DDX3X_MOUSE
ID DDX3X_MOUSE Reviewed; 662 AA.
AC Q62167; O09060; O09143;
DT 01-NOV-1997, integrated into UniProtKB/Swiss-Prot.
DT 23-JAN-2007, sequence version 3.
DT 03-AUG-2022, entry version 198.
DE RecName: Full=ATP-dependent RNA helicase DDX3X;
DE EC=3.6.4.13 {ECO:0000250|UniProtKB:O00571};
DE AltName: Full=D1Pas1-related sequence 2;
DE AltName: Full=DEAD box RNA helicase DEAD3;
DE Short=mDEAD3 {ECO:0000303|PubMed:8144024};
DE AltName: Full=DEAD box protein 3, X-chromosomal;
DE AltName: Full=Embryonic RNA helicase {ECO:0000303|PubMed:8948440};
GN Name=Ddx3x;
GN Synonyms=D1Pas1-rs2, Ddx3, Dead3, Erh {ECO:0000303|PubMed:8948440};
OS Mus musculus (Mouse).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Mus; Mus.
OX NCBI_TaxID=10090;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], TISSUE SPECIFICITY, AND DEVELOPMENTAL STAGE.
RC STRAIN=C57BL/6J; TISSUE=Notochord;
RX PubMed=8948440; DOI=10.1042/bj3080839;
RA Sowden J.C., Putt W., Morrison K., Beddington R., Edwards Y.;
RT "The embryonic RNA helicase gene (ERH): a new member of the DEAD box family
RT of RNA helicases.";
RL Biochem. J. 308:839-846(1995).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Erythroleukemia;
RX PubMed=8144024; DOI=10.1016/0378-1119(94)90541-x;
RA Gee S.L., Conboy J.G.;
RT "Mouse erythroid cells express multiple putative RNA helicase genes
RT exhibiting high sequence conservation from yeast to mammals.";
RL Gene 140:171-177(1994).
RN [3]
RP PROTEIN SEQUENCE OF 2-10, AND ACETYLATION AT SER-2.
RX PubMed=10859333; DOI=10.1084/jem.191.12.2083;
RA Yaguee J., Alvarez I., Rognan D., Ramos M., Vazquez J.,
RA Lopez de Castro J.A.;
RT "An N-acetylated natural ligand of human histocompatibility leukocyte
RT antigen (HLA)-B39. Classical major histocompatibility complex class I
RT proteins bind peptides with a blocked NH(2) terminus in vivo.";
RL J. Exp. Med. 191:2083-2092(2000).
RN [4]
RP PROTEIN SEQUENCE OF 535-548, AND IDENTIFICATION BY MASS SPECTROMETRY.
RC TISSUE=Hippocampus;
RA Lubec G., Klug S.;
RL Submitted (MAR-2007) to UniProtKB.
RN [5]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-104, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=15592455; DOI=10.1038/nbt1046;
RA Rush J., Moritz A., Lee K.A., Guo A., Goss V.L., Spek E.J., Zhang H.,
RA Zha X.-M., Polakiewicz R.D., Comb M.J.;
RT "Immunoaffinity profiling of tyrosine phosphorylation in cancer cells.";
RL Nat. Biotechnol. 23:94-101(2005).
RN [6]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-131, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Liver;
RX PubMed=17242355; DOI=10.1073/pnas.0609836104;
RA Villen J., Beausoleil S.A., Gerber S.A., Gygi S.P.;
RT "Large-scale phosphorylation analysis of mouse liver.";
RL Proc. Natl. Acad. Sci. U.S.A. 104:1488-1493(2007).
RN [7]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Heart, Kidney, Liver, Lung, Pancreas, and Spleen;
RX PubMed=21183079; DOI=10.1016/j.cell.2010.12.001;
RA Huttlin E.L., Jedrychowski M.P., Elias J.E., Goswami T., Rad R.,
RA Beausoleil S.A., Villen J., Haas W., Sowa M.E., Gygi S.P.;
RT "A tissue-specific atlas of mouse protein phosphorylation and expression.";
RL Cell 143:1174-1189(2010).
RN [8]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-55, AND IDENTIFICATION BY MASS
RP SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Embryonic fibroblast;
RX PubMed=23806337; DOI=10.1016/j.molcel.2013.06.001;
RA Park J., Chen Y., Tishkoff D.X., Peng C., Tan M., Dai L., Xie Z., Zhang Y.,
RA Zwaans B.M., Skinner M.E., Lombard D.B., Zhao Y.;
RT "SIRT5-mediated lysine desuccinylation impacts diverse metabolic
RT pathways.";
RL Mol. Cell 50:919-930(2013).
