Protein

ATP-dependent RNA helicase DDX3X

Gene

DDX3X

Organism

Homo sapiens (Human)

Status

Reviewed-Annotation score: -Experimental evidence at protein levelⁱ

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

Catalytic activityⁱ

ATP
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+
H₂O
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=
ADP
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+
H⁺
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+
phosphate
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5 Publications
Manual assertion based on experiment inⁱ
- Ref.10
  "Requirement of DDX3 DEAD box RNA helicase for HIV-1 Rev-RRE export function."
  Yedavalli V.S., Neuveut C., Chi Y.-H., Kleiman L., Jeang K.-T.
  Cell 119:381-392(2004) [PubMed] [Europe PMC] [Abstract]
  Cited for: FUNCTION, FUNCTION (MICROBIAL INFECTION), INTERACTION WITH XPO1, INTERACTION WITH HIV-1 PROTEIN REV (MICROBIAL INFECTION), MUTAGENESIS OF LYS-230 AND SER-382, SUBCELLULAR LOCATION, CATALYTIC ACTIVITY.
- Ref.15
  "Human DEAD-box ATPase DDX3 shows a relaxed nucleoside substrate specificity."
  Franca R., Belfiore A., Spadari S., Maga G.
  Proteins 67:1128-1137(2007) [PubMed] [Europe PMC] [Abstract]
  Cited for: FUNCTION, CATALYTIC ACTIVITY, BIOPHYSICOCHEMICAL PROPERTIES.
- Ref.35
  "A motif unique to the human DEAD-box protein DDX3 is important for nucleic acid binding, ATP hydrolysis, RNA/DNA unwinding and HIV-1 replication."
  Garbelli A., Beermann S., Di Cicco G., Dietrich U., Maga G.
  PLoS ONE 6:E19810-E19810(2011) [PubMed] [Europe PMC] [Abstract]
  Cited for: FUNCTION, FUNCTION (MICROBIAL INFECTION), CATALYTIC ACTIVITY, BIOPHYSICOCHEMICAL PROPERTIES, MUTAGENESIS OF LYS-230 AND 347-ASP--ASP-350.
- Ref.66
  "Exportin-1-Dependent Nuclear Export of DEAD-box Helicase DDX3X is Central to its Role in Antiviral Immunity."
  Heaton S.M., Atkinson S.C., Sweeney M.N., Yang S.N.Y., Jans D.A., Borg N.A.
  Cells 8:0-0(2019) [PubMed] [Europe PMC] [Abstract]
  Cited for: FUNCTION, CATALYTIC ACTIVITY, INTERACTION WITH XPO1, SUBCELLULAR LOCATION, NUCLEAR EXPORT SIGNAL, DOMAIN, MUTAGENESIS OF 12-LEU--LEU-21.
- Ref.70
  "The mechanism of RNA duplex recognition and unwinding by DEAD-box helicase DDX3X."
  Song H., Ji X.
  Nat. Commun. 10:3085-3085(2019) [PubMed] [Europe PMC] [Abstract]
  Cited for: X-RAY CRYSTALLOGRAPHY (2.50 ANGSTROMS) OF 132-607 IN COMPLEX WITH DSRNA, HOMODIMERIZATION, CATALYTIC ACTIVITY.
EC:
3.6.4.13
- Search proteins in UniProtKB for this EC number.
- See the description of this EC number in ENZYME.
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5 Publications
Manual assertion based on experiment inⁱ
- Ref.10
  "Requirement of DDX3 DEAD box RNA helicase for HIV-1 Rev-RRE export function."
  Yedavalli V.S., Neuveut C., Chi Y.-H., Kleiman L., Jeang K.-T.
  Cell 119:381-392(2004) [PubMed] [Europe PMC] [Abstract]
  Cited for: FUNCTION, FUNCTION (MICROBIAL INFECTION), INTERACTION WITH XPO1, INTERACTION WITH HIV-1 PROTEIN REV (MICROBIAL INFECTION), MUTAGENESIS OF LYS-230 AND SER-382, SUBCELLULAR LOCATION, CATALYTIC ACTIVITY.
- Ref.15
  "Human DEAD-box ATPase DDX3 shows a relaxed nucleoside substrate specificity."
  Franca R., Belfiore A., Spadari S., Maga G.
  Proteins 67:1128-1137(2007) [PubMed] [Europe PMC] [Abstract]
  Cited for: FUNCTION, CATALYTIC ACTIVITY, BIOPHYSICOCHEMICAL PROPERTIES.
- Ref.35
  "A motif unique to the human DEAD-box protein DDX3 is important for nucleic acid binding, ATP hydrolysis, RNA/DNA unwinding and HIV-1 replication."
  Garbelli A., Beermann S., Di Cicco G., Dietrich U., Maga G.
  PLoS ONE 6:E19810-E19810(2011) [PubMed] [Europe PMC] [Abstract]
  Cited for: FUNCTION, FUNCTION (MICROBIAL INFECTION), CATALYTIC ACTIVITY, BIOPHYSICOCHEMICAL PROPERTIES, MUTAGENESIS OF LYS-230 AND 347-ASP--ASP-350.
- Ref.66
  "Exportin-1-Dependent Nuclear Export of DEAD-box Helicase DDX3X is Central to its Role in Antiviral Immunity."
  Heaton S.M., Atkinson S.C., Sweeney M.N., Yang S.N.Y., Jans D.A., Borg N.A.
  Cells 8:0-0(2019) [PubMed] [Europe PMC] [Abstract]
  Cited for: FUNCTION, CATALYTIC ACTIVITY, INTERACTION WITH XPO1, SUBCELLULAR LOCATION, NUCLEAR EXPORT SIGNAL, DOMAIN, MUTAGENESIS OF 12-LEU--LEU-21.
- Ref.70
  "The mechanism of RNA duplex recognition and unwinding by DEAD-box helicase DDX3X."
  Song H., Ji X.
  Nat. Commun. 10:3085-3085(2019) [PubMed] [Europe PMC] [Abstract]
  Cited for: X-RAY CRYSTALLOGRAPHY (2.50 ANGSTROMS) OF 132-607 IN COMPLEX WITH DSRNA, HOMODIMERIZATION, CATALYTIC ACTIVITY.
Source:
Rhea
Search for this reaction in UniProtKB.
See the description of this reaction in Rhea.
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ATP
+
H₂O
=
ADP
+
H⁺
+
phosphate
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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

