Affinage

DDX3X

ATP-dependent RNA helicase DDX3X · UniProt O00571

Length
662 aa
Mass
73.2 kDa
Annotated
2026-06-09
100 papers in source corpus 49 papers cited in narrative 49 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

DDX3X is an ATP-dependent DEAD-box RNA helicase that governs translation of structurally complex mRNAs and remodels RNA-protein assemblies, with additional moonlighting roles in signaling, innate immunity, and the DNA damage response (PMID:33905506, PMID:39729994). Biochemically, it binds single-stranded RNA with higher affinity than structured RNA and adopts a domain-closed conformation that stabilizes the unwound state (PMID:38664397), and structural work on its helicase core shows that two DDX3X molecules engage a duplex and cooperatively unwind it upon ATP binding (PMID:31300642); it additionally acts as an ATP-independent nucleic-acid chaperone, with its N- and C-terminal intrinsically disordered tails required for both helicase and annealing activities (PMID:38669753). Through this activity it positions at the ribosomal mRNA entry channel (binding 18S rRNA helix 16) and selectively promotes translation of mRNAs with complex 5' UTRs and IRES elements, including cyclin E1, Rac1, MITF, ATF4, AR, and the core translational machinery, thereby controlling G1/S transition, global protein synthesis, and cell-fate switches (PMID:20837705, PMID:34437837, PMID:33905506, PMID:31216476). DDX3X resolves inhibitory RNA-RNA interactions inside G3BP1-driven condensates to keep them dynamic and translatable, and disease-associated or catalytically inactive variants fail to do so (PMID:39729994); pathogenic missense mutations disrupt helicase activity, induce ectopic RNA-protein granules, and impair cortical neuron generation (PMID:32135084). Beyond translation, DDX3X functions as a regulatory subunit of CK1ε to stimulate Dishevelled phosphorylation and Wnt/β-catenin signaling [#1_wnt], drives NLRP3 inflammasome activation in competition with stress-granule sequestration (PMID:31511697), and promotes type I interferon induction by stimulating IKKα and recruiting an IRF-3/p300/CBP complex to the IFNB promoter (PMID:30341167, PMID:35273248). Its stability, condensation, and activity are tuned by post-translational modifications including PRMT1 methylation, SIRT5 demalonylation, and ubiquitination by TRIM25, WWP2, and KLHL29/CUL3 with deubiquitination by USP8 (PMID:34158847, PMID:38795350, PMID:39042374, PMID:37845393). Pathogenic DDX3X mutations cause an intellectual-disability/neurodevelopmental disorder through loss of helicase function and impaired Wnt signaling (PMID:32135084, PMID:26235985).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 2007 Medium

    Established an early functional requirement for DDX3 in a viral RNA process, hinting at a role in RNA metabolism before its cellular targets were defined.

    Evidence shRNA knockdown with HCV replicon and HCVcc infection assays

    PMID:17855521

    Open questions at the time
    • Did not define whether the requirement is direct helicase action on viral RNA or an indirect host effect
    • No biochemical target identified
  2. 2010 High

    Answered whether DDX3 controls specific mRNAs by showing it drives cyclin E1 translation to gate G1/S, linking its helicase activity to cell-cycle progression.

    Evidence siRNA knockdown, polysome profiling, temperature-sensitive helicase mutant, cell-cycle analysis

    PMID:20837705

    Open questions at the time
    • Did not resolve the 5' UTR structural feature recognized
    • Generality across other complex-UTR mRNAs not yet established
  3. 2013 High

    Revealed a non-translational signaling role by showing DDX3 acts as a CK1ε regulatory subunit stimulating Dishevelled phosphorylation, placing it directly in the Wnt/β-catenin pathway.

    Evidence Co-IP, in vitro kinase assays, multi-organism genetic epistasis (Xenopus, C. elegans)

    PMID:23413191

    Open questions at the time
    • Relationship between helicase activity and kinase stimulation unclear
    • Whether RNA binding is required for CK1ε activation not defined
  4. 2015 High

    Connected cancer-associated mutations to a defined biochemical defect, showing G302/G325 mutants lose RNA-stimulated ATPase activity and an N-terminal ATP-binding loop mediates RNA stimulation.

    Evidence ATPase assays, crystal structures, NMR, ITC, yeast ded1 complementation

    PMID:25724843

    Open questions at the time
    • Did not link individual mutant biochemistry to specific in vivo mRNA targets
    • Structural basis of duplex recognition not yet resolved
  5. 2019 High

    Provided the structural mechanism of unwinding, showing two DDX3X molecules cooperatively recognize and open a dsRNA duplex upon ATP binding.

    Evidence X-ray crystallography of the D1D2:23-bp dsRNA pre-unwound complex

    PMID:31300642

    Open questions at the time
    • Captures a pre-unwound state rather than the full catalytic cycle
    • Role of the IDRs not addressed by the crystallized core
  6. 2020 High

    Established the neurodevelopmental disease mechanism, linking pathogenic missense mutations to disrupted helicase activity, ectopic RNA-protein granules, and impaired cortical neurogenesis.

    Evidence Human genetics, mouse KO/knockin, helicase assays, granule imaging, polysome profiling

    PMID:32135084

    Open questions at the time
    • Which specific mistranslated mRNAs drive the neuronal phenotype not fully resolved
    • Contribution of granule formation versus translation defect to disease unclear
  7. 2021 High

    Defined the ribosomal context of DDX3X action, showing it binds 18S rRNA helix 16 at the mRNA entry channel and selectively supports complex-5'-UTR mRNAs and the translation machinery itself, with implications for buffering MYC-driven proteotoxic stress.

