Affinage

DDX3X

ATP-dependent RNA helicase DDX3X · UniProt O00571

Length
662 aa
Mass
73.2 kDa
Annotated
2026-04-28
100 papers in source corpus 49 papers cited in narrative 49 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

DDX3X is an ATP-dependent DEAD-box RNA helicase that functions as a central translational regulator, unwinding structured 5'UTRs by clamping the eIF4F complex through simultaneous interactions with eIF4G and PABP to promote cap-dependent translation initiation of select mRNAs, while also resolving inhibitory RNA-RNA interactions within RNP condensates to maintain mRNA translatability (PMID:22872150, PMID:39729994, PMID:34437837). Its N-terminal intrinsically disordered region drives liquid-liquid phase separation to nucleate stress granules, and this condensation property is regulated by post-translational modifications including K27-linked deubiquitination by USP8, arginine methylation by PRMT1, K48-linked ubiquitination by RNF39, and K63-linked ubiquitination by WWP2 (PMID:27180681, PMID:38795350, PMID:33674311, PMID:39042374, PMID:37149668). Beyond translation, DDX3X serves as a signaling adaptor that directly stimulates CK1ε kinase activity in Wnt-β-catenin signaling, activates IKKε and IKKα in antiviral innate immune signaling to drive type I interferon production, and interacts with NLRP3 to promote inflammasome activation—with stress granule sequestration of DDX3X acting as a molecular switch between pro-survival and pyroptotic cell fates (PMID:23413191, PMID:30341167, PMID:31511697). De novo loss-of-function DDX3X mutations cause an X-linked intellectual disability syndrome characterized by impaired cortical neurogenesis due to disrupted helicase activity, ectopic RNP granule formation, and defective translation in neural progenitors (PMID:32135084, PMID:35762573, PMID:26235985).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 2003 Medium

    A temperature-sensitive DDX3X mutant established that the gene is required for G1-to-S cell cycle progression and nuclear mRNA export, linking its helicase function to cell proliferation.

    Evidence Temperature-sensitive P267S mutant complementation with cell cycle analysis and mRNA accumulation assay in mammalian cells

    PMID:12944373

    Open questions at the time
    • Mechanism connecting helicase activity to mRNA export not defined
    • Single mutant allele studied
    • Direct substrates not identified
  2. 2007 High

    DDX3X was shown to be required for HCV RNA replication, establishing it as a host factor exploited by RNA viruses.

    Evidence shRNA knockdown with HCV replicon and JFH1 RNA replication assays across multiple viral strains

    PMID:17855521

    Open questions at the time
    • Direct mechanism of DDX3X action on HCV RNA not determined
    • Whether DDX3X acts on viral RNA structure or translation not resolved
  3. 2012 High

    Reconstituted translation assays revealed how DDX3X promotes cap-dependent translation: it binds structured 5'UTRs and clamps eIF4F via simultaneous eIF4G and PABP interactions, enabling 43S PIC attachment.

    Evidence In vitro translation reconstitution with defined protein-RNA interactions, eIF4F co-immunoprecipitation, and ribosome binding assays

    PMID:22872150

    Open questions at the time
    • Genome-wide scope of DDX3X-dependent transcripts not yet defined
    • Structural basis of eIF4G/PABP bridging unclear
  4. 2013 High

    DDX3X was established as a non-catalytic regulatory subunit of CK1ε in Wnt signaling, directly stimulating kinase activity and Dishevelled phosphorylation—a function independent of its RNA helicase activity.

    Evidence Kinase activity assays, reciprocal Co-IP, genetic epistasis in Xenopus, C. elegans, and mammalian cells

    PMID:23413191

    Open questions at the time
    • Whether CK1ε stimulation requires DDX3X conformational change unresolved
    • Stoichiometry and structural basis of DDX3X-CK1ε complex unknown
  5. 2015 High

    Structural and biochemical analysis of cancer-associated DDX3X mutants (G302V, G325E) showed that specific D1 domain residues are critical for RNA-stimulated ATPase activity and dsRNA engagement, and de novo DDX3X mutations cause Wnt pathway loss-of-function in vivo, linking DDX3X to intellectual disability.

    Evidence Crystal structures, NMR, ITC, ATPase assays, yeast complementation; zebrafish Wnt assays and exome sequencing of patients with intellectual disability

    PMID:25724843 PMID:26192917 PMID:26235985

    Open questions at the time
    • Full-length DDX3X structure not available
    • Precise relationship between helicase loss and neurodevelopmental phenotype not mechanistically resolved
  6. 2016 High

    Multiple studies converged to show that DDX3X's N-terminal low-complexity domain drives stress granule assembly, cancer-associated mutations cause SG hyper-assembly with global translation inhibition, and DDX3X translationally activates a Rac1 regulon essential for neurite outgrowth; epiblast-specific knockout demonstrated embryonic lethality with DNA damage accumulation.

    Evidence CLIP-seq, ribosome profiling, SG imaging, domain deletion mutants, polysome profiling in neurons, conditional KO mice with ChIP for DDB2/XPA promoters

    PMID:27058758 PMID:27179789 PMID:27180681 PMID:27656019

    Open questions at the time
    • Which SG components directly interact with DDX3X IDR not fully mapped
    • Whether DNA repair gene regulation is direct transcriptional function or indirect
  7. 2017 High

    Systematic biochemical comparison with yeast Ded1p confirmed DDX3X uses ATP exclusively for unwinding, oligomerizes for efficient helicase activity, and preferentially acts on substrates with 3' unpaired regions; DDX3X was also shown to drive ER stress-dependent ATF4 translation via phospho-eIF2α-dependent reinitiation.

    Evidence In vitro ATPase/unwinding/annealing assays; polyribosome profiling and luciferase reporter assays for ATF4 translation

    PMID:29037760 PMID:29062139

    Open questions at the time
    • Structural basis of DDX3X oligomerization unknown
    • Whether ATF4 translation regulation is direct 5'UTR unwinding or indirect
  8. 2018 High

    DDX3X was positioned as a central adaptor in innate immune kinase signaling by directly activating IKKε (for IRF3/IFN-β) and IKKα (for IRF7/NF-κB); it was also shown to localize to mitochondria where its inhibition impairs mitochondrial translation and bioenergetics.