Regions

Feature key	Position(s)	DescriptionActions	Graphical view	Length
Nucleotide bindingⁱ	200 – 207	ATP		8
Nucleotide bindingⁱ	224 – 231	ATP		8

GO - Molecular functionⁱ

Complete GO annotation on QuickGO ...

GO - Biological processⁱ

Complete GO annotation on QuickGO ...

Keywordsⁱ

Molecular function	DNA-binding, Helicase, Hydrolase, RNA-binding
Biological process	Apoptosis, Chromosome partition, Host-virus interaction, Immunity, Innate immunity, Ribosome biogenesis, Transcription, Transcription regulation, Translation regulation
Ligand	ATP-binding, Nucleotide-binding

Enzyme and pathway databases

BRENDAⁱ	3.6.4.13, 2681
PathwayCommonsⁱ	O00571
Reactomeⁱ	R-HSA-6798695, Neutrophil degranulation
SignaLinkⁱ	O00571
SIGNORⁱ	O00571

Protein family/group databases

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

TCDBⁱ

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

Names & Taxonomyⁱ

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
Gene namesⁱ	Name:DDX3X Synonyms:DBX1 Publication, DDX3
Organismⁱ	Homo sapiens (Human)
Taxonomic identifierⁱ	9606 [NCBI]
Taxonomic lineageⁱ	cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Dipnotetrapodomorpha › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Boreoeutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo
Proteomesⁱ	UP000005640 Componentⁱ: Chromosome X

Organism-specific databases

Human Gene Nomenclature Database More...HGNCⁱ	HGNC:2745, DDX3X
MIMⁱ	300160, gene
neXtProtⁱ	NX_O00571
VEuPathDBⁱ	HostDB:ENSG00000215301