    Evidence Ribosome profiling, PAR-CLIP, polysome profiling, catalytically inactive mutants

    PMID:33905506 PMID:34437837

    Open questions at the time
    • Mechanism distinguishing depletion from catalytic-dead phenotypes not fully explained
    • How target selectivity is encoded structurally remains open
  8. 2021 High

    Clarified the DDX3X/DDX3Y relationship, demonstrating functional redundancy in translation rescue while predicting paralog-specific behavior.

    Evidence Ribosome profiling, in vitro translation, DDX3Y complementation

    PMID:34535544

    Open questions at the time
    • Did not address physiological contexts where the paralogs diverge
    • Quantitative differences in target spectra not mapped
  9. 2022 High

    Distinguished the paralogs biophysically, showing DDX3Y's IDR more strongly drives LLPS and its weaker ATPase slows condensate disassembly, repressing translation and enhancing FUS aggregation.

    Evidence Single-molecule and ensemble LLPS assays, ATPase measurements, translation and aggregation reporters

    PMID:35588748

    Open questions at the time
    • In vivo relevance of paralog LLPS differences not established
    • Link between condensate behavior and disease unclear
  10. 2024 High

    Resolved the core biochemical basis of unwinding, showing preferential ssRNA binding and a domain-closed conformation that stabilizes the denatured state, plus dual helicase and ATP-independent chaperone activities dependent on the IDR tails.

    Evidence Solution NMR, binding/conformational analysis, in vitro helicase/annealing/ATPase assays with truncation mutants

    PMID:38664397 PMID:38669753

    Open questions at the time
    • How chaperone versus helicase modes are selected in cells unknown
    • Substrate determinants of bidirectional unwinding not defined
  11. 2024 High

    Unified the translation and condensate roles by showing DDX3X resolves inhibitory RNA-RNA interactions within G3BP1 condensates to keep them dynamic and translatable, with disease/catalytic-dead variants failing this task.

    Evidence In vitro condensate reconstitution, single-molecule FRET, ribosome profiling, live-cell granule dynamics, catalytic mutants

    PMID:39729994

    Open questions at the time
    • Whether RNA-RNA resolution explains all granule phenotypes in disease not proven
    • Selectivity for specific RNA-RNA contacts not mapped
  12. 2024 Medium

    Showed that nanoscale RNA-protein clustering via N-terminal IDRs fosters DDX3X/DDX3Y catalysis, with RNA release being the key step differentiating their unwinding activities.

    Evidence Multiparameter confocal microscopy, single-molecule photon burst analysis, ensemble biochemistry, IDR truncation mutants

    PMID:39591970

    Open questions at the time
    • Physiological cluster size and composition in cells not defined
    • Single lab characterization
  13. 2024 Medium

    Extended post-translational control by showing PRMT1 methylation stabilizes DDX3X and directs mitochondrial PINK1 translation to support metastasis, and USP8 deubiquitination of the IDR enhances condensation and cGAS-STING signaling.

    Evidence MS, methylation/ubiquitination assays, fractionation, LLPS assays, in vivo models

    PMID:38795350 PMID:39042374

    Open questions at the time
    • Crosstalk among the many DDX3X PTMs not integrated
    • Tissue-specificity of these modification effects unclear

Open questions

Synthesis pass · forward-looking unresolved questions
  • How DDX3X integrates its distinct roles—ribosomal translation, condensate remodeling, kinase regulation, and immune signaling—into a coherent context-dependent program, and which PTMs toggle between them, remains unresolved.
  • No unified model linking PTM state to functional partitioning
  • Determinants of target mRNA selection in vivo undefined
  • Mechanistic relationship between cytoplasmic translation and nuclear/promoter functions unclear

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003723 RNA binding 4 GO:0045182 translation regulator activity 4 GO:0140098 catalytic activity, acting on RNA 3 GO:0044183 protein folding chaperone 2 GO:0098772 molecular function regulator activity 2 GO:0140657 ATP-dependent activity 2
Localization
GO:0005634 nucleus 3 GO:0005829 cytosol 2 GO:0005635 nuclear envelope 1 GO:0005739 mitochondrion 1 GO:0005840 ribosome 1
Pathway
R-HSA-168256 Immune System 3 R-HSA-162582 Signal Transduction 2 R-HSA-1640170 Cell Cycle 2 R-HSA-8953854 Metabolism of RNA 2
Partners
ADAR1CK1ΕIKKΑIRF3NLRP3PRMT1TRIM25USP8
Complex memberships
CK1ε complexNLRP3 inflammasomeeIF4F complex