    Evidence Co-IP with kinase activation assays; mitochondrial fractionation with quantitative proteomics and oxygen consumption measurements

    PMID:28869602 PMID:30341167

    Open questions at the time
    • How DDX3X stimulates kinase autophosphorylation structurally is unknown
    • Identity of mitochondrial mRNA targets not catalogued
  9. 2019 High

    Crystal structure of DDX3X helicase core with dsRNA revealed a cooperative two-molecule unwinding mechanism, and DDX3X was established as a molecular switch between stress granule assembly (pro-survival) and NLRP3 inflammasome activation (pyroptosis).

    Evidence X-ray crystallography of D1D2:dsRNA complex; Co-IP, DDX3X myeloid KO, in vivo cytokine measurements, and SG induction assays

    PMID:31300642 PMID:31511697

    Open questions at the time
    • Whether cooperative unwinding occurs on all substrates or only specific dsRNA lengths unclear
    • How SG sequestration quantitatively titrates DDX3X away from NLRP3 not modeled
  10. 2020 High

    Pathogenic DDX3X missense mutations were shown to disrupt helicase activity, induce ectopic RNP granules, and impair translation in neural progenitors, directly causing cortical development defects; separately, DDX3X was found to possess RNaseH2-like activity supporting ribonucleotide excision repair.

    Evidence Mouse/human genetics with biochemical helicase assays and cortical phenotyping; in vitro RER reconstitution with DDX3X silencing causing genomic rNMP accumulation

    PMID:32135084 PMID:33137198

    Open questions at the time
    • Whether RNaseH2-like activity is physiologically significant relative to canonical RNaseH2 not established
    • Which specific mRNAs drive cortical progenitor phenotype not fully defined
  11. 2021 High

    A wave of post-translational modification studies established that DDX3X is regulated by K48-linked ubiquitination (RNF39, promoting degradation to dampen antiviral signaling), TRIM25-mediated ubiquitination at K55 (cooperative IFN induction), demalonylation by SIRT5 (enhancing TBK1-IRF3 activation), AKT phosphorylation (disrupting NLRP3 interaction), and PARP1-dependent recruitment to DNA damage sites via LLPS.

    Evidence Ubiquitination assays with KO mice (RNF39, SIRT5), phosphorylation assays with in vivo sepsis models, live-cell microirradiation with PARP1 KO, in vitro ubiquitination with mutagenesis

    PMID:33674311 PMID:34083132 PMID:34158847 PMID:34387860 PMID:34445801

    Open questions at the time
    • Hierarchy and interplay among multiple PTMs not integrated
    • Whether PARP1-dependent recruitment involves PAR-binding or phase separation alone not resolved
  12. 2022 High

    DDX3X and DDX3Y were shown to be functionally redundant for mRNA translation but differ in LLPS propensity—DDX3Y has stronger condensation and weaker ATPase activity—explaining sex-biased DDX3X syndrome; DDX3X was also shown to promote cortical development by regulating progenitor cell cycle duration via translation of neurogenesis transcripts.

    Evidence Ribosome profiling with DDX3Y complementation; single-molecule LLPS assays; mouse KO with in vivo ribosome profiling and live progenitor imaging

    PMID:34535544 PMID:35588748 PMID:35762573

    Open questions at the time
    • Whether DDX3Y compensates for all DDX3X functions beyond translation not tested
    • Structural basis for differential LLPS propensity of paralogs not resolved
  13. 2023 High

    New regulatory axes were identified: KLHL29/CUL3-mediated proteasomal degradation of DDX3X destabilizes CCND1 mRNA causing G1 arrest; WWP2 catalyzes K63-linked polyubiquitination for DDX3X degradation; and asparagine endopeptidase cleaves DDX3X under hypoxia generating a nuclear fragment that alters pre-mRNA splicing.

    Evidence Co-IP with ubiquitination assays and organoid validation; endothelial-specific Wwp2 KO mice; biochemical cleavage assays with splicing analysis in glioblastoma organoids and animal models

    PMID:37149668 PMID:37845393 PMID:37988165

    Open questions at the time
    • Whether AEP cleavage represents a general hypoxia response or is glioblastoma-specific unknown
    • Relationship between multiple E3 ligase pathways targeting DDX3X not integrated
  14. 2024 High

    DDX3X was shown to resolve inhibitory RNA-RNA interactions within G3BP1-driven RNP condensates to maintain mRNA translatability, and USP8-mediated removal of K27-linked ubiquitin chains from DDX3X's IDR enhances its condensation to potentiate cGAS-STING signaling; PRMT1-mediated arginine methylation stabilizes DDX3X and promotes its mitochondrial translocation for PINK1 mRNA translation.

    Evidence In vitro condensate assays with single-molecule RNA mobility; deubiquitination and LLPS assays with Trex1-/- mouse model; arginine methylation assays with mitochondrial fractionation and in vivo xenografts

    PMID:38795350 PMID:39042374 PMID:39729994

    Open questions at the time
    • Full repertoire of mitochondrial mRNA targets beyond PINK1 not catalogued
    • How K27-ubiquitin removal mechanistically enhances phase separation not structurally resolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include: (1) how multiple PTMs are coordinated to direct DDX3X between its translation, innate immune, Wnt signaling, and DNA repair functions; (2) the full-length structure of DDX3X including its IDR in condensate contexts; (3) the complete set of mRNA targets whose translation depends on DDX3X helicase activity in different cell types; and (4) the physiological significance of DDX3X's RNaseH2-like activity relative to canonical RNaseH2.
  • No integrated PTM regulatory model
  • No full-length DDX3X structure
  • Cell-type-specific translatome not comprehensively defined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003723 RNA binding 8 GO:0140657 ATP-dependent activity 4 GO:0060090 molecular adaptor activity 3 GO:0098772 molecular function regulator activity 3 GO:0140098 catalytic activity, acting on RNA 1
Localization
GO:0005634 nucleus 3 GO:0005829 cytosol 3 GO:0005739 mitochondrion 2
Pathway
R-HSA-392499 Metabolism of proteins 8 R-HSA-168256 Immune System 7 R-HSA-162582 Signal Transduction 4 R-HSA-1266738 Developmental Biology 3 R-HSA-73894 DNA Repair 3 R-HSA-5357801 Programmed Cell Death 2
Partners
CHUKCSNK1EEIF4G1G3BP1IKBKENLRP3RNF39USP8
Complex memberships
NLRP3 inflammasomeeIF4F translation initiation complexstress granules

