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Entry version 236 (29 Sep 2021)
Sequence version 3 (23 Jan 2007)
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Protein

ATP-dependent RNA helicase DDX3X

Gene

DDX3X

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score:

Annotation score:5 out of 5

<p>The annotation score provides a heuristic measure of the annotation content of a UniProtKB entry or proteome. This score <strong>cannot</strong> be used as a measure of the accuracy of the annotation as we cannot define the 'correct annotation' for any given protein.<p><a href='/help/annotation_score' target='_top'>More...</a></p>
-Experimental evidence at protein leveli <p>This indicates the type of evidence that supports the existence of the protein. Note that the 'protein existence' evidence does not give information on the accuracy or correctness of the sequence(s) displayed.<p><a href='/help/protein_existence' target='_top'>More...</a></p>

<p>This section provides any useful information about the protein, mostly biological knowledge.<p><a href='/help/function_section' target='_top'>More...</a></p>Functioni

Multifunctional ATP-dependent RNA helicase (PubMed:17357160, PubMed:21589879, PubMed:31575075).

The ATPase activity can be stimulated by various ribo-and deoxynucleic acids indicative for a relaxed substrate specificity (PubMed:29222110).

In vitro can unwind partially double-stranded DNA with a preference for 5'-single-stranded DNA overhangs (PubMed:17357160, PubMed:21589879).

Binds RNA G-quadruplex (rG4s) structures, including those located in the 5'-UTR of NRAS mRNA (PubMed:30256975).

Involved in many cellular processes, which do not necessarily require its ATPase/helicase catalytic activities (Probable). Involved in transcription regulation (PubMed:16818630, PubMed:18264132).

Positively regulates CDKN1A/WAF1/CIP1 transcription in an SP1-dependent manner, hence inhibits cell growth. This function requires its ATPase, but not helicase activity (PubMed:16818630, PubMed:18264132).

CDKN1A up-regulation may be cell-type specific (PubMed:18264132).

Binds CDH1/E-cadherin promoter and represses its transcription (PubMed:18264132).

Potentiates HNF4A-mediated MTTP transcriptional activation; this function requires ATPase, but not helicase activity. Facilitates HNF4A acetylation, possibly catalyzed by CREBBP/EP300, thereby increasing the DNA-binding affinity of HNF4 to its response element. In addition, disrupts the interaction between HNF4 and SHP that forms inactive heterodimers and enhances the formation of active HNF4 homodimers. By promoting HNF4A-induced MTTP expression, may play a role in lipid homeostasis (PubMed:28128295).

May positively regulate TP53 transcription (PubMed:28842590).

Associates with mRNPs, predominantly with spliced mRNAs carrying an exon junction complex (EJC) (PubMed:17095540, PubMed:18596238).

Involved in the regulation of translation initiation (PubMed:18628297, PubMed:17667941, PubMed:22872150).

Not involved in the general process of translation, but promotes efficient translation of selected complex mRNAs, containing highly structured 5'-untranslated regions (UTR) (PubMed:20837705, PubMed:22872150).

This function depends on helicase activity (PubMed:20837705, PubMed:22872150).

Might facilitate translation by resolving secondary structures of 5'-UTRs during ribosome scanning (PubMed:20837705).

Alternatively, may act prior to 43S ribosomal scanning and promote 43S pre-initiation complex entry to mRNAs exhibiting specific RNA motifs, by performing local remodeling of transcript structures located close to the cap moiety (PubMed:22872150).

Independently of its ATPase activity, promotes the assembly of functional 80S ribosomes and disassembles from ribosomes prior to the translation elongation process (PubMed:22323517).

Positively regulates the translation of cyclin E1/CCNE1 mRNA and consequently promotes G1/S-phase transition during the cell cycle (PubMed:20837705).

May activate TP53 translation (PubMed:28842590).

Required for endoplasmic reticulum stress-induced ATF4 mRNA translation (PubMed:29062139).

Independently of its ATPase/helicase activity, enhances IRES-mediated translation; this activity requires interaction with EIF4E (PubMed:17667941, PubMed:22323517).

Independently of its ATPase/helicase activity, has also been shown specifically repress cap-dependent translation, possibly by acting on translation initiation factor EIF4E (PubMed:17667941).

Involved in innate immunity, acting as a viral RNA sensor. Binds viral RNAs and promotes the production of type I interferon (IFN-alpha and IFN-beta) (PubMed:31575075, PubMed:20127681, PubMed:21170385).

Potentiate MAVS/DDX58-mediated induction of IFNB in early stages of infection (PubMed:20127681, PubMed:21170385).

Enhances IFNB1 expression via IRF3/IRF7 pathway and participates in NFKB activation in the presence of MAVS and TBK1 (PubMed:18583960, PubMed:18636090, PubMed:21170385, PubMed:27980081, PubMed:19913487).

Involved in TBK1 and IKBKE-dependent IRF3 activation leading to IFNB induction, acts as a scaffolding adapter that links IKBKE and IRF3 and coordinates their activation (PubMed:23478265).

Involved in the TLR7/TLR8 signaling pathway leading to type I interferon induction, including IFNA4 production. In this context, acts as an upstream regulator of IRF7 activation by MAP3K14/NIK and CHUK/IKKA. Stimulates CHUK autophosphorylation and activation following physiological activation of the TLR7 and TLR8 pathways, leading to MAP3K14/CHUK-mediated activatory phosphorylation of IRF7 (PubMed:30341167).

Also stimulates MAP3K14/CHUK-dependent NF-kappa-B signaling (PubMed:30341167).