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. Macrophages use the availability of DDX3X to choose between pro-survival stress granules and pyroptotic ASC specks. Co-immunoprecipitation, loss-of-function (DDX3X KO in myeloid compartment), in vivo cytokine production assays, stress granule induction experiments Nature High 31511697
2013 DDX3 acts as a regulatory subunit of CK1ε in Wnt-β-catenin signaling: in a Wnt-dependent manner, DDX3 binds CK1ε and directly stimulates its kinase activity, promoting phosphorylation of the scaffold protein Dishevelled (Dvl), which activates β-catenin signaling. This function is required in mammalian cells and during Xenopus and C. elegans development. Co-immunoprecipitation, in vitro kinase assays, genetic epistasis in Xenopus and C. elegans, RNAi knockdown Science (New York, N.Y.) High 23413191
2010 DDX3 controls G1/S-phase cell cycle transition by regulating translation of cyclin E1 mRNA. DDX3 knockdown specifically downregulates cyclin E1 protein without affecting its mRNA levels. The RNA helicase activity of DDX3 is required for this translational control. siRNA knockdown, polysome profiling, temperature-sensitive DDX3 mutant hamster cell line (tsET24), cell cycle analysis, mRNA target screening Molecular and cellular biology High 20837705
2019 Crystal structure of DDX3X helicase core (D1D2) in complex with a 23-bp dsRNA in a pre-unwound state reveals that two DDX3X molecules recognize a 2-turn dsRNA, each mainly recognizing one RNA strand, and that ATP-binding-induced conformational changes unwind the RNA duplex cooperatively. X-ray crystallography, structural analysis of D1D2:dsRNA complex Nature communications High 31300642
2015 Cancer-associated DDX3X mutants G302V and G325E (found in pediatric medulloblastoma) are defective in RNA-stimulated ATP hydrolysis. An N-terminal ATP-binding loop (ABL) is critical for RNA stimulation of ATPase activity. DDX3X interacts with dsRNA via its D1 domain, with G302 and G325 as contact residues. The mutants fail to complement a ded1 temperature-sensitive yeast strain. Biochemical ATPase assays, crystal structures, NMR chemical shift perturbation, isothermal titration calorimetry, yeast complementation assay Journal of molecular biology High 25724843
2021 DDX3X promotes translation of mRNAs encoding components of the core translational machinery, thereby driving global protein synthesis. Loss-of-function DDX3X mutations in lymphoma buffer MYC-driven proteotoxic stress by moderating global protein synthesis. Ribosome profiling, polysome profiling, genetic knockdown/KO, reporter assays Molecular cell High 34437837
2021 DDX3 depletion particularly reduces translation of mRNAs with complex 5' UTRs. DDX3 binds helix 16 of the human ribosomal 18S rRNA, placing it adjacent to the mRNA entry channel. Catalytically inactive DDX3X point mutants cause distinct translation changes compared to depletion. Ribosome profiling, RNA-seq, PAR-CLIP, catalytically inactive point mutation analysis Nucleic acids research High 33905506
2022 DDX3X and DDX3Y differ in propensity for liquid-liquid phase separation (LLPS): the N-terminal intrinsically disordered region (IDR) of DDX3Y more strongly promotes LLPS than DDX3X's IDR, and weaker ATPase activity of DDX3Y contributes to slower disassembly of DDX3Y-positive condensates. DDX3Y-dependent LLPS represses mRNA translation and enhances FUS aggregation more strongly than DDX3X-dependent LLPS. Ensemble and single-molecule techniques, in vitro LLPS assays, ATPase activity measurements, translation reporter assays, FUS aggregation assays Molecular cell High 35588748
2021 DDX3X and DDX3Y are functionally redundant in mRNA translation: transcripts sensitive to DDX3X depletion or mutation are rescued by complementation with DDX3Y, as shown by ribosome profiling and in vitro translation. Ribosome profiling, in vitro translation, complementation experiments RNA (New York, N.Y.) High 34535544
2007 DDX3 is required for HCV RNA replication. Knockdown of DDX3 significantly suppressed accumulation of genome-length HCV RNA and replicon RNA, and suppressed JFH1 RNA replication and core protein release. shRNA knockdown via lentiviral vector, HCV RNA quantification, replicon assay, HCVcc infection Journal of virology Medium 17855521
2020 Pathogenic DDX3X missense mutations profoundly disrupt RNA helicase activity, induce ectopic RNA-protein granules in neural progenitors and neurons, and impair translation, thereby impairing neuron generation during cortical development. Ddx3x controls cortical neuron generation in mice. Human genetics, mouse KO/knockin, biochemical helicase activity assays, immunofluorescence for RNA-protein granules, polysome profiling Neuron High 32135084
2014 DDX3 knockdown reduces Rac1 protein levels by impairing translation of Rac1 mRNA, possibly through interaction with its 5' UTR. Reduced Rac1 destabilizes β-catenin in a Rac1-dependent manner, downregulating Wnt/β-catenin target genes and suppressing cell motility, invasion, and metastatic potential. siRNA knockdown, luciferase reporter assays, in vitro invasion assay, in vivo metastasis mouse model, western blotting, co-immunoprecipitation Oncogene Medium 25043297
2016 DDX3 activates translation of a regulon of functionally coherent mRNAs involved in Rac1 activation (including Rac1 and Prkaca) through a 5' UTR-dependent mechanism in neurons, modulating PKA-Rac1 signaling strength to regulate neurite outgrowth and dendritic spine formation. siRNA/shRNA knockdown in neurons, polysome profiling, luciferase reporter assays with 5' UTR constructs, in vivo DDX3 inhibition in neonatal mice, immunofluorescence The Journal of neuroscience Medium 27656019