Evidence

Reading pass · 49 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2019 DDX3X directly interacts with NLRP3 to drive inflammasome activation; assembly of stress granules sequesters DDX3X, thereby inhibiting NLRP3 inflammasome activation and pyroptosis. DDX3X acts as a rheostat between pro-survival stress granules and pyroptotic ASC specks. Co-immunoprecipitation, loss-of-function (DDX3X KO in myeloid compartment), in vivo cytokine measurement, stress granule induction assays Nature High 31511697
2013 DDX3 acts as a regulatory subunit of CK1ε in the Wnt-β-catenin pathway: in a Wnt-dependent manner, DDX3 binds CK1ε, directly stimulates its kinase activity, and promotes phosphorylation of the scaffold protein Dishevelled. Co-immunoprecipitation, kinase activity assays, genetic epistasis in Xenopus and C. elegans development, mammalian cell knockdown Science High 23413191
2012 DDX3 directly binds the 5' cap-proximal region of structured mRNAs and clamps eIF4F entry through simultaneous interactions with eIF4G and PABP, enabling local strand separation to allow 43S pre-initiation complex attachment and translation initiation of selected transcripts with 5' secondary structures. In vitro translation assays, RNA-protein interaction studies, eIF4F co-immunoprecipitation, ribosome binding assays The EMBO journal High 22872150
2019 Crystal structure of the DDX3X helicase core (D1D2) in complex with a 23-bp dsRNA at pre-unwound state reveals that two DDX3X molecules each recognize one RNA strand of a 2-turn dsRNA, and ATP binding-induced conformational changes unwind the duplex cooperatively. X-ray crystallography of D1D2:dsRNA complex Nature communications High 31300642
2015 Cancer-associated DDX3X mutants (G302V and G325E, located in the D1 domain) are defective in RNA-stimulated ATP hydrolysis; an N-terminal ATP-binding loop is critical for stimulation of ATP hydrolysis by RNA. DDX3X interacts with dsRNA specifically through D1 domain residues G302 and G325. Biochemical ATPase assays, crystal structures, NMR chemical shift perturbation, isothermal titration calorimetry, yeast complementation (S. pombe ded1-ts strain) Journal of molecular biology High 25724843
2017 DDX3X and its yeast ortholog Ded1p share core biochemical activities: both use ATP exclusively for unwinding, oligomerize for efficient helicase activity, do not unwind DNA duplexes, and show RNA-stimulated ATPase. DDX3X shows greater preference for substrates with 3' unpaired regions and separates longer duplexes faster than Ded1p. In vitro ATPase assays, RNA unwinding assays, strand annealing assays, quantitative biochemical comparison Journal of molecular biology High 29037760
2016 Cancer-associated DDX3X mutations cause stress granule hyper-assembly that contributes to global translation inhibition; the N-terminal low-complexity domain is required for SG assembly, and deletion of this domain rescues translation impairment caused by mutant DDX3X. CLIP-seq, ribosome profiling, stress granule imaging, N-terminal domain deletion mutants, single-cell translation assessment Scientific reports High 27180681
2016 DDX3 collaborates with the translation initiation machinery through direct binding to 5'UTRs of nearly all coding RNAs and specific sites on 18S rRNA; a medulloblastoma-associated DDX3R534H variant blunts the stress-induced shift of DDX3 binding from 5'UTR into coding regions and selectively preserves translation of chromatin organization genes during arsenite stress. CLIP-seq, polysome profiling, ribosome profiling in primary medulloblastoma tumors Oncotarget High 27058758
2021 DDX3X promotes translation of mRNAs encoding core translational machinery components, thereby driving global protein synthesis; loss-of-function DDX3X mutations moderate MYC-driven global protein synthesis to buffer proteotoxic stress during lymphomagenesis. Ribosome profiling, polysome profiling, genetic loss-of-function in lymphoma models Molecular cell High 34437837
2022 DDX3X and DDX3Y are functionally redundant in mRNA translation; transcripts sensitive to DDX3X depletion or mutation are rescued by DDX3Y complementation, demonstrating equivalent protein synthesis function. Sex-bias in DDX3X syndrome is attributed to expression differences, not paralog-specific biochemical activity. Ribosome profiling, in vitro translation assays, DDX3X depletion/complementation with DDX3Y in human cells RNA High 34535544
2022 DDX3X and DDX3Y differ in their propensities for liquid-liquid phase separation (LLPS): the N-terminal intrinsically disordered region of DDX3Y more strongly promotes LLPS than DDX3X; DDX3Y has weaker ATPase activity contributing to slower condensate disassembly and stronger translation repression and FUS aggregation than DDX3X. Ensemble and single-molecule techniques, LLPS assays, ATPase activity measurements, in vitro translation assays Molecular cell High 35588748
2021 E3 ubiquitin ligase RNF39 mediates K48-linked ubiquitination and proteasomal degradation of DDX3X, thereby inhibiting RIG-I-like receptor (RLR)-dependent antiviral innate immune signaling. Co-immunoprecipitation, ubiquitination assays, Rnf39 knockout mice, viral replication assays Science advances High 33674311
2018 DDX3 directly interacts with IKKε and enhances its activation to facilitate phosphorylation of IRF3 and type I interferon induction; DDX3 also directly interacts with IKKα, enhancing its autophosphorylation and activation, thereby modulating NIK/IKKα-mediated IRF7 phosphorylation and alternative NF-κB activation. Co-immunoprecipitation, kinase activation assays, DDX3 knockdown with cytokine/IFN readouts The Biochemical journal High 30341167
2024 DDX3X resolves inhibitory RNA-RNA interactions inside G3BP1-driven RNP granule-like condensates, rendering condensates dynamic and enabling mRNA translation; disease-associated and catalytically inactive DDX3X variants fail to resolve such RNA-RNA interactions, leading to impaired condensate disassembly and reduced mRNA translatability. In vitro condensate assays, single-molecule RNA mobility measurements, translation assays, DDX3X inhibition in cultured cells Molecular cell High 39729994
2007 DDX3 is required for HCV RNA replication; shRNA-mediated knockdown of DDX3 significantly suppresses accumulation of genome-length HCV RNA, replicon RNA, JFH1 RNA replication, and core protein release. shRNA knockdown, HCV RNA replication assays, HCVcc infection Journal of virology High 17855521
2020 DDX3X has RNaseH2-like activity and can support fully reconstituted in vitro ribonucleotide excision repair (RER) reactions with DNA polymerases δ, β, and λ; DDX3X silencing causes accumulation of ribonucleotides in the cellular genome. In vitro RER reconstitution assay, RNaseH2-like activity assay, DDX3X silencing with genomic rNMP accumulation readout Nucleic acids research High 33137198