Negatively regulates TNF-induced IL6 and IL8 expression, via the NF-kappa-B pathway. May act by interacting with RELA/p65 and trapping it in the cytoplasm (PubMed:27736973).

May also bind IFNB promoter; the function is independent of IRF3 (PubMed:18583960).

Involved in both stress and inflammatory responses (By similarity).

Independently of its ATPase/helicase activity, required for efficient stress granule assembly through its interaction with EIF4E, hence promotes survival in stressed cells (PubMed:21883093).

Independently of its helicase activity, regulates NLRP3 inflammasome assembly through interaction with NLRP3 and hence promotes cell death by pyroptosis during inflammation. This function is independent of helicase activity (By similarity).

Therefore DDX3X availability may be used to interpret stress signals and choose between pro-survival stress granules and pyroptotic NLRP3 inflammasomes and serve as a live-or-die checkpoint in stressed cells (By similarity).

In association with GSK3A/B, negatively regulates extrinsic apoptotic signaling pathway via death domain receptors, including TNFRSF10B, slowing down the rate of CASP3 activation following death receptor stimulation (PubMed:18846110).

Cleavage by caspases may inactivate DDX3X and relieve the inhibition (PubMed:18846110).

Independently of its ATPase/helicase activity, allosteric activator of CSNK1E. Stimulates CSNK1E-mediated phosphorylation of DVL2, thereby involved in the positive regulation of Wnt/beta-catenin signaling pathway. Also activates CSNK1A1 and CSNK1D in vitro, but it is uncertain if these targets are physiologically relevant (PubMed:23413191, PubMed:29222110).

ATPase and casein kinase-activating functions are mutually exclusive (PubMed:29222110).

May be involved in mitotic chromosome segregation (PubMed:21730191).

By similarityCurated30 Publications

(Microbial infection) Facilitates hepatitis C virus (HCV) replication (PubMed:29899501).

During infection, HCV core protein inhibits the interaction between MAVS and DDX3X and therefore impairs MAVS-dependent INFB induction and might recruit DDX3X to HCV replication complex (PubMed:21170385).

2 Publications

(Microbial infection) Facilitates HIV-1 replication (PubMed:15507209, PubMed:18583960, PubMed:21589879, PubMed:22872150, PubMed:29899501).

Acts as a cofactor for XPO1-mediated nuclear export of HIV-1 Rev RNAs (PubMed:15507209, PubMed:18583960, PubMed:29899501).

This function is strongly stimulated in the presence of TBK1 and requires DDX3X ATPase activity (PubMed:18583960).

5 Publications

(Microbial infection) Facilitates Zika virus (ZIKV) replication.

1 Publication

(Microbial infection) Facilitates Dengue virus (DENV) replication.

1 Publication

(Microbial infection) Facilitates Venezuelan equine encephalitis virus (VEEV) replication.

1 Publication

Miscellaneous

Encoded by an chromosome X-linked gene which may escape X chromosome inactivation in females. DDX3Y, its homolog on chromosome Y, is located on the Y non-recombinant portion.1 Publication

Caution

The role of the nuclear export signal (NES) motif in XPO1-mediated DDX3X export is controversial (PubMed:30131165, PubMed:31575075, PubMed:15507209). In one study, NES has been found dispensable for DDX3X export while the helicase domain mediates the interaction with XPO1 (PubMed:15507209). However, in two other studies, DDX3X nuclear export is dependent on both NES and Ran in its GTP-bound form while the helicase domain is not required (PubMed:30131165, PubMed:31575075).3 Publications

<p>This subsection of the <a href="http://www.uniprot.org/help/function_section">Function</a> section describes the catalytic activity of an enzyme, i.e. a chemical reaction that the enzyme catalyzes.<p><a href='/help/catalytic_activity' target='_top'>More...</a></p>Catalytic activityi

<p>This subsection of the 'Function' section describes biophysical and chemical properties, such as maximal absorption, kinetic parameters, pH dependence, redox potentials and temperature dependence.<p><a href='/help/biophysicochemical_properties' target='_top'>More...</a></p>Kineticsi

kcat is 14 min(-1) for ATP hydrolysis in the absence of nucleic acid (PubMed:17357160). kcat is 36 min(-1) for ATP hydrolysis in the presence of ssDNA oligonucleoside dA200 (PubMed:17357160). kcat is 1.6 min(-1) for ATP hydrolysis in the absence of nucleic acid (PubMed:21589879). kcat is 3.2 min(-1) for ATP hydrolysis in the presence of RNA oligo(rU)20 (PubMed:21589879). kcat is 3.8 min(-1) for ATP hydrolysis in the presence of DNA oligo(dT)20 (PubMed:21589879).2 Publications
  1. KM=0.04 mM for ATP (in the absence of nucleic acid)1 Publication
  2. KM=0.03 mM for ATP (in the presence of ssDNA oligonucleoside dA200)1 Publication
  3. KM=0.062 mM for ATP (in the absence of nucleic acid)1 Publication
  4. KM=0.045 mM for ATP (in the presence of RNA oligo(rU)20)1 Publication
  5. KM=0.047 mM for ATP (in the presence of DNA oligo(dT)20)1 Publication

Regions

Feature keyPosition(s)DescriptionActionsGraphical viewLength
<p>This subsection of the <a href="http://www.uniprot.org/help/function_section">Function</a> section describes a region in the protein which binds nucleotide phosphates. It always involves more than one amino acid and includes all residues involved in nucleotide-binding.<p><a href='/help/np_bind' target='_top'>More...</a></p>Nucleotide bindingi200 – 207ATP8
Nucleotide bindingi224 – 231ATP8