2016 DDX3 promotes tumor invasion in colorectal cancer via the CK1ε/Dvl2/β-catenin axis: DDX3 overexpression increases phospho-Dvl2 and nuclear β-catenin, and invasion is suppressed by CK1ε inhibitor (PF4800567) or β-catenin/TCF inhibitor (XAV939). siRNA/overexpression, western blotting, TCF promoter luciferase assay, xenograft tail-vein injection model, pharmacologic inhibition Scientific reports Medium 26892600
2015 DDX3 participates in antiviral innate immunity by facilitating translation of PACT mRNA (which has a structured 5' UTR). PACT activates RIG-I-like receptors for viral RNA sensing. DDX3 knockdown decreased viral RNA detection sensitivity. HCV core protein sequesters DDX3 in stress granules, abrogating DDX3's function in PACT translation. siRNA knockdown, polysome profiling, luciferase reporter assays with PACT 5' UTR, IFN-β/RANTES induction assays, co-localization studies The FEBS journal Medium 26454002
2018 DDX3 directly interacts with IKKα, enhances its autophosphorylation and activation, and thereby modulates NIK/IKKα-mediated IRF7 phosphorylation, type I interferon induction, and alternative NF-κB activation. Co-immunoprecipitation, in vitro kinase assays, siRNA knockdown, reporter assays for IFN and NF-κB The Biochemical journal Medium 30341167
2013 DDX3 associates with p53 (demonstrated by Co-IP), enhances p53 nuclear accumulation after DNA damage in a proteasome-dependent manner, and positively regulates DNA damage-induced apoptotic signaling in cells with wild-type p53. In cells with mutant/non-functional p53, DDX3 instead inhibits extrinsic apoptotic pathway activation. Co-immunoprecipitation, shRNA knockdown, caspase activity assays, proteasome inhibition (MG132), overexpression experiments Biochimica et biophysica acta Medium 23470959
2019 DDX3X controls MITF mRNA translation via an internal ribosome entry site (IRES) in the 5' UTR, thereby directing a proliferative-to-metastatic phenotypic switch in melanoma cells and regulating metastatic potential in vivo. Ribosome profiling (translating ribosome analysis), IRES reporter assays, siRNA knockdown, in vivo melanoma metastasis models Cell reports Medium 31216476
2020 DDX3 is a second molecular target of the translation inhibitor rocaglamide A (RocA). RocA clamps DDX3 protein onto polypurine RNA in an ATP-independent manner, similarly to its clamping of eIF4A. High DDX3 expression strengthens RocA-mediated translational repression through a dominant-negative effect. Proximity-specific fluorescence labeling with O-NBD-conjugated RocA, ribosome profiling, transcriptome analysis, biochemical binding assays Cell chemical biology High 33296667
2017 DDX3 interacts with the m6A RNA demethylase ALKBH5 (via DDX3's ATP domain and ALKBH5's DSBH domain), and DDX3 can modulate mRNA demethylation. DDX3 also interacts with AGO2 and regulates methylation status of microRNAs. Co-immunoprecipitation, domain mapping by truncation mutants, m6A methylation assays Stem cells international Low 29333169
2017 DDX3 is required for ER stress-induced ATF4 mRNA translation. Under ER stress, phospho-eIF2α-mediated ATF4 translation requires DDX3 as part of the eIF4F complex; DDX3 binds the eIF4F complex and promotes ATF4 translation at the translational level. siRNA knockdown, luciferase reporter assays, polyribosome assays, protein-interaction (Co-IP) assays Scientific reports Medium 29062139
2018 DDX3 interacts with NF-κB subunit p65 via the RNA helicase domain of DDX3 binding the N-terminal Rel homology domain (RHD) of p65, suppressing NF-κB (p65/p50)-mediated transcriptional activity and downstream cytokines (IL-6, IL-8). Co-immunoprecipitation, domain mapping, luciferase reporter assays, siRNA knockdown, cytokine measurements PloS one Low 27736973
2021 DDX3X is actively recruited to sites of DNA damage in live cells. Recruitment is mediated by its intrinsically disordered domains and is PARP1-dependent (catalytically active PARP1 is required; PARP1 KO abolishes recruitment). Inhibition of liquid-liquid phase separation reduces DDX3X recruitment. Live-cell microirradiation, fluorescence microscopy, nuclear-export deficient DDX3X mutant construct, CRISPR/Cas9 PARP1 KO, LLPS inhibitor treatment DNA repair Medium 34083132
2021 Sirtuin 5 (Sirt5) demalonylates DDX3 at lysines K66, K130, and K162, which is critical for TBK1-IRF3 activation and type I IFN production. Mutation of these demalonylation sites increases IFN-β transcription, whereas acetylation at K118 also positively regulates IFN-β transcription. Immunoprecipitation, western blot, luciferase reporter assay, mass spectrometry, Sirt5 KO mice, viral infection assays Theranostics Medium 34158847
2021 TRIM25 ubiquitinates DDX3X at lysine 55 (K55). TRIM25 and DDX3X cooperatively enhance IFNB1 induction following RIG-I activation in a manner independent of TRIM25's catalytic activity. Influenza A virus NS1 protein disrupts the TRIM25:DDX3X interaction, abrogating both TRIM25-mediated ubiquitination of DDX3X and cooperative IFNB1 promoter activation. Co-immunoprecipitation, in vitro ubiquitination assays, siRNA knockdown, IFNB1 promoter reporter assay, site-directed mutagenesis (K55) International journal of molecular sciences Medium 34445801