RN [9]
RP SUBCELLULAR LOCATION, TISSUE SPECIFICITY, AND DEVELOPMENTAL STAGE.
RX PubMed=25050112; DOI=10.7555/jbr.27.20130047;
RA Li Q., Zhang P., Zhang C., Wang Y., Wan R., Yang Y., Guo X., Huo R.,
RA Lin M., Zhou Z., Sha J.;
RT "DDX3X regulates cell survival and cell cycle during mouse early embryonic
RT development.";
RL J. Biomed. Res. 28:282-291(2014).
RN [10]
RP METHYLATION [LARGE SCALE ANALYSIS] AT ARG-101; ARG-110 AND ARG-632, AND
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Brain, and Embryo;
RX PubMed=24129315; DOI=10.1074/mcp.o113.027870;
RA Guo A., Gu H., Zhou J., Mulhern D., Wang Y., Lee K.A., Yang V., Aguiar M.,
RA Kornhauser J., Jia X., Ren J., Beausoleil S.A., Silva J.C., Vemulapalli V.,
RA Bedford M.T., Comb M.J.;
RT "Immunoaffinity enrichment and mass spectrometry analysis of protein
RT methylation.";
RL Mol. Cell. Proteomics 13:372-387(2014).
RN [11]
RP DISRUPTION PHENOTYPE, DEVELOPMENTAL STAGE, AND CHROMOSOMAL INACTIVATION.
RX PubMed=27179789; DOI=10.1093/hmg/ddw143;
RA Chen C.Y., Chan C.H., Chen C.M., Tsai Y.S., Tsai T.Y., Wu Lee Y.H.,
RA You L.R.;
RT "Targeted inactivation of murine Ddx3x: essential roles of Ddx3x in
RT placentation and embryogenesis.";
RL Hum. Mol. Genet. 25:2905-2922(2016).
RN [12]
RP FUNCTION, INTERACTION WITH NLRP3, AND SUBCELLULAR LOCATION.
RX PubMed=31511697; DOI=10.1038/s41586-019-1551-2;
RA Samir P., Kesavardhana S., Patmore D.M., Gingras S., Malireddi R.K.S.,
RA Karki R., Guy C.S., Briard B., Place D.E., Bhattacharya A., Sharma B.R.,
RA Nourse A., King S.V., Pitre A., Burton A.R., Pelletier S., Gilbertson R.J.,
RA Kanneganti T.D.;
RT "DDX3X acts as a live-or-die checkpoint in stressed cells by regulating
RT NLRP3 inflammasome.";
RL Nature 573:590-594(2019).
RN [13]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=30475900; DOI=10.1371/journal.ppat.1007397;
RA Szappanos D., Tschismarov R., Perlot T., Westermayer S., Fischer K.,
RA Platanitis E., Kallinger F., Novatchkova M., Lassnig C., Mueller M.,
RA Sexl V., Bennett K.L., Foong-Sobis M., Penninger J.M., Decker T.;
RT "The RNA helicase DDX3X is an essential mediator of innate antimicrobial
RT immunity.";
RL PLoS Pathog. 14:E1007397-E1007397(2018).
RN [14]
RP DISRUPTION PHENOTYPE.
RX PubMed=30613052; DOI=10.1262/jrd.2018-145;
RA Matsumura T., Endo T., Isotani A., Ogawa M., Ikawa M.;
RT "An azoospermic factor gene, Ddx3y and its paralog, Ddx3x are dispensable
RT in germ cells for male fertility.";
RL J. Reprod. Dev. 65:121-128(2019).
CC -!- FUNCTION: Multifunctional ATP-dependent RNA helicase. The ATPase
CC activity can be stimulated by various ribo-and deoxynucleic acids
CC indicative for a relaxed substrate specificity. In vitro can unwind
CC partially double-stranded DNA with a preference for 5'-single-stranded
CC DNA overhangs. Binds RNA G-quadruplex (rG4s) structures, including
CC those located in the 5'-UTR of NRAS mRNA. Involved in many cellular
CC processes, which do not necessarily require its ATPase/helicase
CC catalytic activities. Involved in transcription regulation. Positively
CC regulates CDKN1A/WAF1/CIP1 transcription in an SP1-dependent manner,
CC hence inhibits cell growth. This function requires its ATPase, but not
CC helicase activity. CDKN1A up-regulation may be cell-type specific.