Keywords - Cellular componentⁱ

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

Pathology & Biotechⁱ

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 key	Position(s)	DescriptionActions	Length
Natural variantⁱVAR_075731	214	I → T in MRXSSB; loss-of-function mutation affecting regulation of Wnt signaling. 1 Publication	1
Natural variantⁱVAR_075732	233	A → V in MRXSSB. 1 PublicationCorresponds to variant dbSNP:rs796052223Ensembl.	1
Natural variantⁱVAR_075733	233	Missing in MRXSSB. 1 Publication	1
Natural variantⁱVAR_075734	235	L → P in MRXSSB. 1 PublicationCorresponds to variant dbSNP:rs796052224Ensembl.	1
Natural variantⁱVAR_075735	300	V → F in MRXSSB. 1 Publication	1
Natural variantⁱVAR_075736	326	R → H in MRXSSB; loss-of-function mutation affecting regulation of Wnt signaling. 1 PublicationCorresponds to variant dbSNP:rs797045025EnsemblClinVar.	1
Natural variantⁱVAR_075737	351	R → Q in MRXSSB. 1 PublicationCorresponds to variant dbSNP:rs1057518707EnsemblClinVar.	1
Natural variantⁱVAR_075738	362	R → C in MRXSSB. 1 PublicationCorresponds to variant dbSNP:rs797045026EnsemblClinVar.	1
Natural variantⁱVAR_075739	376	R → 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_075740	392	L → P in MRXSSB. 1 PublicationCorresponds to variant dbSNP:rs796052232EnsemblClinVar.	1
Natural variantⁱVAR_075741	417	Q → P in MRXSSB. 1 PublicationCorresponds to variant dbSNP:rs796052233Ensembl.	1
Natural variantⁱVAR_075742	475	R → G in MRXSSB. 1 PublicationCorresponds to variant dbSNP:rs1064794574EnsemblClinVar.	1
Natural variantⁱVAR_075743	480	R → S in MRXSSB. 1 Publication	1
Natural variantⁱVAR_075744	488	R → H in MRXSSB. 1 PublicationCorresponds to variant dbSNP:rs796052235EnsemblClinVar.	1
Natural variantⁱVAR_075745	507	I → T in MRXSSB; loss-of-function mutation affecting regulation of Wnt signaling. 1 PublicationCorresponds to variant dbSNP:rs797045024EnsemblClinVar.	1
Natural variantⁱVAR_075746	509	N → I in MRXSSB. 1 Publication	1
Natural variantⁱVAR_075747	514	I → T in MRXSSB. 1 PublicationCorresponds to variant dbSNP:rs796052226EnsemblClinVar.	1
Natural variantⁱVAR_075748	534	R → H in MRXSSB; loss-of-function mutation affecting regulation of Wnt signaling. 1 Publication	1
Natural variantⁱVAR_075749	560	Missing in MRXSSB. 1 Publication	1
Natural variantⁱVAR_075750	568	P → L in MRXSSB. 1 PublicationCorresponds to variant dbSNP:rs1057519430EnsemblClinVar.	1

