Affinage

DAZAP2

DAZ-associated protein 2 · UniProt Q15038

Length
168 aa
Mass
17.3 kDa
Annotated
2026-04-28
13 papers in source corpus 9 papers cited in narrative 9 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

DAZAP2 is a cytoplasmic adaptor protein that functions at the intersection of multiple signaling and transcriptional pathways by scaffolding protein–protein interactions and modulating protein turnover. In the Wnt pathway, DAZAP2 interacts with all TCF/LEF transcription factors, occupies chromatin at Wnt target loci, and is required for full Wnt/β-catenin transcriptional output (PMID:19304756); in the DNA damage response, DAZAP2 promotes HIPK2 degradation via SIAH1 in unstressed cells but, upon DNA damage, is phosphorylated by HIPK2, translocates to the nucleus, and co-occupies p53 response elements to specify a subset of p53 target genes (PMID:33591310). DAZAP2 negatively regulates IL-25/IL-17RB signaling by binding IL-17RB and blocking ACT1 recruitment, a brake relieved by TRAF4–SMURF2-mediated proteasomal degradation of DAZAP2 (PMID:25681341, PMID:22070932). DAZAP2 also restricts pan-coronavirus infection by blocking viral membrane fusion and suppressing genomic RNA replication, as demonstrated by enhanced SARS-CoV-2 infection in DAZAP2-knockout mice and primary human airway cells (PMID:40833112).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 2004 Low

    Establishing that DAZAP2 protein resides predominantly in the cytoplasm with a punctate distribution set the stage for understanding it as a cytoplasmic signaling adaptor rather than a nuclear-resident factor.

    Evidence Confocal microscopy of EGFP-DAZAP2 in transfected COS-7 cells

    PMID:15629043

    Open questions at the time
    • Single overexpression system without endogenous antibody validation
    • No functional consequence of localization demonstrated
    • Punctate pattern not assigned to any organelle
  2. 2009 High

    Identification of DAZAP2 as a direct TCF/LEF-binding partner that occupies chromatin and modulates Wnt/β-catenin transcriptional activity established its first known nuclear function and linked it to a major developmental signaling pathway.

    Evidence Co-IP, deletion mapping, ChIP, and siRNA knockdown with Wnt reporter assays in human cells

    PMID:19304756

    Open questions at the time
    • Structural basis of DAZAP2–TCF interaction not resolved
    • Whether DAZAP2 acts as a co-activator, co-repressor, or context-dependent modulator not fully delineated
  3. 2009 Medium

    Demonstration that Dazap2 acts downstream of FGF receptor activation for posterior neural patterning in Xenopus, independently of Wnt/Cdx, revealed a second signaling axis in which DAZAP2 participates during embryogenesis.

    Evidence Morpholino knockdown in Xenopus with epistasis analysis across FGF, Wnt, and Cdx pathways

    PMID:19555680

    Open questions at the time
    • Direct FGF-pathway binding partner of Dazap2 not identified
    • Mammalian relevance of this FGF-dependent role unconfirmed
  4. 2011 Medium

    Discovery that DAZAP2 directly binds the IL-17RB cytoplasmic domain and is degraded by SMURF2 upon IL-17E stimulation revealed DAZAP2 as a negative checkpoint in IL-25 signaling, regulated by proteasomal turnover.

    Evidence Yeast two-hybrid, deletion mutagenesis, confocal microscopy, and co-IP

    PMID:22070932

    Open questions at the time
    • SMURF2-mediated ubiquitination sites on DAZAP2 not mapped
    • Functional consequence of DAZAP2 loss on IL-25 downstream signaling not shown in this study
  5. 2015 High

    Validation in Traf4-knockout mice that TRAF4 recruits SMURF2 to degrade DAZAP2 and thereby relieve its inhibition of ACT1–IL-25R association provided in vivo confirmation of DAZAP2's gatekeeper role in type 2 immune signaling.

    Evidence Traf4−/− mice, siRNA, co-IP, in vivo cytokine and eosinophil measurements

    PMID:25681341

    Open questions at the time
    • Whether DAZAP2 inhibition of IL-25R signaling operates in human disease settings not tested
    • Relative contribution of DAZAP2 versus other ACT1 regulators unclear
  6. 2015 Medium

    Identification of maternal Dazap2 as a Bucky ball-binding protein that maintains germ granules in primordial germ cells by counteracting Dynein expanded DAZAP2's roles to germ cell biology and RNA granule dynamics.