2015 DDX3X mutations identified in NKTCL exhibit decreased RNA-unwinding activity, loss of suppressive effects on cell-cycle progression in NK cells, and transcriptional activation of NF-κB and MAPK pathways compared to wild-type DDX3X. RNA unwinding assays, cell cycle analysis, NF-κB/MAPK reporter assays, exome and targeted sequencing Nature genetics High 26192917
2015 De novo DDX3X mutations cause loss-of-function effects on the Wnt signaling pathway in vivo; all tested de novo mutations showed consistent Wnt pathway defects in zebrafish, with gender-differential effects consistent with dose-dependent DDX3X expression. Zebrafish Wnt pathway assays, exome sequencing, genetic dose-response analysis American journal of human genetics High 26235985
2020 Pathogenic DDX3X missense mutations profoundly disrupt RNA helicase activity, induce ectopic RNA-protein granules in neural progenitors and neurons, and impair translation, thereby disrupting cortical neuron generation during brain development. Mouse and human genetics, biochemical helicase assays, neural progenitor imaging, translation assays, cortical development phenotyping Neuron High 32135084
2022 DDX3X controls cortical development by regulating cell cycle duration and neurogenic divisions in neural progenitors; ribosome profiling in vivo identified DDX3X-dependent translated transcripts essential for neurogenesis. DDX3Y compensates for DDX3X in male developing neocortex. Mouse knockout, live imaging of progenitor cell cycles, in vivo ribosome profiling eLife High 35762573
2016 DDX3 depletion in neurons impairs neurite development by downregulating Rac1 level and activation; DDX3 translationally activates a regulon of mRNAs involved in Rac1 activation (including Rac1 itself and Prkaca/PKA) via a 5'UTR-dependent mechanism. shRNA knockdown in neurons, polysome profiling, luciferase reporter assays, in vivo neonatal mouse DDX3 inhibition, dendritic spine imaging The Journal of neuroscience High 27656019
2018 TRPV4 cation channel binds DDX3X; TRPV4-mediated Ca2+ influx releases DDX3X from the channel and drives DDX3X nuclear translocation via calmodulin and CaM-dependent kinase II. Inhibition of TRPV4 diminishes DDX3X-dependent nuclear viral export and translation. Co-immunoprecipitation, live-cell imaging of DDX3X translocation, pharmacological inhibition, viral infectivity assays Nature communications High 29899501
2021 DDX3X is recruited to sites of DNA damage in live cells in a PARP1-dependent manner; DDX3X recruitment is mediated by its intrinsically disordered domains and requires liquid-liquid phase separation, as PARP1 knockout or catalytically inactive PARP1 ablates recruitment. Live-cell microirradiation, nuclear-export deficient DDX3X mutant, CRISPR/Cas9 PARP1 knockout, LLPS inhibition DNA repair High 34083132
2021 Sirtuin 5 (SIRT5) demalonylates DDX3 at lysines K66, K130, and K162, and this demalonylation is critical for TBK1-IRF3 activation and antiviral type I IFN production. Immunoprecipitation, Western blot, luciferase reporter assays, Sirt5 KO mice, site-directed mutagenesis of malonylation sites Theranostics High 34158847
2021 TRIM25 ubiquitinates DDX3X at lysine K55; TRIM25 and DDX3X cooperatively enhance IFNB1 induction following RIG-I activation, but cooperative IFN induction is independent of TRIM25's catalytic activity. Influenza A NS1 disrupts the TRIM25:DDX3X interaction, abrogating DDX3X ubiquitination and cooperative IFNB1 activation. In vitro ubiquitination assays, knockdown studies, Co-immunoprecipitation, IFNB1 promoter reporter assays International journal of molecular sciences High 34445801
2024 USP8 deubiquitinates DDX3X by cleaving K27-linked ubiquitin chains from its intrinsically disordered region (IDR), enhancing DDX3X condensation and promoting cGAS phase separation and activation, thereby potentiating cGAS-STING innate immune signaling. Co-immunoprecipitation, deubiquitination assays, LLPS assays, Trex1-/- mouse model, SLE database correlation Cell reports High 38795350
2024 PRMT1 induces arginine methylation of DDX3X, enhancing its protein stability and preventing proteasomal degradation; methylated DDX3X translocates to mitochondria where it facilitates PINK1 (PTEN-induced kinase 1) mRNA translation, promoting mitophagy and mitochondrial biogenesis to support breast cancer metastasis. Co-immunoprecipitation, arginine methylation assays, mitochondrial fractionation, PINK1 translation assays, in vivo xenograft models Cancer research High 39042374
2021 DDX3X interacts with NLRP11 (via NLRP11's LRR domain); NLRP11 abolishes IKKε-mediated phosphorylation of DDX3X, lowering type I IFN induction upon viral infection. NLRP11 also suppresses NLRP3-mediated caspase-1 activation in an LRR-dependent manner, suggesting sequestration of DDX3X from NLRP3. Co-immunoprecipitation, LC-MS/MS, kinase phosphorylation assays, caspase-1 activation assays, domain mapping Frontiers in immunology High 34054816
2021 AKT phosphorylates DDX3X and impairs the interaction between DDX3X and NLRP3, thereby inhibiting NLRP3 inflammasome activation; reactive oxygen species generated by NLRP3 activation inhibit AKT activity, creating a regulatory feedback loop. Phosphorylation assays, Co-immunoprecipitation, AKT agonist/antagonist treatment, in vivo sepsis and peritonitis models FEBS letters High 34387860
2017 DDX3 interacts with the eIF4F complex and drives ER stress-induced ATF4 mRNA translation via a phospho-eIF2α-dependent translational re-initiation mechanism; DDX3 knockdown reduces ATF4 expression, shown by luciferase reporter and polyribosome assays. Co-immunoprecipitation, luciferase reporter assays, polyribosome profiling, DDX3 depletion Scientific reports High 29062139
2020 DDX3X is a second molecular target of rocaglamide A (RocA); RocA clamps DDX3X onto polypurine RNA in an ATP-independent manner, and high expression of DDX3X strengthens RocA-mediated translational repression through a dominant-negative effect. Proximity-specific fluorescence labeling, ribosome profiling, biochemical RNA clamping assays Cell chemical biology High 33296667
2019 DDX3X controls MITF mRNA translation via an internal ribosome entry site (IRES) in the 5'UTR; DDX3X-driven MITF translation directs a proliferative-to-metastatic phenotypic switch in melanoma cells in vivo. Ribosome profiling (translating ribosome analysis), IRES reporter assays, in vivo melanoma metastasis models Cell reports High 31216476