Mutagenesis

Feature key	Position(s)	DescriptionActions	Length
Mutagenesisⁱ	12 – 21	LDQQFAGLDL → ADQQAAGADA: Impairs nuclear export and interaction with XPO1/CMR1. 1 Publication	10
Mutagenesisⁱ	19 – 21	LDL → ADA: Impairs nuclear export and interaction with XPO1/CMR1. 1 Publication	3
Mutagenesisⁱ	38	Y → 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 Publications	1
Mutagenesisⁱ	43	L → 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 Publications	1
Mutagenesisⁱ	71	S → A: Reduces total phosphorylation by 60%. No effect on interaction with IKBKE. 1 Publication	1
Mutagenesisⁱ	82 – 83	SS → AA: Reduces total phosphorylation by 50%. No effect on interaction with IKBKE. 1 Publication	2
Mutagenesisⁱ	84 – 85	FF → AA: Loss of interaction with VACV protein K7, IRF3 activation and IFNB1 promoter induction. 1 Publication	2
Mutagenesisⁱ	102	S → A: Reduces total phosphorylation by 30%. Abolishes interaction with IRF3 and fails to enhance IFNB promoter induction. No effect on interaction with IKBKE. 1 Publication	1
Mutagenesisⁱ	102	S → D: Interacts with IRF3 and enhances IFNB promoter induction. 1 Publication	1
Mutagenesisⁱ	142 – 144	PSE → ASA: Loss of interaction with TRAF3, reduced TRAF3 'K-63'-linked autoubiquitination. 1 Publication	3
Mutagenesisⁱ	152	S → A: Reduces total phosphorylation by 60%. No effect on interaction with IKBKE. 1 Publication	1
Mutagenesisⁱ	181	S → 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 Publication	1
Mutagenesisⁱ	183	S → 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 Publication	1
Mutagenesisⁱ	200	Y → A: No effect on general translation; when associated with A-207; A-230; A-347 and A-348. 1 Publication	1
Mutagenesisⁱ	207	Q → 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 Publications	1
Mutagenesisⁱ	230	K → A: No effect on general translation; when associated with A-200; A-207; A-347 and A-348. 1 Publication	1
Mutagenesisⁱ	230	K → 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 Publications	1
Mutagenesisⁱ	240	S → 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 Publication	1
Mutagenesisⁱ	269	S → 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 Publication	1
Mutagenesisⁱ	275 – 277	TRE → RRV: Increased NF-kappa-B-mediated transcriptional activity, contrary to wild-type which is inhibitory in this experimental setting. 1 Publication	3
Mutagenesisⁱ	347 – 350	DEAD → AEAA: Loss of ATPase activity. 1 Publication	4
Mutagenesisⁱ	347	D → A: No effect on general translation; when associated with A-200; A-207; A-230 and A-348. 1 Publication	1
Mutagenesisⁱ	348	E → A: No effect on general translation; when associated with A-200; A-207; A-230 and A-347. 2 Publications	1
Mutagenesisⁱ	348	E → 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 Publications	1
Mutagenesisⁱ	382 – 384	SAT → 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 Publications	3
Mutagenesisⁱ	382	S → 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 Publications	1
Mutagenesisⁱ	429	S → 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 Publication	1
Mutagenesisⁱ	438	T → 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 Publication	1
Mutagenesisⁱ	442	S → 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 Publication	1
Mutagenesisⁱ	456	S → 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 Publication	1
Mutagenesisⁱ	520	S → 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 Publication	1

Keywords - Diseaseⁱ

Disease variant, Mental retardation

Organism-specific databases

DisGeNET More...DisGeNETⁱ	1654
GeneReviewsⁱ	DDX3X
MalaCards human disease database More...MalaCardsⁱ	DDX3X
MIMⁱ	300958, phenotype
Open Targets More...OpenTargetsⁱ	ENSG00000215301
Orphanetⁱ	99861, Precursor T-cell acute lymphoblastic leukemia 3338, Toriello-Carey syndrome 457260, X-linked intellectual disability-hypotonia-movement disorder syndrome
PharmGKBⁱ	PA27216

Miscellaneous databases

Pharosⁱ	O00571, Tchem

Pharosⁱ

O00571, Tchem

Chemistry databases

ChEMBLⁱ	CHEMBL5553

ChEMBLⁱ

CHEMBL5553

Genetic variation databases

BioMutaⁱ	DDX3X

BioMutaⁱ

DDX3X

PTM / Processingⁱ

Molecule processing

Feature key	Position(s)	DescriptionActions	Graphical view	Length
Initiator methionineⁱ		RemovedCombined sources1 Publication
ChainⁱPRO_0000055009	2 – 662	ATP-dependent RNA helicase DDX3XAdd BLAST		661