<p>The <a href="http://www.geneontology.org/">Gene Ontology (GO)</a> project provides a set of hierarchical controlled vocabulary split into 3 categories:<p><a href='/help/gene_ontology' target='_top'>More...</a></p>GO - Molecular functioni

GO - Biological processi

<p>UniProtKB Keywords constitute a <a href="http://www.uniprot.org/keywords">controlled vocabulary</a> with a hierarchical structure. Keywords summarise the content of a UniProtKB entry and facilitate the search for proteins of interest.<p><a href='/help/keywords' target='_top'>More...</a></p>Keywordsi

Molecular functionDNA-binding, Helicase, Hydrolase, RNA-binding
Biological processApoptosis, Chromosome partition, Host-virus interaction, Immunity, Innate immunity, Ribosome biogenesis, Transcription, Transcription regulation, Translation regulation
LigandATP-binding, Nucleotide-binding

Enzyme and pathway databases

BRENDA Comprehensive Enzyme Information System

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BRENDAi
3.6.4.13, 2681

Pathway Commons web resource for biological pathway data

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PathwayCommonsi
O00571

Reactome - a knowledgebase of biological pathways and processes

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Reactomei
R-HSA-6798695, Neutrophil degranulation

SIGNOR Signaling Network Open Resource

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SIGNORi
O00571

Protein family/group databases

Transport Classification Database

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TCDBi
1.I.1.1.3, the nuclear pore complex (npc) family

<p>This section provides information about the protein and gene name(s) and synonym(s) and about the organism that is the source of the protein sequence.<p><a href='/help/names_and_taxonomy_section' target='_top'>More...</a></p>Names & Taxonomyi

<p>This subsection of the <a href="http://www.uniprot.org/help/names_and_taxonomy_section">Names and taxonomy</a> section provides an exhaustive list of all names of the protein, from commonly used to obsolete, to allow unambiguous identification of a protein.<p><a href='/help/protein_names' target='_top'>More...</a></p>Protein namesi
Recommended name:
ATP-dependent RNA helicase DDX3X (EC:3.6.4.135 Publications)
Alternative name(s):
CAP-Rf
DEAD box protein 3, X-chromosomal
DEAD box, X isoform
Short name:
DBX
Helicase-like protein 2
Short name:
HLP2
<p>This subsection of the <a href="http://www.uniprot.org/help/names_and_taxonomy_section">Names and taxonomy</a> section indicates the name(s) of the gene(s) that code for the protein sequence(s) described in the entry. Four distinct tokens exist: 'Name', 'Synonyms', 'Ordered locus names' and 'ORF names'.<p><a href='/help/gene_name' target='_top'>More...</a></p>Gene namesi
Name:DDX3X
Synonyms:DBX1 Publication, DDX3
<p>This subsection of the <a href="http://www.uniprot.org/help/names_and_taxonomy_section">Names and taxonomy</a> section provides information on the name(s) of the organism that is the source of the protein sequence.<p><a href='/help/organism-name' target='_top'>More...</a></p>OrganismiHomo sapiens (Human)
<p>This subsection of the <a href="http://www.uniprot.org/help/names_and_taxonomy_section">Names and taxonomy</a> section shows the unique identifier assigned by the NCBI to the source organism of the protein. This is known as the 'taxonomic identifier' or 'taxid'.<p><a href='/help/taxonomic_identifier' target='_top'>More...</a></p>Taxonomic identifieri9606 [NCBI]
<p>This subsection of the <a href="http://www.uniprot.org/help/names_and_taxonomy_section">Names and taxonomy</a> section contains the taxonomic hierarchical classification lineage of the source organism. It lists the nodes as they appear top-down in the taxonomic tree, with the more general grouping listed first.<p><a href='/help/taxonomic_lineage' target='_top'>More...</a></p>Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
<p>This subsection of the <a href="http://www.uniprot.org/help/names_and_taxonomy_section">Names and taxonomy</a> section is present for entries that are part of a <a href="http://www.uniprot.org/proteomes">proteome</a>, i.e. of a set of proteins thought to be expressed by organisms whose genomes have been completely sequenced.<p><a href='/help/proteomes_manual' target='_top'>More...</a></p>Proteomesi
  • UP000005640 <p>A UniProt <a href="http://www.uniprot.org/manual/proteomes_manual">proteome</a> can consist of several components.<br></br>The component name refers to the genomic component encoding a set of proteins.<p><a href='/help/proteome_component' target='_top'>More...</a></p> Componenti: Chromosome X

Organism-specific databases

Human Gene Nomenclature Database

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HGNCi
HGNC:2745, DDX3X

Online Mendelian Inheritance in Man (OMIM)

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MIMi
300160, gene

neXtProt; the human protein knowledge platform

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neXtProti
NX_O00571

Eukaryotic Pathogen, Vector and Host Database Resources

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VEuPathDBi
HostDB:ENSG00000215301

<p>This section provides information on the location and the topology of the mature protein in the cell.<p><a href='/help/subcellular_location_section' target='_top'>More...</a></p>Subcellular locationi

Keywords - Cellular componenti

Cell membrane, Cell projection, Cytoplasm, Cytoskeleton, Inflammasome, Membrane, Nucleus

<p>This section provides information on the disease(s) and phenotype(s) associated with a protein.<p><a href='/help/pathology_and_biotech_section' target='_top'>More...</a></p>Pathology & Biotechi