2022 DDX3X promotes IFNB transcription by interacting with IRF-3 through IRF-3's DNA-binding domain and promoting recruitment of IRF-3/p300/CBP transcriptional complex to the IFNB promoter. The ATP-binding pocket of DDX3 is essential for this transcriptional activation function. Co-immunoprecipitation, ChIP, EMSA, luciferase reporter assay, ATP-binding pocket mutants Scientific reports Medium 35273248
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 STING signaling activation. Co-immunoprecipitation, ubiquitination assays, LLPS experiments, USP8 inhibitor treatment, Trex1-/- mouse model Cell reports Medium 38795350
2024 PRMT1 methylates DDX3X (arginine methylation), enhancing its protein stability by preventing proteasomal degradation. Methylated DDX3X translocates to mitochondria where it facilitates translation of PINK1 mRNA, promoting mitochondrial biogenesis and mitophagy to support breast cancer metastasis. Mass spectrometry, Co-immunoprecipitation, in vitro methylation assay, pulse-chase protein stability assay, mitochondrial fractionation, PINK1 translation reporter, xenograft models Cancer research Medium 39042374
2023 WWP2 E3 ubiquitin ligase catalyzes K63-linked polyubiquitination of DDX3X, targeting it for proteasomal degradation. In T2DM, JNK activation downregulates WWP2, leading to DDX3X accumulation and endothelial injury. Co-immunoprecipitation, mass spectrometry, ubiquitination assay (K63-linkage specific), pulse-chase assay, endothelial-specific WWP2 KO mice Cardiovascular diabetology Medium 37149668
2023 Asparagine endopeptidase (AEP) cleaves DDX3X in a HIF1A-dependent manner under hypoxia/nutrient deprivation, generating a truncated C-terminal fragment (tDDX3X-C) that translocates to the nucleus and complexes with splicing factors to drive alternative splicing events in cancer cells. In vitro cleavage assays, cellular fractionation, Co-IP with splicing factors, RNA splicing analysis, glioblastoma organoids, animal models The Journal of clinical investigation Medium 37988165
2018 DDX3X depletion impairs translation of KLF4 mRNA in breast cancer cells, but also directly interacts with KLF4 mRNA and regulates its splicing, thereby modulating KLF4 expression and downstream cell cycle gene regulation. siRNA knockdown, RIP (RNA immunoprecipitation), splicing assays, cell proliferation and cell cycle assays FEBS letters Low 29782654
2019 DDX3 interacts with hnRNPK (Co-IP) and is required for efficient translation of JUND mRNA in pancreatic β cells during metabolic stress. Loss of hnRNPK reduced DDX3X binding to translation machinery, suggesting cooperative regulation of translation. Co-immunoprecipitation, RNA immunoprecipitation, translating ribosome affinity purification (TRAP), CRISPR-Cas9 knockdown Molecular metabolism Low 31178390
2019 DDX3 is required for HIV-1 Tat function (Tat-dependent transcription). DDX3 colocalizes and physically interacts with HIV-1 Tat in cytoplasmic foci. The ATPase-dependent RNA helicase activity of DDX3 is required for this Tat-stimulatory function, which is specific to DDX3 among tested DEAD-box helicases. Co-immunoprecipitation, co-localization microscopy, Tat-dependent reporter assays, ATPase mutant DDX3, siRNA knockdown Biochemical and biophysical research communications Low 24183723
2015 DDX3X loss of function impairs canonical Wnt signaling in zebrafish, as demonstrated using zebrafish Wnt defects as a surrogate. All tested de novo DDX3X mutations from ID patients show consistent loss-of-function effects on the Wnt pathway, with gender-differential activity possibly reflecting dose-dependent DDX3X expression. Zebrafish Wnt pathway functional assay (injection of mutant mRNAs), genetic epistasis American journal of human genetics Medium 26235985
2018 DDX3 translational control targets include PACT, STAT1, GNB2, Rac1, TAK1, and p38 MAPK in human cells; DDX3 knockdown reduces translational efficiency of these target mRNAs (confirmed by polysome profiling and luciferase reporters). DDX3 is crucial for macrophage migration, phagocytosis, and chemokine secretion in response to inflammatory stimuli. siRNA knockdown, polysome profiling, luciferase reporter assays, cytokine antibody array, flow cytometry, cell migration assays, transgenic zebrafish inflammation assay Molecular and cellular biology Medium 30373933
2019 DDX3X is required for neural crest induction in Xenopus by regulating AKT kinase activity. DDX3X depletion decreases AKT activity and AKT-dependent inhibitory phosphorylation of GSK3β, reducing β-catenin and Snai1 levels. This function is mediated by RAC1 (a GTPase whose translation depends on DDX3X helicase activity). Xenopus morpholino knockdown, rescue experiments, western blotting for AKT/GSK3β phosphorylation, RAC1 translation reporter Development (Cambridge, England) Medium 33318149
2024 DDX3X depletion causes aberrant cytoplasmic accumulation of endogenous cellular dsRNAs, triggering type I IFN production through the MDA5-mediated dsRNA-sensing pathway. DDX3X interacts with ADAR1, and dual depletion of DDX3X and ADAR1 synergistically activates the cytosolic dsRNA pathway. siRNA knockdown, dsRNA immunofluorescence/staining, IFN reporter assays, Co-immunoprecipitation (DDX3X-ADAR1), mouse mammary tumor model Cancer research Medium 33941613
2023 RNA helicase DDX3X modulates herpes simplex virus 1 (HSV-1) nuclear egress: DDX3X is redirected to the nuclear envelope upon HSV-1 infection and physically interacts with the viral nuclear egress complex (NEC) at the inner nuclear membrane. DDX3X also binds and stimulates incorporation of pUs3 (a viral kinase) into mature particles to promote nuclear release across the outer nuclear membrane. Co-immunoprecipitation, confocal imaging, viral depletion/knockdown experiments, virus titer assays Communications biology Medium 36725983