Amino acid modifications

Feature key	Position(s)	DescriptionActions	Length
Modified residueⁱ	2	N-acetylserineCombined sources1 Publication	1
Modified residueⁱ	55	N6-acetyllysineBy similarity	1
Modified residueⁱ	82	PhosphoserineCombined sources	1
Modified residueⁱ	86	PhosphoserineCombined sources	1
Modified residueⁱ	90	PhosphoserineCombined sources	1
Modified residueⁱ	101	Omega-N-methylarginineBy similarity	1
Modified residueⁱ	102	Phosphoserine; by IKKE1 Publication	1
Modified residueⁱ	104	PhosphotyrosineBy similarity	1
Modified residueⁱ	110	Omega-N-methylarginineBy similarity	1
Modified residueⁱ	118	N6-acetyllysineCombined sources	1
Modified residueⁱ	131	PhosphoserineCombined sources	1
Modified residueⁱ	181	Phosphoserine; by TBK1; in vitro1 Publication	1
Modified residueⁱ	183	Phosphoserine; by TBK1Combined sources1 Publication	1
Cross-linkⁱ	215	Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO2)Combined sources
Modified residueⁱ	240	Phosphoserine; by TBK1; in vitro1 Publication	1
Modified residueⁱ	269	Phosphoserine; by TBK1; in vitro1 Publication	1
Modified residueⁱ	429	Phosphoserine; by CSNK1E and TBK1; in vitro2 Publications	1
Modified residueⁱ	438	Phosphothreonine; by TBK1; in vitro1 Publication	1
Modified residueⁱ	442	Phosphoserine; by TBK1; in vitro1 Publication	1
Modified residueⁱ	456	Phosphoserine; by TBK1; in vitro1 Publication	1
Modified residueⁱ	469	Phosphothreonine; by CSNK1E; in vitro1 Publication	1
Modified residueⁱ	470	Phosphoserine; by CSNK1E; in vitro1 Publication	1
Modified residueⁱ	520	Phosphoserine; by TBK1; in vitro1 Publication	1
Modified residueⁱ	542	Phosphothreonine; by TBK1; in vitro1 Publication	1
Modified residueⁱ	543	Phosphoserine; by CSNK1E and TBK1; in vitro2 Publications	1
Modified residueⁱ	592	Omega-N-methylarginineCombined sources	1
Modified residueⁱ	594	PhosphoserineCombined sources	1
Modified residueⁱ	605	PhosphoserineCombined sources	1
Modified residueⁱ	612	PhosphoserineCombined sources	1
Modified residueⁱ	617	Omega-N-methylarginineCombined sources	1
Modified residueⁱ	632	Omega-N-methylarginineCombined sources	1

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

EPDⁱ	O00571
jPOSTⁱ	O00571
MassIVEⁱ	O00571
MaxQB - The MaxQuant DataBase More...MaxQBⁱ	O00571
PaxDbⁱ	O00571
PeptideAtlas More...PeptideAtlasⁱ	O00571
PRIDEⁱ	O00571
ProteomicsDBⁱ	47982 [O00571-1] 47983 [O00571-2]

2D gel databases

REPRODUCTION-2DPAGE More...REPRODUCTION-2DPAGEⁱ	IPI00215637
SWISS-2DPAGEⁱ	O00571

PTM databases

CarbonylDBⁱ	O00571
GlyGenⁱ	O00571, 2 sites, 1 O-linked glycan (2 sites)
iPTMnetⁱ	O00571
MetOSiteⁱ	O00571
PhosphoSitePlusⁱ	O00571
SwissPalmⁱ	O00571

Expressionⁱ

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

Bgeeⁱ	ENSG00000215301, Expressed in substantia nigra and 252 other tissues
ExpressionAtlasⁱ	O00571, baseline and differential
Genevisibleⁱ	O00571, HS