2017 DDX3X interacts with ALKBH5, an m6A RNA demethylase; the ATP domain of DDX3X and DSBH domain of ALKBH5 are required for their interaction. DDX3X modulates mRNA demethylation and also interacts with AGO2, regulating methylation status of microRNAs. Co-immunoprecipitation, domain deletion mapping, m6A methylation assays Stem cells international Medium 29333169
2013 DDX3 associates with p53 by co-immunoprecipitation; overexpression of DDX3 increases p53 nuclear accumulation after DNA damage, and DDX3 depletion reduces camptothecin-induced p53 stabilization in a proteasome-dependent manner. Co-immunoprecipitation, DDX3 shRNA knockdown, proteasome inhibition, nuclear fractionation Biochimica et biophysica acta Medium 23470959
2016 DDX3 interacts with NF-κB subunit p65 via its ATP-dependent RNA helicase domain binding to the N-terminal Rel homology domain (RHD) of p65, suppressing NF-κB (p65/p50)-mediated transcriptional activity. Co-immunoprecipitation, domain mapping, NF-κB reporter assays, RNAi knockdown PloS one Medium 27736973
2018 DDX3X localizes to mitochondria; DDX3X inhibition with RK-33 reduces mitochondrial translation, decreasing oxygen consumption and ATP concentrations while increasing reactive oxygen species, causing radiosensitization in breast cancer. Quantitative proteomics, mitochondrial fractionation, oxygen consumption measurement, ATP assays, ROS measurement Oncogene High 28869602
2018 DDX3 knockdown reduces translational efficiency of PACT, STAT1, GNB2, Rac1, TAK1, and p38 MAPK mRNAs; DDX3 knockdown impairs macrophage migration and phagocytosis and reduces chemokine production after LPS/poly(I:C) stimulation. Polysome profiling, luciferase reporter assays, cell migration assay, flow cytometry phagocytosis assay, cytokine antibody array, zebrafish transgenic inflammation model Molecular and cellular biology High 30373933
2023 WWP2 E3 ubiquitin ligase catalyzes K63-linked polyubiquitination of DDX3X targeting it for proteasomal degradation; JNK activation in high glucose/palmitic acid conditions downregulates WWP2, leading to DDX3X accumulation and endothelial injury. Co-immunoprecipitation, mass spectrometry, ubiquitination assays, pulse-chase assay, endothelial-specific Wwp2 KO mice Cardiovascular diabetology High 37149668
2023 Asparagine endopeptidase (AEP) cleaves DDX3X in a HIF1A-dependent manner under hypoxia/nutrient deprivation; the resulting C-terminal truncated fragment (tDDX3X-C) translocates to the nucleus where it complexes with splicing factors to induce alternative splicing of pre-mRNAs including PRDM2 and ARRB1. Biochemical cleavage assays, nuclear fractionation, mass spectrometry, splicing assays, glioblastoma organoids, animal models The Journal of clinical investigation High 37988165
2022 DDX3X promotes IFNB transcription by interacting with IRF-3 through IRF-3's DNA-binding domain and promoting recruitment of IRF-3 and transcriptional co-activator p300/CBP to the IFNB promoter; DDX3X's ATP-binding pocket is essential for this transcriptional activation. Co-immunoprecipitation, ChIP assay, EMSA, luciferase reporter assays, ATP-binding domain mutagenesis Scientific reports High 35273248
2018 DDX3X exhibits nucleo-cytoplasmic shuttling controlled by an N-terminal Nuclear Export Signal (NES) required for nuclear export, and three independent regions facilitating nuclear import; DDX3X nuclear localization increases during prophase of mitosis concomitant with increased DDX3X expression. High Content Analysis, NES/NLS mutant constructs, live-cell imaging during mitosis European journal of cell biology Medium 30131165
2016 DDX3 interacts with influenza A virus NS1 and NP proteins; DDX3 helicase domain does not mediate NS1/NP binding but is essential for DDX3 localization to virus-induced stress granules; DDX3 knockdown impairs stress granule formation and increases influenza virus titers. Immunoprecipitation, stress granule imaging, DDX3 knockdown, viral titer assays Journal of virology Medium 26792746
2019 An ERK/hnRNPK/DDX3X pathway mediates metabolic stress response in pancreatic β cells; DDX3X is a binding partner of hnRNPK required for efficient translation of JUND mRNA, and loss of hnRNPK reduces DDX3X binding to translation machinery. RNA immunoprecipitation, co-immunoprecipitation, TRAP-qPCR, CRISPR-Cas9 KO, phos-tag analysis Molecular metabolism Medium 31178390
2016 DDX3 knockdown reduces basal Snail protein and mRNA levels in HeLa and MCF-7 cells, associated with reduced cell proliferation and migration; DDX3 is required for increases in Snail induced by HDAC inhibitors or camptothecin. shRNA knockdown, cell proliferation and migration assays, immunoblotting Biochimica et biophysica acta Low 21237216
2003 DDX3X (DBX) is required for G1-to-S phase cell cycle progression; a temperature-sensitive point mutation (P267S, between helicase motifs I and Ia) causes G1 arrest and nuclear mRNA accumulation at non-permissive temperature, with reduction of cyclin A mRNA. Temperature-sensitive mutant complementation, cell cycle analysis, mRNA nuclear accumulation assay Journal of biochemistry Medium 12944373
2021 In vivo, DDX3X is essential for hematopoiesis and innate immunity; mice lacking DDX3X during hematopoiesis show altered leukocyte composition in bone marrow and spleen and are unable to combat Listeria monocytogenes infection due to decreased effector cell availability, function, and sex-dependent impairment of cytokine synthesis. Conditional DDX3X KO in hematopoietic cells, bacterial infection challenge, cytokine measurements, immune cell phenotyping PLoS pathogens High 30475900
2016 Targeted Ddx3x ablation in mouse epiblast causes widespread apoptosis and abnormal growth resulting in embryonic lethality around E11.5; loss of Ddx3x leads to DNA damage (γH2AX, p-p53Ser15 increases), cell cycle arrest via upregulation of p21WAF1/Cip1 and p15Ink4b. Ddx3x binds promoter regions and regulates expression of DNA repair factors DDB2 and XPA. Conditional KO mice, γH2AX immunostaining, ChIP analysis of DDB2 and XPA promoters, cell cycle analysis Human molecular genetics High 27179789
2021 DDX3X directly binds and unwinds in vitro transcribed 5' terminal regions of Japanese encephalitis virus (Kd ~1.66 µM) and Zika virus (Kd ~7.05 µM) in helicase assays using recombinant DDX3X. Microscale thermophoresis binding assays, in vitro helicase unwinding assays with recombinant DDX3X International journal of molecular sciences Medium 33401776
2023 KLHL29 recruits CUL3 E3-ligase to DDX3X, leading to proteasomal degradation of DDX3X; DDX3X downregulation destabilizes CCND1 mRNA, causing G0/G1 cell cycle arrest in TNBC. Co-immunoprecipitation, ubiquitination assays, CCND1 mRNA stability assays, cell cycle analysis, patient-derived organoids Oncogene High 37845393