CC Binds CDH1/E-cadherin promoter and represses its transcription.
CC Potentiates HNF4A-mediated MTTP transcriptional activation; this
CC function requires ATPase, but not helicase activity. Facilitates HNF4A
CC acetylation, possibly catalyzed by CREBBP/EP300, thereby increasing the
CC DNA-binding affinity of HNF4 to its response element. In addition,
CC disrupts the interaction between HNF4 and SHP that forms inactive
CC heterodimers and enhances the formation of active HNF4 homodimers. By
CC promoting HNF4A-induced MTTP expression, may play a role in lipid
CC homeostasis. May positively regulate TP53 transcription. Associates
CC with mRNPs, predominantly with spliced mRNAs carrying an exon junction
CC complex (EJC). Involved in the regulation of translation initiation.
CC Not involved in the general process of translation, but promotes
CC efficient translation of selected complex mRNAs, containing highly
CC structured 5'-untranslated regions (UTR). This function depends on
CC helicase activity. Might facilitate translation by resolving secondary
CC structures of 5'-UTRs during ribosome scanning. Alternatively, may act
CC prior to 43S ribosomal scanning and promote 43S pre-initiation complex
CC entry to mRNAs exhibiting specific RNA motifs, by performing local
CC remodeling of transcript structures located close to the cap moiety.
CC Independently of its ATPase activity, promotes the assembly of
CC functional 80S ribosomes and disassembles from ribosomes prior to the
CC translation elongation process. Positively regulates the translation of
CC cyclin E1/CCNE1 mRNA and consequently promotes G1/S-phase transition
CC during the cell cycle. May activate TP53 translation. Required for
CC endoplasmic reticulum stress-induced ATF4 mRNA translation.
CC Independently of its ATPase/helicase activity, enhances IRES-mediated
CC translation; this activity requires interaction with EIF4E.
CC Independently of its ATPase/helicase activity, has also been shown
CC specifically repress cap-dependent translation, possibly by acting on
CC translation initiation factor EIF4E. Involved in innate immunity,
CC acting as a viral RNA sensor. Binds viral RNAs and promotes the
CC production of type I interferon (IFN-alpha and IFN-beta). Potentiate
CC MAVS/DDX58-mediated induction of IFNB in early stages of infection (By
CC similarity). Enhances IFNB1 expression via IRF3/IRF7 pathway and
CC participates in NFKB activation in the presence of MAVS and TBK1
CC (PubMed:30475900). Involved in TBK1 and IKBKE-dependent IRF3 activation
CC leading to IFNB induction, acts as a scaffolding adapter that links
CC IKBKE and IRF3 and coordinates their activation. Involved in the
CC TLR7/TLR8 signaling pathway leading to type I interferon induction,
CC including IFNA4 production. In this context, acts as an upstream
CC regulator of IRF7 activation by MAP3K14/NIK and CHUK/IKKA. Stimulates
CC CHUK autophosphorylation and activation following physiological
CC activation of the TLR7 and TLR8 pathways, leading to MAP3K14/CHUK-
CC mediated activatory phosphorylation of IRF7. Also stimulates
CC MAP3K14/CHUK-dependent NF-kappa-B signaling. Negatively regulates TNF-
CC induced IL6 and IL8 expression, via the NF-kappa-B pathway. May act by
CC interacting with RELA/p65 and trapping it in the cytoplasm. May also
CC bind IFNB promoter; the function is independent of IRF3 (By
CC similarity). Involved in both stress and inflammatory responses
CC (PubMed:31511697). Independently of its ATPase/helicase activity,
CC required for efficient stress granule assembly through its interaction
CC with EIF4E, hence promotes survival in stressed cells (By similarity).
CC Independently of its helicase activity, regulates NLRP3 inflammasome
CC assembly through interaction with NLRP3 and hence promotes cell death
CC by pyroptosis during inflammation. This function is independent of
CC helicase activity. Therefore DDX3X availability may be used to
CC interpret stress signals and choose between pro-survival stress
CC granules and pyroptotic NLRP3 inflammasomes and serve as a live-or-die
CC checkpoint in stressed cells (PubMed:31511697). In association with
CC GSK3A/B, negatively regulates extrinsic apoptotic signaling pathway via
CC death domain receptors, including TNFRSF10B, slowing down the rate of
CC CASP3 activation following death receptor stimulation. Cleavage by
CC caspases may inactivate DDX3X and relieve the inhibition. Independently
CC of its ATPase/helicase activity, allosteric activator of CSNK1E.
