protein blocks membrane fusion is unexplained\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Connected DAZAP2 to BMP/SMAD signaling, showing miR-378a suppression of DAZAP2 enhances nuclear p-SMAD1/5/9 and osteogenic differentiation.\",\n      \"evidence\": \"miRNA overexpression, target identification, 3'UTR reporter, DAZAP2 rescue, and Western blot for nuclear p-SMAD\",\n      \"pmids\": [\"42185189\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab study with implied (not shown) reporter validation\", \"Direct molecular link between DAZAP2 and SMAD nuclear translocation is not defined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"A unifying biochemical activity that explains how one small adaptor influences Wnt, IL-25, p53, BMP, developmental patterning, and antiviral pathways remains undefined.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model or defined domain-level activity ties the disparate functions together\", \"Whether a common partner-binding mode underlies all roles is unknown\", \"The relationship between cytoplasmic and nuclear pools across contexts is unresolved\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [1, 2]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [2, 7]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [3, 8]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0001618\", \"supporting_discovery_ids\": []}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"TCF7L2\", \"IL17RB\", \"TRAF4\", \"SMURF2\", \"HIPK2\", \"SIAH1\", \"TP53\"]\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}