2019 DDX3X promotes FMR1 CGG repeat-associated RAN translation and repeat-induced toxicity. Disrupting belle/DDX3X selectively inhibited FMR1 RAN translation in Drosophila in vivo and in human cells, and mitigated repeat-induced toxicity in Drosophila and primary rodent neurons. Drosophila genetic screen, cell-based RAN translation reporter assays, Drosophila in vivo genetic disruption, primary neuron toxicity assays EMBO reports Medium 31347257
2024 NMR spectroscopy demonstrates that DDX3X has significantly higher intrinsic binding affinity for single-stranded RNA (ssRNA) than for structured RNA elements. This preferential binding, accompanied by formation of a domain-closed conformation in complex with ssRNA, effectively stabilizes the denatured ssRNA state, underlying DDX3X's unwinding activity. Solution NMR spectroscopy, binding affinity measurements, conformational analysis Nature communications High 38664397
2024 DDX3X functions both as an ATP-dependent bidirectional RNA helicase (unwinding RNA duplexes and RNA-DNA hybrids) and as an ATP-independent nucleic acid chaperone that destabilizes structured DNA and RNA and promotes their annealing. The N-terminal and C-terminal intrinsically disordered tails are critical for these biochemical activities. In vitro helicase assays, annealing assays, ATPase assays, truncation mutant analysis Biochemical and biophysical research communications Medium 38669753
2024 KLHL29 recruits the CUL3 E3 ubiquitin ligase to DDX3X, leading to proteasomal degradation of DDX3X. DDX3X stabilizes CCND1 mRNA, and its degradation causes CCND1 mRNA destabilization and G0/G1 cell cycle arrest in breast cancer. Co-immunoprecipitation, ubiquitination assay, mass spectrometry, mRNA stability assay, cell cycle analysis Oncogene Medium 37845393
2024 G3BP1-driven RNP granules establish RNA-RNA interactions that limit mRNA mobility and translatability. DDX3X resolves these inhibitory RNA-RNA interactions inside RNP condensates, rendering condensates dynamic and enabling mRNA translation. Disease-associated and catalytically inactive DDX3X variants fail to resolve RNA-RNA interactions. DDX3X inhibition in cells accelerates RNP granule assembly and delays disassembly. In vitro condensate reconstitution, single-molecule FRET, ribosome profiling, cell-based granule dynamics (live imaging), catalytically inactive DDX3X mutants Molecular cell High 39729994
2024 DDX3X and DDX3Y form nanometer-scale RNA-protein clusters (RPCs) mediated by their N-terminal intrinsically disordered regions (IDRs), and these clusters foster catalytic activities in vitro and in cells. RNA release is a major step differentiating unwinding activities of DDX3X and DDX3Y, with N-terminal IDRs being the major differentiators of enzymatic activities. Multiparameter confocal microscopy, single-molecule photon burst analysis, ensemble biochemistry, IDR truncation mutants Current biology : CB Medium 39591970
2023 DDX3X binds to a specific 20-nucleotide motif present in TGF-β1-responsive mRNAs and mediates TGF-β1-stimulated upregulation of their translation (including NEU3 mRNA). Deletion of the motif abolishes TGF-β1 upregulation of translation; insertion confers responsiveness. RNA immunoprecipitation, deletion/insertion mutagenesis of RNA motif, translation reporter assays, DDX3 inhibitor (RK-33) in vivo mouse model JCI insight Medium 36821384
2020 DDX3 regulates androgen receptor (AR) protein levels by binding AR mRNA and sequestering it in stress granules, thereby repressing its translation in castration-resistant prostate cancer. Inhibiting DDX3 restores AR protein expression, AR signaling, and sensitivity to AR-signaling inhibitors. RNA immunoprecipitation, Co-IP with stress granule marker PABP1, immunofluorescence, siRNA/pharmacologic inhibition, in vivo xenograft Proceedings of the National Academy of Sciences of the United States of America Medium 33106406
2018 DDX3X regulates expression of DNA repair factors DDB2 and XPA by binding to their promoter regions (demonstrated by chromatin immunoprecipitation). Loss of DDX3X in hepatocytes decreases DDB2 and XPA expression, leading to accumulation of DNA strand breaks and replication stress, ultimately promoting liver tumorigenesis. Hepatocyte-specific Ddx3x KO mice, chromatin immunoprecipitation (ChIP), comet assay, γH2AX analysis Molecular cancer research : MCR Medium 30297359
2022 TLR4 promotes DDX3X expression via the JAK2/STAT1 signaling pathway after spinal cord injury, where STAT1 acts as a transcription factor that directly promotes DDX3X transcription (confirmed by ChIP and dual-luciferase reporter assay). DDX3X in turn mediates NLRP3 inflammasome activation and microglial pyroptosis. TLR4-KO mice, ChIP, dual-luciferase reporter assay, Co-IP, western blot, TMT proteomics Clinical and translational medicine Medium 35692100
2024 SIRT7 deacetylates DDX3X, stabilizing it. SIRT7 inhibition mediates DDX3X depletion, which disrupts NLRP3 inflammasome assembly and suppresses ERK1/2 signaling downstream of NLRP3-mediated IL-1β, thereby overcoming sorafenib resistance in hepatocellular carcinoma. Mass spectrometry (SIRT7-DDX3X interaction), Co-IP, deacetylation assay, in vivo xenograft model Drug resistance updates Low 38277756