<p>This subsection of the 'Pathology and Biotech' section provides information on the disease(s) associated with genetic variations in a given protein. The information is extracted from the scientific literature and diseases that are also described in the <a href="http://www.ncbi.nlm.nih.gov/sites/entrez?db=omim">OMIM</a> database are represented with a <a href="http://www.uniprot.org/diseases">controlled vocabulary</a> in the following way:<p><a href='/help/involvement_in_disease' target='_top'>More...</a></p>Involvement in diseasei

Intellectual developmental disorder, X-linked, syndromic, Snijders Blok type (MRXSSB)1 Publication
The disease is caused by variants affecting the gene represented in this entry.
Disease descriptionA disorder characterized by mild to severe intellectual disability, hypotonia, movement disorders, behavior problems, corpus callosum hypoplasia, and epilepsy. Additionally, patients manifest variable non-neurologic features such as joint hyperlaxity, skin pigmentary abnormalities, cleft lip and/or palate, hearing and visual impairment, and precocious puberty.
Related information in OMIM
Feature keyPosition(s)DescriptionActionsGraphical viewLength
<p>This subsection of the 'Sequence' section describes natural variant(s) of the protein sequence.<p><a href='/help/variant' target='_top'>More...</a></p>Natural variantiVAR_075731214I → T in MRXSSB; loss-of-function mutation affecting regulation of Wnt signaling. 1 Publication1
Natural variantiVAR_075732233A → V in MRXSSB. 1 PublicationCorresponds to variant dbSNP:rs796052223Ensembl.1
Natural variantiVAR_075733233Missing in MRXSSB. 1 Publication1
Natural variantiVAR_075734235L → P in MRXSSB. 1 PublicationCorresponds to variant dbSNP:rs796052224Ensembl.1
Natural variantiVAR_075735300V → F in MRXSSB. 1 Publication1
Natural variantiVAR_075736326R → H in MRXSSB; loss-of-function mutation affecting regulation of Wnt signaling. 1 PublicationCorresponds to variant dbSNP:rs797045025EnsemblClinVar.1
Natural variantiVAR_075737351R → Q in MRXSSB. 1 PublicationCorresponds to variant dbSNP:rs1057518707EnsemblClinVar.1
Natural variantiVAR_075738362R → C in MRXSSB. 1 PublicationCorresponds to variant dbSNP:rs797045026EnsemblClinVar.1
Natural variantiVAR_075739376R → C in MRXSSB; also found as a somatic mutation in medulloblastoma; loss of ATPase activity; increased interaction with CSNK1E in the absence of dsRNA; contrary to wild-type protein, strongly interacts with CSNK1A1 and CSNK1D in vivo; strongly increased ability to activate CSNK1E kinase activity, leading to increased DVL phosphorylation, thereby activating Wnt/beta-catenin signaling; increased RNA-binding; no effect on subcellular location. 2 PublicationsCorresponds to variant dbSNP:rs796052231EnsemblClinVar.1
Natural variantiVAR_075740392L → P in MRXSSB. 1 PublicationCorresponds to variant dbSNP:rs796052232Ensembl.1
Natural variantiVAR_075741417Q → P in MRXSSB. 1 PublicationCorresponds to variant dbSNP:rs796052233Ensembl.1
Natural variantiVAR_075742475R → G in MRXSSB. 1 PublicationCorresponds to variant dbSNP:rs1064794574EnsemblClinVar.1
Natural variantiVAR_075743480R → S in MRXSSB. 1 Publication1
Natural variantiVAR_075744488R → H in MRXSSB. 1 PublicationCorresponds to variant dbSNP:rs796052235EnsemblClinVar.1
Natural variantiVAR_075745507I → T in MRXSSB; loss-of-function mutation affecting regulation of Wnt signaling. 1 PublicationCorresponds to variant dbSNP:rs797045024EnsemblClinVar.1
Natural variantiVAR_075746509N → I in MRXSSB. 1 Publication1
Natural variantiVAR_075747514I → T in MRXSSB. 1 PublicationCorresponds to variant dbSNP:rs796052226EnsemblClinVar.1
Natural variantiVAR_075748534R → H in MRXSSB; loss-of-function mutation affecting regulation of Wnt signaling. 1 Publication1
Natural variantiVAR_075749560Missing in MRXSSB. 1 Publication1
Natural variantiVAR_075750568P → L in MRXSSB. 1 PublicationCorresponds to variant dbSNP:rs1057519430EnsemblClinVar.1