CC Stimulates CSNK1E-mediated phosphorylation of DVL2, thereby involved in
CC the positive regulation of Wnt/beta-catenin signaling pathway. Also
CC activates CSNK1A1 and CSNK1D in vitro, but it is uncertain if these
CC targets are physiologically relevant. ATPase and casein kinase-
CC activating functions are mutually exclusive. May be involved in mitotic
CC chromosome segregation (By similarity). {ECO:0000250|UniProtKB:O00571,
CC ECO:0000269|PubMed:30475900, ECO:0000269|PubMed:31511697}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + H2O = ADP + H(+) + phosphate; Xref=Rhea:RHEA:13065,
CC ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:30616,
CC ChEBI:CHEBI:43474, ChEBI:CHEBI:456216; EC=3.6.4.13;
CC Evidence={ECO:0000250|UniProtKB:O00571};
CC -!- SUBUNIT: Homodimer; can bind RNA as a monomer and as a dimer/oligomer.
CC Interacts with TDRD3. When phosphorylated, interacts with IRF3; the
CC interaction facilitates the phosphorylation and activation of IRF3 by
CC IKBKE. Directly interacts with XPO1/CRM1. The interaction with
CC XPO1/CMR1 is dependent on the DDX3X nuclear export signal motif and
CC XPO1 interaction with GTPase RAN in its active GTP-bound form. Weakly
CC interacts with TBKBP1/SINTBAD. Directly interacts with TRAF3; this
CC interaction stimulates TRAF3 'Lys-63' ubiquitination. Interacts with
CC CSNK1E in a Wnt-dependent manner; this interaction greatly enhances
CC CSNK1E affinity for ATP, stimulates its kinase activity and promotes
CC CSNK1E-mediated DVL2 phosphorylation. In the presence of RNA, the
CC interaction is decreased. Also interacts with CSNK1D and stimulates its
CC kinase activity. Interacts with TRPV4; this interaction is decreased
CC when the TRPV4 channel is activated, leading to DDX3X relocalization to
CC the nucleus. Interacts with MAP3K14/NIK. Directly interacts with
CC CHUK/IKKA after physiological activation of the TLR7 and TLR8 pathways;
CC this interaction enhances CHUK autophosphorylation. May associate with
CC EIF4F complex, composed of at least EIF4A, EIF4E and EIF4G1/EIF4G3.
CC Directly interacts with EIF4E in an RNA-independent manner; this
CC interaction enhances EIF4E cap-binding ability. Directly interacts with
CC EIF4G1 in an RNA-independent manner. DDX3X competes with EIF4G1 for
CC interaction with EIF4E. Interacts with EIF4A1 and EIF2S1 in an RNA-
CC independent manner. Associates with the eukaryotic translation
CC initiation factor 3 (eIF-3) complex, including with EIF3B and EIF3C
CC subunits. Directly interacts with IKBKE/IKKE; this interaction
CC stimulates IKBKE activating autophosphorylation and is induced upon
CC viral infection. Interacts with TBK1. Interacts with SP1; this
CC interaction potentiates SP1-induced CDKN1A/WAF1/CIP1 transcription.
CC Interacts with GSK3A and GSK3B. Interacts with several death receptors,
CC inclusing FAS, TNFRSF10A and TNFRSF10B. Recruited to TNFRSF10B in the
CC absence of receptor stimulation. When TNFRSF10B is stimulated, further
CC recruited to the receptor and cleaved by caspases. A large proteolytic
CC fragment remains associated with TNFRSF10B. Interacts (via C-terminus)
CC with NXF1/TAP; this interaction may be partly involved in DDX3X nuclear
CC export and in NXF1 localization to stress granules. Identified in an
CC mRNP complex, composed of at least DHX9, DDX3X, ELAVL1, HNRNPU,
CC IGF2BP1/2, ILF3, PABPC1, PCBP2, PTBP2, STAU1, STAU2, SYNCRIP and YBX1.
CC The interaction with IGF2BP1/2 is RNA-dependent. Directly interacts
CC with PABPC1/PABP1 in an RNA-independent manner. This interaction
CC increases in stressed cells and decreases during cell recovery.