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2019 DDX3X acts as a live-or-die checkpoint in stressed cells by regulating NLRP3 inflammasome. Nature 339 31511697
2015 Exome sequencing identifies somatic mutations of DDX3X in natural killer/T-cell lymphoma. Nature genetics 304 26192917
2015 Mutations in DDX3X Are a Common Cause of Unexplained Intellectual Disability with Gender-Specific Effects on Wnt Signaling. American journal of human genetics 232 26235985
2012 DEAD-box protein DDX3 associates with eIF4F to promote translation of selected mRNAs. The EMBO journal 232 22872150
2007 DDX3 DEAD-box RNA helicase is required for hepatitis C virus RNA replication. Journal of virology 220 17855521
2008 Oncogenic role of DDX3 in breast cancer biogenesis. Oncogene 188 18264132
2021 DDX3X: structure, physiologic functions and cancer. Molecular cancer 185 33627125
2013 RNA helicase DDX3 is a regulatory subunit of casein kinase 1 in Wnt-β-catenin signaling. Science (New York, N.Y.) 182 23413191
2020 Pathogenic DDX3X Mutations Impair RNA Metabolism and Neurogenesis during Fetal Cortical Development. Neuron 160 32135084
2014 The Ded1/DDX3 subfamily of DEAD-box RNA helicases. Critical reviews in biochemistry and molecular biology 145 25039764
2016 Cancer-associated DDX3X mutations drive stress granule assembly and impair global translation. Scientific reports 139 27180681
2013 The role of the DEAD-box RNA helicase DDX3 in mRNA metabolism. Wiley interdisciplinary reviews. RNA 118 23606618
2020 DDX3 modulates cisplatin resistance in OSCC through ALKBH5-mediated m6A-demethylation of FOXM1 and NANOG. Apoptosis : an international journal on programmed cell death 117 31974865
2019 The mechanism of RNA duplex recognition and unwinding by DEAD-box helicase DDX3X. Nature communications 95 31300642
2015 RNA helicase DDX3: at the crossroad of viral replication and antiviral immunity. Reviews in medical virology 93 26174373
2022 TLR4 aggravates microglial pyroptosis by promoting DDX3X-mediated NLRP3 inflammasome activation via JAK2/STAT1 pathway after spinal cord injury. Clinical and translational medicine 89 35692100
2016 Targeted inactivation of murine Ddx3x: essential roles of Ddx3x in placentation and embryogenesis. Human molecular genetics 83 27179789
2022 Sexually dimorphic RNA helicases DDX3X and DDX3Y differentially regulate RNA metabolism through phase separation. Molecular cell 81 35588748
2023 Exosomal Lnc NEAT1 from endothelial cells promote bone regeneration by regulating macrophage polarization via DDX3X/NLRP3 axis. Journal of nanobiotechnology 75 36941678
2009 The current understanding of Ded1p/DDX3 homologs from yeast to human. RNA biology 74 19106629
2016 RK-33 Radiosensitizes Prostate Cancer Cells by Blocking the RNA Helicase DDX3. Cancer research 72 27634756
2015 Cancer-associated mutants of RNA helicase DDX3X are defective in RNA-stimulated ATP hydrolysis. Journal of molecular biology 69 25724843
2017 Targeting mitochondrial translation by inhibiting DDX3: a novel radiosensitization strategy for cancer treatment. Oncogene 68 28869602
2016 Medulloblastoma-associated DDX3 variant selectively alters the translational response to stress. Oncotarget 68 27058758
2021 Sequential inverse dysregulation of the RNA helicases DDX3X and DDX3Y facilitates MYC-driven lymphomagenesis. Molecular cell 66 34437837
2016 DDX3 Interacts with Influenza A Virus NS1 and NP Proteins and Exerts Antiviral Function through Regulation of Stress Granule Formation. Journal of virology 66 26792746
2018 The TRPV4 channel links calcium influx to DDX3X activity and viral infectivity. Nature communications 65 29899501
1996 Regionalized expression of the Dbx family homeobox genes in the embryonic CNS of the mouse. Mechanisms of development 65 8798145
2020 DEAD-box RNA Helicase DDX3: Functional Properties and Development of DDX3 Inhibitors as Antiviral and Anticancer Drugs. Molecules (Basel, Switzerland) 64 32102413
2019 The X-Linked DDX3X RNA Helicase Dictates Translation Reprogramming and Metastasis in Melanoma. Cell reports 64 31216476
2018 The RNA helicase DDX3X is an essential mediator of innate antimicrobial immunity. PLoS pathogens 64 30475900
2011 The role of DDX3 in regulating Snail. Biochimica et biophysica acta 63 21237216
2015 Ketorolac salt is a newly discovered DDX3 inhibitor to treat oral cancer. Scientific reports 60 25918862
2016 Multifunctional DDX3: dual roles in various cancer development and its related signaling pathways. American journal of cancer research 59 27186411
2020 TCONS_00012883 promotes proliferation and metastasis via DDX3/YY1/MMP1/PI3K-AKT axis in colorectal cancer. Clinical and translational medicine 58 33135346