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
<p>This subsection of the <a href="http://www.uniprot.org/manual/pathology_and_biotech_section">'Pathology and Biotech'</a> section describes the effect of the experimental mutation of one or more amino acid(s) on the biological properties of the protein.<p><a href='/help/mutagen' target='_top'>More...</a></p>Mutagenesisi12 – 21LDQQFAGLDL → ADQQAAGADA: Impairs nuclear export and interaction with XPO1/CMR1. 1 Publication10
Mutagenesisi19 – 21LDL → ADA: Impairs nuclear export and interaction with XPO1/CMR1. 1 Publication3
Mutagenesisi38Y → A: Impaired interaction with EIF4E; impaired stress granule formation, decreased repression of cap-dependent translation and decreased ability to enhance IRES-mediated translation. No effect on translation of HIV-1 RNA; when associated with A-43. 3 Publications1
Mutagenesisi43L → A: Impaired interaction with EIF4E; decreased repression of cap-dependent translation. Fails to induce stress granule assembly and to rescue cell viability after stress. No effect on translation of HIV-1 RNA; when associated with A-38. 3 Publications1
Mutagenesisi71S → A: Reduces total phosphorylation by 60%. No effect on interaction with IKBKE. 1 Publication1
Mutagenesisi82 – 83SS → AA: Reduces total phosphorylation by 50%. No effect on interaction with IKBKE. 1 Publication2
Mutagenesisi84 – 85FF → AA: Loss of interaction with VACV protein K7, IRF3 activation and IFNB1 promoter induction. 1 Publication2
Mutagenesisi102S → A: Reduces total phosphorylation by 30%. Abolishes interaction with IRF3 and fails to enhance IFNB promoter induction. No effect on interaction with IKBKE. 1 Publication1
Mutagenesisi102S → D: Interacts with IRF3 and enhances IFNB promoter induction. 1 Publication1
Mutagenesisi142 – 144PSE → ASA: Loss of interaction with TRAF3, reduced TRAF3 'K-63'-linked autoubiquitination. 1 Publication3
Mutagenesisi152S → A: Reduces total phosphorylation by 60%. No effect on interaction with IKBKE. 1 Publication1
Mutagenesisi181S → A: Greatly impairs phosphorylation by TBK1 and fails to synergize with TBK1 in IFNB1 induction; when associated with A-183; A-240 and A-269. 1 Publication1
Mutagenesisi183S → A: Greatly impairs phosphorylation by TBK1 and fails to synergize with TBK1 in IFN-beta induction; when associated with A-181; A-240 and A-269. 1 Publication1
Mutagenesisi200Y → A: No effect on general translation; when associated with A-207; A-230; A-347 and A-348. 1 Publication1
Mutagenesisi207Q → A: Does not promote the translation of HIV-1 RNA. No effect on general translation; when associated with A-200; A-230: A-347 and A-348. 2 Publications1
Mutagenesisi230K → A: No effect on general translation; when associated with A-200; A-207; A-347 and A-348. 1 Publication1
Mutagenesisi230K → E: Complete loss of ATPase and RNA-unwinding activities. Loss of HIV-1 mRNA nuclear export. Does not promote the translation of HIV-1 RNA. No effect on IFNB1 induction. No effect on RNA-binding. Loss of inhibition of NF-kappa-B-mediated transcriptional activity. 6 Publications1
Mutagenesisi240S → A: Greatly impairs phosphorylation by TBK1 and fails to synergize with TBK1 in IFN-beta induction; when associated with A-181; A-183 and A-269. 1 Publication1
Mutagenesisi269S → A: Greatly impairs phosphorylation by TBK1 and fails to synergize with TBK1 in IFN-beta induction; when associated with A-181; A-183 and A-240. 1 Publication1
Mutagenesisi275 – 277TRE → RRV: Increased NF-kappa-B-mediated transcriptional activity, contrary to wild-type which is inhibitory in this experimental setting. 1 Publication3
Mutagenesisi347 – 350DEAD → AEAA: Loss of ATPase activity. 1 Publication4
Mutagenesisi347D → A: No effect on general translation; when associated with A-200; A-207; A-230 and A-348. 1 Publication1
Mutagenesisi348E → A: No effect on general translation; when associated with A-200; A-207; A-230 and A-347. 2 Publications1
Mutagenesisi348E → Q: Loss of both ATPase and RNA helicase activities; decreased up-regulation of CDKN1A promoter activity and HNF4A-mediated MTTP transcriptional activation; no effect on the repression of cap- and IRES-dependent translation, WNT/beta catenin signaling, nor on stress granule assembly. Does not promote the translation of HIV-1 RNA. 5 Publications1
Mutagenesisi382 – 384SAT → AAA: Loss of RNA helicase, but not ATPase activity; no effect on the repression of cap- and IRES-dependent translation, WNT/beta catenin signaling, up-regulation of CDKN1A promoter activity, HNF4A-mediated MTTP transcriptional activation, nor on stress granule assembly. 4 Publications3
Mutagenesisi382S → L: Strong decrease in ATPase activity and RNA-unwinding activity. Does not promote the translation of mRNAs containing long structured 5'UTRs, including that of CCNE1. No effect on the translation of HIV-1 RNA. 4 Publications1
Mutagenesisi429S → A: Impairs phosphorylation by TBK1 and fails to synergize with TBK1 in IFN-beta induction; when associated with A-438; A-442; A-456 and A-520. 1 Publication1
Mutagenesisi438T → A: Impairs phosphorylation by TBK1 and fails to synergize with TBK1 in IFN-beta induction; when associated with A-429; A-442; A-456 and A-520. 1 Publication1
Mutagenesisi442S → A: Impairs phosphorylation by TBK1 and fails to synergize with TBK1 in IFN-beta induction; when associated with A-429; A-438; A-456 and A-520. 1 Publication1
Mutagenesisi456S → A: Impairs phosphorylation by TBK1 and fails to synergize with TBK1 in IFN-beta induction; when associated with A-429; A-438; A-442 and A-520. 1 Publication1
Mutagenesisi520S → A: Impairs phosphorylation by TBK1 and fails to synergize with TBK1 in IFN-beta induction; when associated with A-429; A-438; A-442 and A-456. 1 Publication1

Keywords - Diseasei

Disease variant, Mental retardation

Organism-specific databases

DisGeNET

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DisGeNETi
1654

GeneReviews a resource of expert-authored, peer-reviewed disease descriptions.