CC Interacts (via C-terminus) with MAVS/IPS-1; this interaction
CC potentiates MAVS-mediated IFNB induction. Interacts with ERCC6/CBS.
CC Interacts with DHX33 in an RNA-independent manner. Interacts with DDX5
CC in the cytoplasm; this interaction may be more efficient when both
CC proteins are unphosphorylated. Interacts with DDX58/RIG-1. Interacts
CC with IFIH1/MDA5. Interacts with NCAPH; this interaction may be
CC important for the NCAPH localization at condensing chromosomes during
CC mitosis (By similarity). Interacts with NLRP3 (via NACHT domain) under
CC inflammasome-activating conditions (PubMed:31511697). Interacts with
CC CAPRIN1. Interacts with HNF4A and NR0B2/SHP in an RNA-independent
CC manner; this interaction disrupts the interaction between HNF4 and
CC NR0B2 that forms inactive heterodimers and enhances the formation of
CC active HNF4 homodimers. Interacts with CREBBP/CBP. Interacts with
CC EP300/p300. Interacts with gamma-tubulin. Interacts with phosphorylated
CC TP53. Directly interacts with RELA/p65; this interaction may trap RELA
CC in the cytoplasm, impairing nuclear relocalization upon TNF activating
CC signals (By similarity). {ECO:0000250|UniProtKB:O00571,
CC ECO:0000269|PubMed:31511697}.
CC -!- INTERACTION:
CC Q62167; Q9UHD2: TBK1; Xeno; NbExp=8; IntAct=EBI-773173, EBI-356402;
CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000250|UniProtKB:O00571}.
CC Nucleus {ECO:0000269|PubMed:25050112}. Cytoplasm
CC {ECO:0000269|PubMed:25050112}. Cytoplasm, Stress granule
CC {ECO:0000269|PubMed:31511697}. Inflammasome
CC {ECO:0000269|PubMed:31511697}. Cell projection, lamellipodium
CC {ECO:0000250|UniProtKB:O00571}. Note=Shuttles between the nucleus and
CC the cytosol. Exported from the nucleus partly through the XPO1/CRM1
CC system and partly through NXF1/TAP. Localizes to nuclear pores on the
CC outer side of the nuclear membrane. In the cytosol, partly colocalizes
CC with mitochondria. At G0, predominantly located in nucleus. In G1/S
CC phase, predominantly cytoplasmic. During prophase/prometaphase,
CC localizes in close proximity to the condensing chromosomes. During
CC telophase, localizes around the newly synthesized nuclear membrane and
CC in the cytoplasm. Colocalizes with TRPV4 at the plasma membrane. When
CC TRPV4 channel is activated, intracellular Ca(2+) levels increase and
CC the calmodulin/CAMKII pathway is activated, relocalizes to the nucleus.
CC WNT3A stimulation promotes DDX3 recruitment to the plasma membrane.
CC {ECO:0000250|UniProtKB:O00571}.
CC -!- TISSUE SPECIFICITY: Expressed in ovary, including in germinal vesicle
CC immature and metaphase II (MII) stage oocytes (at protein level)
CC (PubMed:8948440, PubMed:25050112). In the brain, expressed in the
CC granule cells of the cerebellum and dentate gyrus, the pyramidal cells
CC of the hippocampus, the ependymal cells lining the ventricles, choroid
CC plexi and olfactory bulb. Also accumulates in the thalamic nuclei, the
CC dorsal region of the colliculi and the pontine nucleus
CC (PubMed:8948440). {ECO:0000269|PubMed:25050112,
CC ECO:0000269|PubMed:8948440}.
CC -!- DEVELOPMENTAL STAGE: In oocytes, expression levels increase from
CC germinal vesicle immature oocytes to metaphase II (MII) and decline
CC after fertilization in 1-cell and 2-cell embryos (at protein level)
CC (PubMed:25050112). At 7.5 dpc, highly expressed in all embryonic cells
CC and extraembryonic tissues, including ectoplacental cone, chorion,
CC extraembryonic endoderm and parietal endoderm (at protein level)
CC (PubMed:27179789). At 8.5-9.5 dpc, widely expressed (PubMed:8948440).