    Evidence Zebrafish genetic mutants, co-IP for Dazap2–Bucky ball, epistasis with Tdrd7 and Dynein, confocal imaging

    PMID:26119733

    Open questions at the time
    • Biochemical mechanism by which Dazap2 antagonizes Dynein unknown
    • Conservation of germ-granule role in mammals not established
  7. 2019 Medium

    Elucidation that p38/MAPK–CREB drives DAZAP2 transcription and that promoter CpG methylation silences DAZAP2 in myeloma cells revealed an epigenetic layer controlling DAZAP2 expression in cancer.

    Evidence Bisulfite sequencing, luciferase reporters, ChIP for CREB, p38 inhibition, 5-aza-2'-deoxycytidine treatment in myeloma lines

    PMID:31034872

    Open questions at the time
    • Functional consequence of DAZAP2 re-expression on myeloma cell behavior not demonstrated
    • Whether methylation-driven silencing occurs in other cancer types unknown
  8. 2021 High

    Discovery that DAZAP2 promotes HIPK2 degradation via SIAH1 in unstressed cells and, upon DNA damage, is phosphorylated by HIPK2 to switch from kinase destructor to p53 co-factor at chromatin established a feedback-driven, damage-responsive nuclear role for DAZAP2.

    Evidence siRNA, CRISPR KO, ubiquitination and phosphorylation assays, ChIP, co-IP, mouse xenograft model

    PMID:33591310

    Open questions at the time
    • Specific HIPK2 phosphorylation sites on DAZAP2 that trigger nuclear translocation not fully characterized
    • Which p53 target genes are DAZAP2-dependent in physiological tissues remains limited to xenograft data
  9. 2025 High

    Genome-wide CRISPR screening and in vivo KO studies revealed DAZAP2 as a pan-coronavirus restriction factor that blocks viral membrane fusion at entry and independently suppresses genomic RNA replication, establishing a previously unrecognized innate antiviral function.

    Evidence CRISPR KO screen, DAZAP2 KO in mouse models and primary human airway epithelial cells, viral entry/fusion and RNA replication assays

    PMID:40833112

    Open questions at the time
    • Molecular target on the viral machinery (spike, replicase) through which DAZAP2 acts not identified
    • Whether DAZAP2 restricts non-coronavirus RNA viruses is untested
    • Mechanism coupling membrane-fusion blockade and replication suppression unclear

Open questions

Synthesis pass · forward-looking unresolved questions
  • How DAZAP2 integrates its diverse adaptor functions — Wnt transcription, p53 specification, IL-25 inhibition, germ-granule maintenance, and antiviral restriction — through a single small protein with no recognized enzymatic domain remains an open mechanistic question.
  • No structural model of DAZAP2 or any of its complexes exists
  • Post-translational modification landscape beyond HIPK2 phosphorylation is uncharacterized
  • Whether distinct DAZAP2 pools are partitioned to different functions (e.g., by modifications or binding partners) is unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 4 GO:0098772 molecular function regulator activity 3
Localization
GO:0005634 nucleus 2 GO:0005829 cytosol 2
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-168256 Immune System 2 R-HSA-1643685 Disease 1 R-HSA-5357801 Programmed Cell Death 1
Partners
BUCHIPK2IL17RBSIAH1SMURF2TCF7L2TP53TRAF4