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GeneReviewsi
DDX3X

MalaCards human disease database

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MalaCardsi
DDX3X
MIMi300958, phenotype

Open Targets

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OpenTargetsi
ENSG00000215301

Orphanet; a database dedicated to information on rare diseases and orphan drugs

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Orphaneti
99861, Precursor T-cell acute lymphoblastic leukemia
3338, Toriello-Carey syndrome
457260, X-linked intellectual disability-hypotonia-movement disorder syndrome

The Pharmacogenetics and Pharmacogenomics Knowledge Base

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PharmGKBi
PA27216

Miscellaneous databases

Pharos NIH Druggable Genome Knowledgebase

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Pharosi
O00571, Tchem

Chemistry databases

ChEMBL database of bioactive drug-like small molecules

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ChEMBLi
CHEMBL5553

Genetic variation databases

BioMuta curated single-nucleotide variation and disease association database

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BioMutai
DDX3X

<p>This section describes post-translational modifications (PTMs) and/or processing events.<p><a href='/help/ptm_processing_section' target='_top'>More...</a></p>PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
<p>This subsection of the <a href="http://www.uniprot.org/help/ptm_processing_section">PTM / Processing</a> section indicates that the initiator methionine is cleaved from the mature protein.<p><a href='/help/init_met' target='_top'>More...</a></p>Initiator methionineiRemovedCombined sources1 Publication
<p>This subsection of the 'PTM / Processing' section describes the extent of a polypeptide chain in the mature protein following processing or proteolytic cleavage.<p><a href='/help/chain' target='_top'>More...</a></p>ChainiPRO_00000550092 – 662ATP-dependent RNA helicase DDX3XAdd BLAST661

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
<p>This subsection of the 'PTM / Processing' section specifies the position and type of each modified residue excluding <a href="http://www.uniprot.org/manual/lipid">lipids</a>, <a href="http://www.uniprot.org/manual/carbohyd">glycans</a> and <a href="http://www.uniprot.org/manual/crosslnk">protein cross-links</a>.<p><a href='/help/mod_res' target='_top'>More...</a></p>Modified residuei2N-acetylserineCombined sources1 Publication1
Modified residuei55N6-acetyllysineBy similarity1
Modified residuei82PhosphoserineCombined sources1
Modified residuei86PhosphoserineCombined sources1
Modified residuei90PhosphoserineCombined sources1
Modified residuei101Omega-N-methylarginineBy similarity1
Modified residuei102Phosphoserine; by IKKE1 Publication1
Modified residuei104PhosphotyrosineBy similarity1
Modified residuei110Omega-N-methylarginineBy similarity1
Modified residuei118N6-acetyllysineCombined sources1
Modified residuei131PhosphoserineCombined sources1
Modified residuei181Phosphoserine; by TBK1; in vitro1 Publication1
Modified residuei183Phosphoserine; by TBK1Combined sources1 Publication1
<p>This subsection of the <a href="http://www.uniprot.org/help/ptm_processing_section">PTM / Processing</a> section describes <strong>covalent linkages</strong> of various types formed <strong>between two proteins (interchain cross-links)</strong> or <strong>between two parts of the same protein (intrachain cross-links)</strong>, except the disulfide bonds that are annotated in the <a href="http://www.uniprot.org/manual/disulfid">'Disulfide bond'</a> subsection.<p><a href='/help/crosslnk' target='_top'>More...</a></p>Cross-linki215Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO2)Combined sources
Modified residuei240Phosphoserine; by TBK1; in vitro1 Publication1
Modified residuei269Phosphoserine; by TBK1; in vitro1 Publication1
Modified residuei429Phosphoserine; by CSNK1E and TBK1; in vitro2 Publications1
Modified residuei438Phosphothreonine; by TBK1; in vitro1 Publication1
Modified residuei442Phosphoserine; by TBK1; in vitro1 Publication1
Modified residuei456Phosphoserine; by TBK1; in vitro1 Publication1
Modified residuei469Phosphothreonine; by CSNK1E; in vitro1 Publication1
Modified residuei470Phosphoserine; by CSNK1E; in vitro1 Publication1
Modified residuei520Phosphoserine; by TBK1; in vitro1 Publication1
Modified residuei542Phosphothreonine; by TBK1; in vitro1 Publication1
Modified residuei543Phosphoserine; by CSNK1E and TBK1; in vitro2 Publications1
Modified residuei592Omega-N-methylarginineCombined sources1
Modified residuei594PhosphoserineCombined sources1
Modified residuei605PhosphoserineCombined sources1
Modified residuei612PhosphoserineCombined sources1
Modified residuei617Omega-N-methylarginineCombined sources1
Modified residuei632Omega-N-methylarginineCombined sources1

<p>This subsection of the <a href="http://www.uniprot.org/help/ptm_processing_section">PTM/processing</a> section describes post-translational modifications (PTMs). This subsection <strong>complements</strong> the information provided at the sequence level or describes modifications for which <strong>position-specific data is not yet available</strong>.<p><a href='/help/post-translational_modification' target='_top'>More...</a></p>Post-translational modificationi

Phosphorylated by TBK1; the phosphorylation is required for the synergistic induction of IFNB mediated by TBK1 and DDX3X (PubMed:18583960). Phosphorylated by IKBKE at Ser-102 after ssRNA viral infection; enhances the induction of INFB promoter by IRF3 (PubMed:18583960, PubMed:23478265). The cytoplasmic form is highly phosphorylated in the G1/S phase of the cell cycle and much less at G2/M (PubMed:22034099). Phosphorylation by CSNK1E may inhibit RNA-stimulated ATPase activity (PubMed:29222110).4 Publications
Upon stimulation of death receptors, including TNFRSF10B, recruited to receptors and cleaved by caspases. Proteolytic fragments remain associated with the receptors. This cleavage presumably inactivates DDX3X anti-apoptotic function.1 Publication