CC At 8.5 dpc, levels decrease in extraembryonic tissues
CC (PubMed:27179789). As development proceeds, expression becomes more
CC restricted. At 11.5 dpc, most abundant in the neural tube, but still
CC expressed at moderate levels in a number of other sites, including the
CC mesenchyme of limbs and the face and in liver. At 14.5 dpc, highly
CC expressed in the developing brain and caudal neural tube, but absent
CC from the marginal layer of the neural tube. Also expressed in the
CC developing metanephros and lung. At 15.5 dpc, expressed in the brain
CC and spinal cord, as well as in teeth primordia, the lung and in the
CC developing limb (PubMed:8948440). At 16.5 dpc, moderate, but non-
CC uniform expression levels in the placenta (PubMed:27179789).
CC {ECO:0000269|PubMed:25050112, ECO:0000269|PubMed:27179789,
CC ECO:0000269|PubMed:8948440}.
CC -!- DOMAIN: The C-terminus (residues 536-662) is dispensable for DDX3X
CC trafficking. {ECO:0000250|UniProtKB:O00571}.
CC -!- PTM: Phosphorylated by TBK1; the phosphorylation is required for the
CC synergistic induction of IFNB mediated by TBK1 and DDX3X.
CC Phosphorylated by IKBKE. Also phosphorylated by CSNK1E; this
CC phosphorylation may inhibit RNA-stimulated ATPase activity.
CC {ECO:0000250|UniProtKB:O00571}.
CC -!- PTM: Upon stimulation of death receptors, including TNFRSF10B,
CC recruited to receptors and cleaved by caspases. Proteolytic fragments
CC remain associated with the receptors. This cleavage presumably
CC inactivates DDX3X anti-apoptotic function.
CC {ECO:0000250|UniProtKB:O00571}.
CC -!- DISRUPTION PHENOTYPE: In mutant males, loss of DDX3X leads to early
CC post-implantation lethality. In mutant females with a maternally
CC inherited Ddx3x null allele, paternal X chromosome inactivation affects
CC trophoblast differentiation, which leads to aberrant placental layers
CC and defective vascularization in placental labyrinth. These placental
CC abnormalities impair maternal blood supply to the embryo and ultimately
CC lead to fetal growth restriction and lethality. Heterozygous females
CC with a paternally inherited null allele are born at the expected
CC Mendelian ratio, develop normally and are indistinguishable from their
CC littermate controls (PubMed:27179789). Epiblast-specific knockout
CC embryos exhibit multiple anomalies, including defective neural tube
CC closure, underdeveloped brain, poorly developed myocardial trabeculae,
CC which ultimately lead to embryonic lethality around 11.5 dpc
CC (PubMed:27179789). DDX3X and DDX3Y double knockout is embryonic lethal
CC (PubMed:30613052). DDX3X and DDX3Y double knockout germ cells can
CC differentiate into spermatozoa (PubMed:30613052). Bone-marrow
CC macrophage-specific knockout leads to a reduction in the expression of
CC several cytokines, including IL1B, IL6, IL12 and IFNB1, in response to
CC Listeria monocytogenes infection and pathogen-associated molecular
CC patterns (PAMPs), including poly (I:C), poly (dA:dT) and LPS. This
CC effect is more prononced in females than in male macrophages, probably
CC due to the functional redundancy with DDX3Y gene located on chromosome
CC Y (PubMed:30475900). {ECO:0000269|PubMed:27179789,
CC ECO:0000269|PubMed:30475900, ECO:0000269|PubMed:30613052}.
CC -!- MISCELLANEOUS: Encoded by an chromosome X-linked gene which escapes X
CC chromosome inactivation (XCI) in females, but exhibits
CC developmental- and tissue-specific differences in escape from XCI.
CC DDX3Y, its homolog on chromosome Y, is located in the Y non-recombinant
CC portion (By similarity). In 8 to 16 cell stage embryos, expression from
CC paternal and maternal copies of DDX3X is detected. Paternally derived
CC DDX3X is preferentially inactivated in extraembryonic tissues of
CC embryos from 6.5 dpc (PubMed:27179789). {ECO:0000250|UniProtKB:O00571,
CC ECO:0000269|PubMed:27179789}.
CC -!- SIMILARITY: Belongs to the DEAD box helicase family. DDX3/DED1
CC subfamily. {ECO:0000305}.
CC -!- CAUTION: The role of the nuclear export signal (NES) motif in XPO1-
CC mediated DDX3X export is controversial (By similarity). In one study,
CC NES has been found dispensable for DDX3X export while the helicase
CC domain mediates the interaction with XPO1 (By similarity). However, in
CC two other studies, DDX3X nuclear export is dependent on both NES and
CC Ran in its GTP-bound form while the helicase domain is not required (By
CC similarity). {ECO:0000250|UniProtKB:O00571}.