Organism-specific databases

Human Protein Atlas More...HPAⁱ	ENSG00000215301, Low tissue specificity

HPAⁱ

ENSG00000215301, Low tissue specificity

Interactionⁱ

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

Binary interactionsⁱ

Hide details

O00571

With	#Exp.	IntAct
DCANP1 [Q8TF63]	3	EBI-353779,EBI-10275670
DDX58 [O95786]	2	EBI-353779,EBI-995350
EIF2S1 [P05198]	3	EBI-353779,EBI-1056162
EIF3B [P55884]	5	EBI-353779,EBI-366696
EIF3C [Q99613]	3	EBI-353779,EBI-353741
EIF4G1 [Q04637]	3	EBI-353779,EBI-73711
IKBKE [Q14164]	4	EBI-353779,EBI-307369
MAVS [Q7Z434]	4	EBI-353779,EBI-995373
MZT2A [Q6P582]	3	EBI-353779,EBI-2558548
NCAPH [Q15003]	2	EBI-353779,EBI-1046410
NXF1 [Q9UBU9]	5	EBI-353779,EBI-398874
PABPC1 [P11940]	10	EBI-353779,EBI-81531
TARDBP [Q13148]	6	EBI-353779,EBI-372899
TFF2 [Q03403]	3	EBI-353779,EBI-4314702
K7R [P68467] from Vaccinia virus (strain Copenhagen).	6	EBI-353779,EBI-8022707
L [P14240] from Lymphocytic choriomeningitis virus (strain Armstrong).	2	EBI-353779,EBI-26968662
PB2 [P03427] from Influenza A virus (strain A/Wilson-Smith/1933 H1N1).	3	EBI-353779,EBI-8430745
tat [P04608] from Human immunodeficiency virus type 1 group M subtype B (isolate HXB2).	4	EBI-353779,EBI-6164389
Trpm7 [Q923J1] from Mus musculus.	2	EBI-353779,EBI-8010314
VACWR039 [P68466] from Vaccinia virus (strain Western Reserve).	6	EBI-353779,EBI-6152154
Core protein precursor (PRO_0000037517) from Hepatitis C virus genotype 1a (isolate 1).	3	EBI-353779,EBI-9209740
Core protein precursor (PRO_0000037566) from Hepatitis C virus genotype 1a (isolate H77).	11	EBI-353779,EBI-6377335
Core protein precursor (PRO_0000037559) from Hepatitis C virus (isolate Glasgow).	4	EBI-353779,EBI-9254385
Q99IB8 from Hepatitis C virus genotype 2a (isolate JFH-1).	9	EBI-353779,EBI-6674379
Core protein precursor (PRO_0000037541) from Hepatitis C virus genotype 1b (isolate Con1).	4	EBI-353779,EBI-6863754

GO - Molecular functionⁱ

Complete GO annotation on QuickGO ...

Protein-protein interaction databases

BioGRIDⁱ	108020, 437 interactors
CORUMⁱ	O00571
Database of interacting proteins More...DIPⁱ	DIP-27551N
ELMⁱ	O00571
IntActⁱ	O00571, 153 interactors
Molecular INTeraction database More...MINTⁱ	O00571
STRINGⁱ	9606.ENSP00000382840

Chemistry databases

BindingDBⁱ	O00571

BindingDBⁱ

O00571

Miscellaneous databases

RNActⁱ	O00571, protein

RNActⁱ

O00571, protein

UniProtKB

UniParc

Help

UniRef

Proteomes

Annotation systems

Supporting data

UniProtKB - O00571 (DDX3X_HUMAN)

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ATP-dependent RNA helicase DDX3X

DDX3X

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<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

Miscellaneous

Caution

<p>This subsection of the <a href="http://www.uniprot.org/help/function%5Fsection">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

Regions

<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

Enzyme and pathway databases

Protein family/group databases

<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

Organism-specific databases

<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

Nucleus

Cytoplasm and Cytosol

Plasma membrane

Cytoskeleton

Other locations

Cytoskeleton

Cytosol

Extracellular region or secreted

Nucleus

Plasma Membrane

Other locations

Keywords - Cellular componenti

<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

Mutagenesis

Keywords - Diseasei

Organism-specific databases

Miscellaneous databases

Chemistry databases

Genetic variation databases

<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

Amino acid modifications

Keywords - PTMi

Proteomic databases

2D gel databases

PTM databases

<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

Gene expression databases

Organism-specific databases

<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

O00571

GO - Molecular functioni

Protein-protein interaction databases

Chemistry databases

Miscellaneous databases

<p>This section provides information on the tertiary and secondary structure of a protein.<p><a href='/help/structure_section' target='_top'>More...</a></p>Structurei<

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Functionⁱ

Catalytic activityⁱ

Kineticsⁱ

GO - Molecular functionⁱ

GO - Biological processⁱ

Names & Taxonomyⁱ

Subcellular locationⁱ

Keywords - Cellular componentⁱ

Pathology & Biotechⁱ

Keywords - Diseaseⁱ

PTM / Processingⁱ

Keywords - PTMⁱ

Expressionⁱ

Interactionⁱ

GO - Molecular functionⁱ

Structure^i<