Keywords - PTMi

Acetylation, Isopeptide bond, Methylation, Phosphoprotein, Ubl conjugation

Proteomic databases

Encyclopedia of Proteome Dynamics

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EPDi
O00571

jPOST - Japan Proteome Standard Repository/Database

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jPOSTi
O00571

MassIVE - Mass Spectrometry Interactive Virtual Environment

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MassIVEi
O00571

MaxQB - The MaxQuant DataBase

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MaxQBi
O00571

PaxDb, a database of protein abundance averages across all three domains of life

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PaxDbi
O00571

PeptideAtlas

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PeptideAtlasi
O00571

PRoteomics IDEntifications database

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PRIDEi
O00571

ProteomicsDB: a multi-organism proteome resource

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ProteomicsDBi
47982 [O00571-1]
47983 [O00571-2]

2D gel databases

REPRODUCTION-2DPAGE

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REPRODUCTION-2DPAGEi
IPI00215637

Two-dimensional polyacrylamide gel electrophoresis database from the Geneva University Hospital

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SWISS-2DPAGEi
O00571

PTM databases

CarbonylDB database of protein carbonylation sites

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CarbonylDBi
O00571

GlyGen: Computational and Informatics Resources for Glycoscience

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GlyGeni
O00571, 2 sites, 1 O-linked glycan (2 sites)

iPTMnet integrated resource for PTMs in systems biology context

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iPTMneti
O00571

MetOSite database of methionine sulfoxide sites

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MetOSitei
O00571

Comprehensive resource for the study of protein post-translational modifications (PTMs) in human, mouse and rat.

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PhosphoSitePlusi
O00571

SwissPalm database of S-palmitoylation events

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SwissPalmi
O00571

<p>This section provides information on the expression of a gene at the mRNA or protein level in cells or in tissues of multicellular organisms.<p><a href='/help/expression_section' target='_top'>More...</a></p>Expressioni

<p>This subsection of the 'Expression' section provides information on the expression of a gene at the mRNA or protein level in cells or in tissues of multicellular organisms. By default, the information is derived from experiments at the mRNA level, unless specified 'at protein level'.<br></br>Examples: <a href="http://www.uniprot.org/uniprot/P92958#expression">P92958</a>, <a href="http://www.uniprot.org/uniprot/Q8TDN4#expression">Q8TDN4</a>, <a href="http://www.uniprot.org/uniprot/O14734#expression">O14734</a><p><a href='/help/tissue_specificity' target='_top'>More...</a></p>Tissue specificityi

Widely expressed (PubMed:15294876). In testis, expressed in spermatids (PubMed:15294876). Expressed in epidermis and liver (at protein level) (PubMed:16818630, PubMed:16301996).3 Publications

Gene expression databases

Bgee dataBase for Gene Expression Evolution

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Bgeei
ENSG00000215301, Expressed in substantia nigra and 252 other tissues

ExpressionAtlas, Differential and Baseline Expression

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ExpressionAtlasi
O00571, baseline and differential

Genevisible search portal to normalized and curated expression data from Genevestigator

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Genevisiblei
O00571, HS

Organism-specific databases

Human Protein Atlas

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HPAi
ENSG00000215301, Low tissue specificity

<p>This section provides information on the quaternary structure of a protein and on interaction(s) with other proteins or protein complexes.<p><a href='/help/interaction_section' target='_top'>More...</a></p>Interactioni

<p>This subsection of the <a href="http://www.uniprot.org/help/interaction_section">'Interaction'</a> section provides information about the protein quaternary structure and interaction(s) with other proteins or protein complexes (with the exception of physiological receptor-ligand interactions which are annotated in the <a href="http://www.uniprot.org/help/function_section">'Function'</a> section).<p><a href='/help/subunit_structure' target='_top'>More...</a></p>Subunit structurei

Homodimer; can bind RNA as a monomer and as a dimer/oligomer (PubMed:27546789, PubMed:31300642).

Interacts with TDRD3 (PubMed:18632687).

Interacts (when phosphorylated at Ser-102) with IRF3; the interaction facilitates the phosphorylation and activation of IRF3 by IKBKE (PubMed:23478265, PubMed:27980081). Directly interacts with XPO1/CRM1 (PubMed:15507209, PubMed:30131165, PubMed:31575075). The interaction with XPO1/CMR1 is dependent on the DDX3X nuclear export signal motif and XPO1 interaction with GTPase RAN in its active GTP-bound form (PubMed:31575075, PubMed:30131165). Weakly interacts with TBKBP1/SINTBAD (PubMed:27980081). Directly interacts with TRAF3; this interaction stimulates TRAF3 'Lys-63' ubiquitination (PubMed:27980081).

Interacts with CSNK1E in a Wnt-dependent manner; this interaction greatly enhances CSNK1E affinity for ATP, stimulates its kinase activity and promotes CSNK1E-mediated DVL2 phosphorylation (PubMed:23413191, PubMed:29222110). In the presence of RNA, the interaction is decreased (PubMed:29222110).

Also interacts with CSNK1D and stimulates its kinase activity (PubMed:23413191, PubMed:29222110).

Interacts with TRPV4; this interaction is decreased when the TRPV4 channel is activated, leading to DDX3X relocalization to the nucleus (PubMed:29899501).

Interacts with MAP3K14/NIK (PubMed:30341167). Directly interacts with CHUK/IKKA after physiological activation of the TLR7 and TLR8 pathways; this interaction enhances CHUK autophosphorylation (PubMed:30341167). May associate with EIF4F complex, composed of at least EIF4A, EIF4E and EIF4G1/EIF4G3 (Probable). Directly interacts with EIF4E in an RNA-independent manner; this interaction enhances EIF4E cap-binding ability (PubMed:17667941, PubMed:21883093, PubMed:28733330). Directly interacts with EIF4G1 in an RNA-independent manner (PubMed:22872150). DDX3X competes with EIF4G1 for interaction with EIF4E (PubMed:17667941, PubMed:21883093).