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DR EMBL; Z38117; CAA86261.1; -; mRNA.
DR EMBL; L25126; AAA53630.1; -; mRNA.
DR CCDS; CCDS30027.1; -.
DR PIR; I84741; I84741.
DR RefSeq; NP_034158.1; NM_010028.3.
DR AlphaFoldDB; Q62167; -.
DR SMR; Q62167; -.
DR BioGRID; 199084; 84.
DR IntAct; Q62167; 15.
DR MINT; Q62167; -.
DR STRING; 10090.ENSMUSP00000000804; -.
DR ChEMBL; CHEMBL3751657; -.
DR iPTMnet; Q62167; -.
DR PhosphoSitePlus; Q62167; -.
DR SwissPalm; Q62167; -.
DR REPRODUCTION-2DPAGE; Q62167; -.
DR EPD; Q62167; -.
DR jPOST; Q62167; -.
DR MaxQB; Q62167; -.
DR PaxDb; Q62167; -.
DR PRIDE; Q62167; -.
DR ProteomicsDB; 279851; -.
DR Antibodypedia; 463; 712 antibodies from 41 providers.
DR DNASU; 13205; -.
DR Ensembl; ENSMUST00000000804; ENSMUSP00000000804; ENSMUSG00000000787.
DR GeneID; 13205; -.
DR KEGG; mmu:13205; -.
DR UCSC; uc009srl.2; mouse.
DR CTD; 1654; -.
DR MGI; MGI:103064; Ddx3x.
DR VEuPathDB; HostDB:ENSMUSG00000000787; -.
DR eggNOG; KOG0335; Eukaryota.
DR GeneTree; ENSGT00940000154443; -.
DR HOGENOM; CLU_003041_16_3_1; -.
DR InParanoid; Q62167; -.
DR OMA; IMRGQPV; -.
DR OrthoDB; 595675at2759; -.
DR PhylomeDB; Q62167; -.
DR TreeFam; TF300332; -.
DR BRENDA; 3.6.4.13; 3474.
DR Reactome; R-MMU-6798695; Neutrophil degranulation.
DR BioGRID-ORCS; 13205; 26 hits in 76 CRISPR screens.
DR ChiTaRS; Ddx3x; mouse.
DR PRO; PR:Q62167; -.
DR Proteomes; UP000000589; Chromosome X.
DR RNAct; Q62167; protein.
DR Bgee; ENSMUSG00000000787; Expressed in maxillary prominence and 279 other tissues.
DR ExpressionAtlas; Q62167; baseline and differential.
DR Genevisible; Q62167; MM.
DR GO; GO:0031252; C:cell leading edge; ISS:UniProtKB.
DR GO; GO:0005813; C:centrosome; ISS:UniProtKB.
DR GO; GO:0005737; C:cytoplasm; ISS:UniProtKB.
DR GO; GO:0010494; C:cytoplasmic stress granule; IDA:UniProtKB.
DR GO; GO:0005829; C:cytosol; ISO:MGI.
DR GO; GO:0022627; C:cytosolic small ribosomal subunit; ISO:MGI.
DR GO; GO:0005852; C:eukaryotic translation initiation factor 3 complex; ISO:MGI.
DR GO; GO:0030027; C:lamellipodium; IEA:UniProtKB-SubCell.
DR GO; GO:0072559; C:NLRP3 inflammasome complex; IDA:UniProtKB.
DR GO; GO:0005654; C:nucleoplasm; ISO:MGI.
DR GO; GO:0005634; C:nucleus; ISS:UniProtKB.
DR GO; GO:0043186; C:P granule; IBA:GO_Central.
DR GO; GO:0005886; C:plasma membrane; ISS:UniProtKB.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0016887; F:ATP hydrolysis activity; ISS:UniProtKB.
DR GO; GO:0043273; F:CTPase activity; ISO:MGI.
DR GO; GO:0003677; F:DNA binding; ISS:UniProtKB.
DR GO; GO:0003678; F:DNA helicase activity; ISS:UniProtKB.
DR GO; GO:0008190; F:eukaryotic initiation factor 4E binding; ISS:UniProtKB.
DR GO; GO:0043015; F:gamma-tubulin binding; ISS:UniProtKB.
DR GO; GO:0003924; F:GTPase activity; ISO:MGI.