2020 Dual targeting of DDX3 and eIF4A by the translation inhibitor rocaglamide A. Cell chemical biology 58 33296667
2017 The DEAD-Box RNA Helicase DDX3 Interacts with m6A RNA Demethylase ALKBH5. Stem cells international 58 29333169
2013 DDX3 regulates DNA damage-induced apoptosis and p53 stabilization. Biochimica et biophysica acta 53 23470959
2017 Biochemical Differences and Similarities between the DEAD-Box Helicase Orthologs DDX3X and Ded1p. Journal of molecular biology 52 29037760
2021 DDX3X and DDX3Y are redundant in protein synthesis. RNA (New York, N.Y.) 51 34535544
2018 A double-edged function of DDX3, as an oncogene or tumor suppressor, in cancer progression (Review). Oncology reports 51 29328432
2021 Aluminum impairs cognitive function by activating DDX3X-NLRP3-mediated pyroptosis signaling pathway. Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association 50 34614429
2020 Ribosomal Protein L13 Promotes IRES-Driven Translation of Foot-and-Mouth Disease Virus in a Helicase DDX3-Dependent Manner. Journal of virology 50 31619563
2016 DDX3 Modulates Neurite Development via Translationally Activating an RNA Regulon Involved in Rac1 Activation. The Journal of neuroscience : the official journal of the Society for Neuroscience 50 27656019
2023 Saturation genome editing of DDX3X clarifies pathogenicity of germline and somatic variation. Nature communications 48 38057330
2022 Aberrant cortical development is driven by impaired cell cycle and translational control in a DDX3X syndrome model. eLife 48 35762573
2022 The human DEAD-box helicase DDX3X as a regulator of mRNA translation. Frontiers in cell and developmental biology 47 36393867
2021 Prospective and detailed behavioral phenotyping in DDX3X syndrome. Molecular autism 47 33993884
2021 Proteomic analysis identifies the RNA helicase DDX3X as a host target against SARS-CoV-2 infection. Antiviral research 45 33781803
2011 Viruses and the human DEAD-box helicase DDX3: inhibition or exploitation? Biochemical Society transactions 45 21428961
2021 Selective cell death in HIV-1-infected cells by DDX3 inhibitors leads to depletion of the inducible reservoir. Nature communications 43 33931637
2021 RNF39 mediates K48-linked ubiquitination of DDX3X and inhibits RLR-dependent antiviral immunity. Science advances 41 33674311
2018 DDX3 suppresses type I interferons and favors viral replication during Arenavirus infection. PLoS pathogens 41 30001425
2007 Regulation and function of Dbx genes in the zebrafish spinal cord. Developmental dynamics : an official publication of the American Association of Anatomists 40 17994542
2019 An azoospermic factor gene, Ddx3y and its paralog, Ddx3x are dispensable in germ cells for male fertility. The Journal of reproduction and development 39 30613052
2018 DDX3 Participates in Translational Control of Inflammation Induced by Infections and Injuries. Molecular and cellular biology 37 30373933
2003 A temperature-sensitive mutant of the mammalian RNA helicase, DEAD-BOX X isoform, DBX, defective in the transition from G1 to S phase. Journal of biochemistry 36 12944373
2018 DNA Damage, Liver Injury, and Tumorigenesis: Consequences of DDX3X Loss. Molecular cancer research : MCR 35 30297359
2021 Developmental and Behavioral Phenotypes in a Mouse Model of DDX3X Syndrome. Biological psychiatry 34 34344536
2009 dbx mediates neuronal specification and differentiation through cross-repressive, lineage-specific interactions with eve and hb9. Development (Cambridge, England) 34 19710170
2023 The variant landscape and function of DDX3X in cancer and neurodevelopmental disorders. Trends in molecular medicine 33 37422363
2021 RNA Helicase DDX3: A Double-Edged Sword for Viral Replication and Immune Signaling. Microorganisms 33 34204859
2017 DDX3 regulates endoplasmic reticulum stress-induced ATF4 expression. Scientific reports 33 29062139
2021 DDX3X Links NLRP11 to the Regulation of Type I Interferon Responses and NLRP3 Inflammasome Activation. Frontiers in immunology 32 34054816
2019 Metabolic stress activates an ERK/hnRNPK/DDX3X pathway in pancreatic β cells. Molecular metabolism 32 31178390
2018 DDX3 directly facilitates IKKα activation and regulates downstream signalling pathways. The Biochemical journal 32 30341167
2020 Targeting host DEAD-box RNA helicase DDX3X for treating viral infections. Antiviral research 31 33301755
2018 Investigating nucleo-cytoplasmic shuttling of the human DEAD-box helicase DDX3. European journal of cell biology 31 30131165