Interacts with EIF4A1 and EIF2S1 in an RNA-independent manner (PubMed:18596238, PubMed:22323517). Associates with the eukaryotic translation initiation factor 3 (eIF-3) complex, including with EIF3B and EIF3C subunits (PubMed:18628297, PubMed:22323517). Directly interacts with IKBKE/IKKE; this interaction stimulates IKBKE activating autophosphorylation and is induced upon viral infection (PubMed:18636090, PubMed:20657822, PubMed:23478265, PubMed:27980081).

Interacts with TBK1 (PubMed:20375222).

Interacts with SP1; this interaction potentiates SP1-induced CDKN1A/WAF1/CIP1 transcription (PubMed:16818630).

Interacts with GSK3A and GSK3B (PubMed:18846110).

Interacts with several death receptors, inclusing FAS, TNFRSF10A and TNFRSF10B (PubMed:18846110). Recruited to TNFRSF10B in the absence of receptor stimulation. When TNFRSF10B is stimulated, further recruited to the receptor and cleaved by caspases. A large proteolytic fragment remains associated with TNFRSF10B (PubMed:18846110).

Interacts (via C-terminus) with NXF1/TAP; this interaction may be partly involved in DDX3X nuclear export and in NXF1 localization to stress granules (PubMed:18596238).

Identified in an mRNP complex, composed of at least DHX9, DDX3X, ELAVL1, HNRNPU, IGF2BP1/2, ILF3, PABPC1, PCBP2, PTBP2, STAU1, STAU2, SYNCRIP and YBX1 (PubMed:19029303). The interaction with IGF2BP1/2 is RNA-dependent (PubMed:22323517). Directly interacts with PABPC1/PABP1 in an RNA-independent manner (PubMed:18596238, PubMed:21883093, PubMed:22872150, PubMed:28733330). This interaction increases in stressed cells and decreases during cell recovery (PubMed:21883093).

Interacts (via C-terminus) with MAVS/IPS-1; this interaction occurs rapidly, but transiently after Sendai virus infection (PubMed:20127681, PubMed:21170385, PubMed:27980081). The interaction potentiates MAVS-mediated IFNB induction (PubMed:20127681, PubMed:21170385).

Interacts with ERCC6/CBS (PubMed:26030138).

Interacts with DHX33 in an RNA-independent manner (PubMed:26100019).

Interacts with DDX5 in the cytoplasm; this interaction may be more efficient when both proteins are unphosphorylated (PubMed:22034099).

Interacts with DDX58/RIG-1 (PubMed:20127681).

Interacts with IFIH1/MDA5 (PubMed:20127681).

Interacts with NCAPH; this interaction may be important for the NCAPH localization at condensing chromosomes during mitosis (PubMed:21730191).

Interacts with NLRP3 (via NACHT domain) under inflammasome-activating conditions (By similarity).

Interacts with CAPRIN1 (PubMed:28733330).

Interacts with HNF4A and NR0B2/SHP in an RNA-independent manner; this interaction disrupts the interaction between HNF4 and NR0B2 that forms inactive heterodimers and enhances the formation of active HNF4 homodimers (PubMed:28128295).

Interacts with CREBBP/CBP (PubMed:28128295).

Interacts with EP300/p300 (PubMed:28128295).

Interacts with gamma-tubulin (PubMed:28842590).

Interacts with phosphorylated TP53 (PubMed:28842590). Directly interacts with RELA/p65; this interaction may trap RELA in the cytoplasm, impairing nuclear relocalization upon TNF activating signals (PubMed:27736973).

By similarity5 Publications34 Publications

(Microbial infection) Interacts with hepatitis B virus (HBV) polymerase in the cytoplasm; this interaction may inhibit DDX3X interaction with the IKBKE/TBK1 complex, and hence impair IKBKE/TBK1-mediated increase in IFNB production.

2 Publications

(Microbial infection) Directly interacts with hepatitis C virus (HCV) core protein in the cytoplasm.

1 Publication

(Microbial infection) Interacts with vaccinia virus (VACV) protein K7.

2 Publications

(Microbial infection) Interacts with HIV-1 protein Rev.

1 Publication

(Microbial infection) Interacts with Venezuelan equine encephalitis virus non-structural protein 3.

1 Publication

<p>This subsection of the '<a href="http://www.uniprot.org/help/interaction_section">Interaction</a>' section provides information about binary protein-protein interactions. The data presented in this section are a quality-filtered subset of binary interactions automatically derived from the <a href="https://www.ebi.ac.uk/intact/">IntAct database</a>. It is updated at every <a href="http://www.uniprot.org/help/synchronization">UniProt release</a>.<p><a href='/help/binary_interactions' target='_top'>More...</a></p>Binary interactionsi

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GO - Molecular functioni

Protein-protein interaction databases

The Biological General Repository for Interaction Datasets (BioGRID)

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BioGRIDi
108020, 408 interactors

CORUM comprehensive resource of mammalian protein complexes

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CORUMi
O00571

Database of interacting proteins

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DIPi
DIP-27551N

The Eukaryotic Linear Motif resource for Functional Sites in Proteins

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ELMi
O00571

Protein interaction database and analysis system

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IntActi
O00571, 150 interactors

Molecular INTeraction database

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MINTi
O00571

STRING: functional protein association networks

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STRINGi
9606.ENSP00000382840

Chemistry databases

BindingDB database of measured binding affinities

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BindingDBi