Evidence

Reading pass · 9 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2009 DAZAP2 interacts with TCF-4 (and all TCF/LEF family members) via a short region proximal to the TCF-4 HMG box, modulates TCF-4 affinity for its DNA-recognition motif, and knockdown of DAZAP2 reduces Wnt/beta-catenin transcriptional reporter activity and alters Wnt target gene expression. Co-immunoprecipitation, deletion mapping, chromatin immunoprecipitation (ChIP), siRNA knockdown with reporter assays Nucleic acids research High 19304756
2015 DAZAP2 binds the IL-25 receptor (IL-17RB) and acts as an inhibitor of ACT1/IL-25R interaction; upon IL-25 stimulation, TRAF4 recruits the E3 ligase SMURF2 to polyubiquitinate and degrade DAZAP2, thereby enabling ACT1 to associate with IL-25R and initiate downstream signaling. Genetic knockout mice (Traf4−/−), siRNA knockdown, co-immunoprecipitation, in vivo cytokine/eosinophil measurements Journal of immunology High 25681341
2011 DAZAP2 directly binds the cytoplasmic domain of IL-17RB (between aa 329–347) via its SH2-binding domains; SMURF2 (E3 ubiquitin ligase) interacts with DAZAP2 and mediates its proteasome-dependent degradation; IL-17E stimulation induces cytoplasmic accumulation of DAZAP2. Yeast two-hybrid screening, deletion mutagenesis (tyrosine-to-alanine substitutions), confocal microscopy, co-immunoprecipitation Immunobiology Medium 22070932
2021 In unstressed cells, DAZAP2 promotes HIPK2 polyubiquitination and proteasomal degradation through interplay with the E3 ubiquitin ligase SIAH1; upon DNA damage, HIPK2 site-specifically phosphorylates DAZAP2, terminating its HIPK2-degrading activity and triggering DAZAP2 re-localization to the nucleus where it interacts with p53 and co-occupies p53 response elements to modulate a specific subset of p53 target genes. siRNA knockdown, CRISPR deletion, ubiquitination assays, phosphorylation assays, co-immunoprecipitation, chromatin immunoprecipitation, mouse xenograft model Nucleic acids research High 33591310
2009 In Xenopus embryos, Dazap2 is required downstream of FGF receptor activation for posterior neural patterning (hoxb9 expression), acting in a branch independent of Cdx and canonical Wnt signaling. Morpholino knockdown in Xenopus embryos, epistasis analysis (FGF, Wnt, Cdx pathway perturbations), in situ hybridization for neural markers Developmental biology Medium 19555680
2015 In zebrafish, maternal Dazap2 (MDazap2) binds Bucky ball (an essential regulator of oocyte polarity and germ plasm assembly), co-localizes with germ plasm in oocytes and primordial germ cells, and is required to maintain germ granules in primordial germ cells by counteracting Dynein activity; MDazap2 is epistatic to Tdrd7 in this process. Genetic mutant analysis, co-immunoprecipitation (Dazap2–Bucky ball interaction), molecular epistasis (Tdrd7, Dynein), confocal microscopy Cell reports Medium 26119733
2019 The p38/MAPK signaling pathway drives DAZAP2 expression by phosphorylating CREB, which binds the DAZAP2 promoter CpG island 2; hypermethylation of the CREB binding motif blocks CREB binding and silences DAZAP2 expression in multiple myeloma cells; demethylation with 5-aza-2'-deoxycytidine restores CREB binding and DAZAP2 expression. Bisulfite genomic sequencing, luciferase reporter assays, ChIP for CREB, p38 inhibition/activation, 5-aza-2'-deoxycytidine treatment Cellular signalling Medium 31034872
2004 DAZAP2 protein is predominantly localized in the cytoplasm with a discrete punctuated distribution pattern, as determined by confocal microscopy in transfected cells. Confocal microscopy of EGFP-DAZAP2 fusion protein in transfected COS-7 cells Genomics, proteomics & bioinformatics Low 15629043
2025 DAZAP2 functions as a pan-coronavirus restriction factor that inhibits SARS-CoV-2 entry by blocking virion fusion with endolysosomal and plasma membranes, and independently suppresses 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. Genome-wide CRISPR knockout screen, DAZAP2 KO in mouse models and primary human airway epithelial cells, viral entry/fusion assays, RNA replication assays mBio High 40833112

Source papers

Stage 0 corpus · 13 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2009 Dazap2 modulates transcription driven by the Wnt effector TCF-4. Nucleic acids research 31 19304756
2015 TRAF4-SMURF2-mediated DAZAP2 degradation is critical for IL-25 signaling and allergic airway inflammation. Journal of immunology (Baltimore, Md. : 1950) 30 25681341
2021 DAZAP2 acts as specifier of the p53 response to DNA damage. Nucleic acids research 15 33591310
2011 Smurf2 regulates IL17RB by proteasomal degradation of its novel binding partner DAZAP2. Immunobiology 15 22070932
2020 The hsa-miR-302 cluster controls ectodermal differentiation of human pluripotent stem cell via repression of DAZAP2. Regenerative therapy 14 32490061
2004 The structure, expression and function prediction of DAZAP2, a down-regulated gene in multiple myeloma. Genomics, proteomics & bioinformatics 11 15629043
2015 Maternal dazap2 Regulates Germ Granules by Counteracting Dynein in Zebrafish Primordial Germ Cells. Cell reports 8 26119733
2019 Promoter methylation induced epigenetic silencing of DAZAP2, a downstream effector of p38/MAPK pathway, in multiple myeloma cells. Cellular signalling 7 31034872
2012 The effects of promoter methylation on downregulation of DAZAP2 in multiple myeloma cell lines. PloS one 7 22792345
2007 Molecular features and expression of DAZAP2 in human multiple myeloma. Chinese medical journal 7 17935665
2009 Dazap2 is required for FGF-mediated posterior neural patterning, independent of Wnt and Cdx function. Developmental biology 6 19555680
2025 DAZAP2 functions as a pan-coronavirus restriction factor by inhibiting viral entry and genomic replication. mBio 3 40833112
2026 Comprehensive analysis of the critical transcript function of the DAZAP2 gene in porcine testis. Archives animal breeding 0 42027905