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 345 31511697
2015 Mutations in DDX3X Are a Common Cause of Unexplained Intellectual Disability with Gender-Specific Effects on Wnt Signaling. American journal of human genetics 236 26235985
2007 DDX3 DEAD-box RNA helicase is required for hepatitis C virus RNA replication. Journal of virology 220 17855521
2021 DDX3X: structure, physiologic functions and cancer. Molecular cancer 190 33627125
2013 RNA helicase DDX3 is a regulatory subunit of casein kinase 1 in Wnt-β-catenin signaling. Science (New York, N.Y.) 184 23413191
2020 Pathogenic DDX3X Mutations Impair RNA Metabolism and Neurogenesis during Fetal Cortical Development. Neuron 164 32135084
2010 DDX3 regulates cell growth through translational control of cyclin E1. Molecular and cellular biology 155 20837705
2014 The Ded1/DDX3 subfamily of DEAD-box RNA helicases. Critical reviews in biochemistry and molecular biology 147 25039764
2013 The role of the DEAD-box RNA helicase DDX3 in mRNA metabolism. Wiley interdisciplinary reviews. RNA 119 23606618
2015 DDX3, a potential target for cancer treatment. Molecular cancer 116 26541825
2014 DDX3 modulates cell adhesion and motility and cancer cell metastasis via Rac1-mediated signaling pathway. Oncogene 116 25043297
2014 Multiple functions of DDX3 RNA helicase in gene regulation, tumorigenesis, and viral infection. Frontiers in genetics 113 25538732
2019 The mechanism of RNA duplex recognition and unwinding by DEAD-box helicase DDX3X. Nature communications 100 31300642
2021 DDX3 depletion represses translation of mRNAs with complex 5' UTRs. Nucleic acids research 98 33905506
2015 RNA helicase DDX3: at the crossroad of viral replication and antiviral immunity. Reviews in medical virology 98 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 91 35692100
1992 Expression pattern of a murine homeobox gene, Dbx, displays extreme spatial restriction in embryonic forebrain and spinal cord. Proceedings of the National Academy of Sciences of the United States of America 85 1355604
2022 Sexually dimorphic RNA helicases DDX3X and DDX3Y differentially regulate RNA metabolism through phase separation. Molecular cell 82 35588748
2023 Exosomal Lnc NEAT1 from endothelial cells promote bone regeneration by regulating macrophage polarization via DDX3X/NLRP3 axis. Journal of nanobiotechnology 81 36941678
2009 The current understanding of Ded1p/DDX3 homologs from yeast to human. RNA biology 74 19106629
2015 Cancer-associated mutants of RNA helicase DDX3X are defective in RNA-stimulated ATP hydrolysis. Journal of molecular biology 71 25724843
2021 Sequential inverse dysregulation of the RNA helicases DDX3X and DDX3Y facilitates MYC-driven lymphomagenesis. Molecular cell 69 34437837
2020 DEAD-box RNA Helicase DDX3: Functional Properties and Development of DDX3 Inhibitors as Antiviral and Anticancer Drugs. Molecules (Basel, Switzerland) 66 32102413
2018 The RNA helicase DDX3X is an essential mediator of innate antimicrobial immunity. PLoS pathogens 66 30475900
2019 The X-Linked DDX3X RNA Helicase Dictates Translation Reprogramming and Metastasis in Melanoma. Cell reports 65 31216476
1996 Regionalized expression of the Dbx family homeobox genes in the embryonic CNS of the mouse. Mechanisms of development 65 8798145
2020 DDX3X Suppresses the Susceptibility of Hindbrain Lineages to Medulloblastoma. Developmental cell 63 32553121
2020 Dual targeting of DDX3 and eIF4A by the translation inhibitor rocaglamide A. Cell chemical biology 62 33296667
2016 Multifunctional DDX3: dual roles in various cancer development and its related signaling pathways. American journal of cancer research 60 27186411
2017 The DEAD-Box RNA Helicase DDX3 Interacts with m6A RNA Demethylase ALKBH5. Stem cells international 59 29333169
2019 DDX3X and specific initiation factors modulate FMR1 repeat-associated non-AUG-initiated translation. EMBO reports 57 31347257
2015 RNA helicase DDX3: a novel therapeutic target in Ewing sarcoma. Oncogene 54 26364611
2021 DDX3X and DDX3Y are redundant in protein synthesis. RNA (New York, N.Y.) 53 34535544
2013 DDX3 regulates DNA damage-induced apoptosis and p53 stabilization. Biochimica et biophysica acta 53 23470959
2018 A double-edged function of DDX3, as an oncogene or tumor suppressor, in cancer progression (Review). Oncology reports 52 29328432
2022 The human DEAD-box helicase DDX3X as a regulator of mRNA translation. Frontiers in cell and developmental biology 51 36393867
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 51 27656019
2013 Expression of the RNA helicase DDX3 and the hypoxia response in breast cancer. PloS one 51 23696831
2021 Prospective and detailed behavioral phenotyping in DDX3X syndrome. Molecular autism 47 33993884
2016 DDX3 promotes tumor invasion in colorectal cancer via the CK1ε/Dvl2 axis. Scientific reports 45 26892600
2011 Viruses and the human DEAD-box helicase DDX3: inhibition or exploitation? Biochemical Society transactions 45 21428961
2021 Targeting DDX3X Triggers Antitumor Immunity via a dsRNA-Mediated Tumor-Intrinsic Type I Interferon Response. Cancer research 44 33941613
2007 Regulation and function of Dbx genes in the zebrafish spinal cord. Developmental dynamics : an official publication of the American Association of Anatomists 41 17994542
2001 Gene structure of the human DDX3 and chromosome mapping of its related sequences. Molecules and cells 40 11710523
2018 DDX3X RNA helicase affects breast cancer cell cycle progression by regulating expression of KLF4. FEBS letters 39 29782654
2014 DDX3X regulates cell survival and cell cycle during mouse early embryonic development. Journal of biomedical research 39 25050112
2018 DDX3 Participates in Translational Control of Inflammation Induced by Infections and Injuries. Molecular and cellular biology 38 30373933
2016 DDX3 Represses Stemness by Epigenetically Modulating Tumor-suppressive miRNAs in Hepatocellular Carcinoma. Scientific reports 36 27344963
2021 Developmental and Behavioral Phenotypes in a Mouse Model of DDX3X Syndrome. Biological psychiatry 35 34344536
2018 DNA Damage, Liver Injury, and Tumorigenesis: Consequences of DDX3X Loss. Molecular cancer research : MCR 35 30297359