2016 DDX3 DEAD-box RNA helicase plays a central role in mitochondrial protein quality control in Leishmania. Cell death & disease 31 27735940
2017 Combination treatment using DDX3 and PARP inhibitors induces synthetic lethality in BRCA1-proficient breast cancer. Medical oncology (Northwood, London, England) 29 28138868
2024 Stress granule-localized USP8 potentiates cGAS-mediated type I interferonopathies through deubiquitination of DDX3X. Cell reports 28 38795350
2019 Downregulation of miR-322 promotes apoptosis of GC-2 cell by targeting Ddx3x. Reproductive biology and endocrinology : RB&E 28 31382975
2024 Arginine Methylation of DDX3 by PRMT1 Mediates Mitochondrial Homeostasis to Promote Breast Cancer Metastasis. Cancer research 27 39042374
2021 AKT controls NLRP3 inflammasome activation by inducing DDX3X phosphorylation. FEBS letters 27 34387860
2023 AEP-cleaved DDX3X induces alternative RNA splicing events to mediate cancer cell adaptation in harsh microenvironments. The Journal of clinical investigation 25 37988165
2019 From the magic bullet to the magic target: exploiting the diverse roles of DDX3X in viral infections and tumorigenesis. Future medicinal chemistry 25 30816053
2023 Down-regulation of WWP2 aggravates Type 2 diabetes mellitus-induced vascular endothelial injury through modulating ubiquitination and degradation of DDX3X. Cardiovascular diabetology 24 37149668
2021 RNA helicase, DDX3X, is actively recruited to sites of DNA damage in live cells. DNA repair 24 34083132
2021 Demalonylation of DDX3 by Sirtuin 5 promotes antiviral innate immune responses. Theranostics 24 34158847
2016 The DEAD-Box RNA Helicase DDX3 Interacts with NF-κB Subunit p65 and Suppresses p65-Mediated Transcription. PloS one 24 27736973
2023 Hepatocyte DDX3X protects against drug-induced acute liver injury via controlling stress granule formation and oxidative stress. Cell death & disease 23 37407573
2021 The RNA helicase DDX3 induces neural crest by promoting AKT activity. Development (Cambridge, England) 23 33318149
2018 DDX3 in HIV-1 infection and sensing: A paradox. Cytokine & growth factor reviews 23 29580812
2024 Inhibition of SIRT7 overcomes sorafenib acquired resistance by suppressing ERK1/2 phosphorylation via the DDX3X-mediated NLRP3 inflammasome in hepatocellular carcinoma. Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy 22 38277756
2021 TRIM25 and DEAD-Box RNA Helicase DDX3X Cooperate to Regulate RIG-I-Mediated Antiviral Immunity. International journal of molecular sciences 21 34445801
2021 Human DDX3X Unwinds Japanese Encephalitis and Zika Viral 5' Terminal Regions. International journal of molecular sciences 19 33401776
2024 DDX3X and Stress Granules: Emerging Players in Cancer and Drug Resistance. Cancers 18 38539466
2024 G3BP-driven RNP granules promote inhibitory RNA-RNA interactions resolved by DDX3X to regulate mRNA translatability. Molecular cell 18 39729994
2018 Diosgenin increased DDX3 expression in hepatocellular carcinoma. American journal of translational research 18 30662610
1996 Separate cis-acting elements determine the expression of mouse Dbx gene in multiple spatial domains of the central nervous system. Mechanisms of development 18 8887327
2023 ITPR1-AS1 promotes small cell lung cancer metastasis by facilitating P21HRAS splicing and stabilizing DDX3X to activate the cRaf-MEK-ERK cascade. Cancer letters 17 37820992
2022 DDX3X structural analysis: Implications in the pharmacology and innate immunity. Current research in immunology 16 35647523
2017 Rottlerin upregulates DDX3 expression in hepatocellular carcinoma. Biochemical and biophysical research communications 16 29203243
2024 A comprehensive review on DDX3X liquid phase condensation in health and neurodevelopmental disorders. International journal of biological macromolecules 15 38218270
2023 The mRNA-binding protein DDX3 mediates TGF-β1 upregulation of translation and promotes pulmonary fibrosis. JCI insight 15 36821384
2023 KLHL29-mediated DDX3X degradation promotes chemosensitivity by abrogating cell cycle checkpoint in triple-negative breast cancer. Oncogene 15 37845393
2022 A Dual Role of DDX3X in dsRNA-Derived Innate Immune Signaling. Frontiers in molecular biosciences 15 35874614
2022 The RNA helicase DDX3 promotes IFNB transcription via enhancing IRF-3/p300 holocomplex binding to the IFNB promoter. Scientific reports 14 35273248
2020 Murine cytomegaloviruses m139 targets DDX3 to curtail interferon production and promote viral replication. PLoS pathogens 14 33031466
2020 Novel alternative ribonucleotide excision repair pathways in human cells by DDX3X and specialized DNA polymerases. Nucleic acids research 14 33137198