2017 DDX3 regulates endoplasmic reticulum stress-induced ATF4 expression. Scientific reports 35 29062139
2015 DDX3 functions in antiviral innate immunity through translational control of PACT. The FEBS journal 35 26454002
2021 RNA Helicase DDX3: A Double-Edged Sword for Viral Replication and Immune Signaling. Microorganisms 34 34204859
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
2020 Targeting host DEAD-box RNA helicase DDX3X for treating viral infections. Antiviral research 33 33301755
2018 DDX3 directly facilitates IKKα activation and regulates downstream signalling pathways. The Biochemical journal 33 30341167
2016 DDX3 DEAD-box RNA helicase plays a central role in mitochondrial protein quality control in Leishmania. Cell death & disease 33 27735940
2019 Metabolic stress activates an ERK/hnRNPK/DDX3X pathway in pancreatic β cells. Molecular metabolism 32 31178390
2013 DDX3 RNA helicase is required for HIV-1 Tat function. Biochemical and biophysical research communications 30 24183723
2024 Stress granule-localized USP8 potentiates cGAS-mediated type I interferonopathies through deubiquitination of DDX3X. Cell reports 29 38795350
2024 Arginine Methylation of DDX3 by PRMT1 Mediates Mitochondrial Homeostasis to Promote Breast Cancer Metastasis. Cancer research 29 39042374
2020 RNA-binding protein DDX3 mediates posttranscriptional regulation of androgen receptor: A mechanism of castration resistance. Proceedings of the National Academy of Sciences of the United States of America 29 33106406
2019 Chicken DDX3X Activates IFN-β via the chSTING-chIRF7-IFN-β Signaling Axis. Frontiers in immunology 28 31057547
2023 AEP-cleaved DDX3X induces alternative RNA splicing events to mediate cancer cell adaptation in harsh microenvironments. The Journal of clinical investigation 27 37988165
2023 Down-regulation of WWP2 aggravates Type 2 diabetes mellitus-induced vascular endothelial injury through modulating ubiquitination and degradation of DDX3X. Cardiovascular diabetology 26 37149668
2021 RNA helicase, DDX3X, is actively recruited to sites of DNA damage in live cells. DNA repair 25 34083132
2021 Demalonylation of DDX3 by Sirtuin 5 promotes antiviral innate immune responses. Theranostics 25 34158847
2016 The DEAD-Box RNA Helicase DDX3 Interacts with NF-κB Subunit p65 and Suppresses p65-Mediated Transcription. PloS one 25 27736973
2021 The RNA helicase DDX3 induces neural crest by promoting AKT activity. Development (Cambridge, England) 24 33318149
2018 DDX3 in HIV-1 infection and sensing: A paradox. Cytokine & growth factor reviews 24 29580812
1994 Mouse homeobox gene Dbx: sequence, gene structure and expression pattern during mid-gestation. Mechanisms of development 24 7811640
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
2024 G3BP-driven RNP granules promote inhibitory RNA-RNA interactions resolved by DDX3X to regulate mRNA translatability. Molecular cell 22 39729994
2022 DEAD-Box RNA Helicases DDX3X and DDX5 as Oncogenes or Oncosuppressors: A Network Perspective. Cancers 22 35954483
2021 TRIM25 and DEAD-Box RNA Helicase DDX3X Cooperate to Regulate RIG-I-Mediated Antiviral Immunity. International journal of molecular sciences 21 34445801
2024 DDX3X and Stress Granules: Emerging Players in Cancer and Drug Resistance. Cancers 20 38539466
2019 Expression and Localization of DDX3 in Prostate Cancer Progression and Metastasis. The American journal of pathology 20 30926334
2018 Diosgenin increased DDX3 expression in hepatocellular carcinoma. American journal of translational research 19 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
2024 NMR characterization of RNA binding property of the DEAD-box RNA helicase DDX3X and its implications for helicase activity. Nature communications 17 38664397
2023 RNA helicase DDX3X modulates herpes simplex virus 1 nuclear egress. Communications biology 17 36725983
2017 Rottlerin upregulates DDX3 expression in hepatocellular carcinoma. Biochemical and biophysical research communications 17 29203243
2024 PRRSV hijacks DDX3X protein and induces ferroptosis to facilitate viral replication. Veterinary research 16 39155369
2023 KLHL29-mediated DDX3X degradation promotes chemosensitivity by abrogating cell cycle checkpoint in triple-negative breast cancer. Oncogene 16 37845393
2022 DDX3X structural analysis: Implications in the pharmacology and innate immunity. Current research in immunology 16 35647523
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
2022 The RNA helicase DDX3 promotes IFNB transcription via enhancing IRF-3/p300 holocomplex binding to the IFNB promoter. Scientific reports 15 35273248
2022 DDX3 acts as a tumor suppressor in colorectal cancer as loss of DDX3 in advanced cancer promotes tumor progression by activating the MAPK pathway. International journal of biological sciences 15 35844798
2022 A Dual Role of DDX3X in dsRNA-Derived Innate Immune Signaling. Frontiers in molecular biosciences 15 35874614
2024 Targeting RNA helicase DDX3X with a small molecule inhibitor for breast cancer bone metastasis treatment. Cancer letters 14 39306228
2024 Dual mode of DDX3X as an ATP-dependent RNA helicase and ATP-independent nucleic acid chaperone. Biochemical and biophysical research communications 13 38669753
2024 RNA helicases DDX3X and DDX3Y form nanometer-scale RNA-protein clusters that support catalytic activity. Current biology : CB 13 39591970
2024 DDX3X syndrome: From clinical phenotypes to biological insights. Journal of neurochemistry 12 38976626
2023 DDX3-mediated miR-34 expression inhibits autophagy and HBV replication in hepatic cells. Journal of viral hepatitis 12 36597176
2023 Inhibition of DDX3X ameliorated CD4+ T cells pyroptosis and improves survival in septic mice. Molecular immunology 12 36603305
2023 Protective and Adverse Roles of DDX3X in Different Cell Types in Nonalcoholic Steatohepatitis Progression. Research (Washington, D.C.) 12 38090607
2022 The X-Linked Helicase DDX3X Is Required for Lymphoid Differentiation and MYC-Driven Lymphomagenesis. Cancer research 12 35815807
2019 Targeting RNA helicase DDX3 in stem cell maintenance and teratoma formation. Genes & cancer 12 30899416

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