DR GO; GO:0048027; F:mRNA 5'-UTR binding; ISS:UniProtKB.
DR GO; GO:0003729; F:mRNA binding; ISS:UniProtKB.
DR GO; GO:0017111; F:nucleoside-triphosphatase activity; ISO:MGI.
DR GO; GO:0008143; F:poly(A) binding; ISS:UniProtKB.
DR GO; GO:0070878; F:primary miRNA binding; IDA:MGI.
DR GO; GO:0043539; F:protein serine/threonine kinase activator activity; ISS:UniProtKB.
DR GO; GO:0043024; F:ribosomal small subunit binding; ISS:UniProtKB.
DR GO; GO:0003723; F:RNA binding; ISS:UniProtKB.
DR GO; GO:0003724; F:RNA helicase activity; ISS:UniProtKB.
DR GO; GO:0035613; F:RNA stem-loop binding; ISS:UniProtKB.
DR GO; GO:0033592; F:RNA strand annealing activity; ISO:MGI.
DR GO; GO:0008134; F:transcription factor binding; ISS:UniProtKB.
DR GO; GO:0031369; F:translation initiation factor binding; ISS:UniProtKB.
DR GO; GO:0030154; P:cell differentiation; IBA:GO_Central.
DR GO; GO:0071243; P:cellular response to arsenic-containing substance; ISS:UniProtKB.
DR GO; GO:0071470; P:cellular response to osmotic stress; ISS:UniProtKB.
DR GO; GO:0098586; P:cellular response to virus; ISO:MGI.
DR GO; GO:0007059; P:chromosome segregation; ISS:UniProtKB.
DR GO; GO:0008625; P:extrinsic apoptotic signaling pathway via death domain receptors; ISS:UniProtKB.
DR GO; GO:0007276; P:gamete generation; IBA:GO_Central.
DR GO; GO:0006954; P:inflammatory response; IEA:UniProtKB-KW.
DR GO; GO:0045087; P:innate immune response; ISS:UniProtKB.
DR GO; GO:0035556; P:intracellular signal transduction; ISS:UniProtKB.
DR GO; GO:0097193; P:intrinsic apoptotic signaling pathway; ISS:UniProtKB.
DR GO; GO:0055088; P:lipid homeostasis; ISS:UniProtKB.
DR GO; GO:0042256; P:mature ribosome assembly; ISS:UniProtKB.
DR GO; GO:0043066; P:negative regulation of apoptotic process; ISS:UniProtKB.
DR GO; GO:0030308; P:negative regulation of cell growth; ISO:MGI.
DR GO; GO:0043154; P:negative regulation of cysteine-type endopeptidase activity involved in apoptotic process; ISS:UniProtKB.
DR GO; GO:1902042; P:negative regulation of extrinsic apoptotic signaling pathway via death domain receptors; ISS:UniProtKB.
DR GO; GO:2001243; P:negative regulation of intrinsic apoptotic signaling pathway; ISS:UniProtKB.
DR GO; GO:1901223; P:negative regulation of NIK/NF-kappaB signaling; ISS:UniProtKB.
DR GO; GO:0031333; P:negative regulation of protein-containing complex assembly; ISS:UniProtKB.
DR GO; GO:0017148; P:negative regulation of translation; ISS:UniProtKB.
DR GO; GO:0043065; P:positive regulation of apoptotic process; ISS:UniProtKB.
DR GO; GO:0090263; P:positive regulation of canonical Wnt signaling pathway; ISS:UniProtKB.
DR GO; GO:0030307; P:positive regulation of cell growth; ISS:UniProtKB.
DR GO; GO:0043280; P:positive regulation of cysteine-type endopeptidase activity involved in apoptotic process; ISS:UniProtKB.
DR GO; GO:1900087; P:positive regulation of G1/S transition of mitotic cell cycle; ISS:UniProtKB.
DR GO; GO:0010628; P:positive regulation of gene expression; ISO:MGI.
DR GO; GO:0032727; P:positive regulation of interferon-alpha production; ISS:UniProtKB.
DR GO; GO:0032728; P:positive regulation of interferon-beta production; ISS:UniProtKB.
DR GO; GO:1901224; P:positive regulation of NIK/NF-kappaB signaling; ISS:UniProtKB.
DR GO; GO:1900227; P:positive regulation of NLRP3 inflammasome complex assembly; IDA:UniProtKB.
DR GO; GO:1901985; P:positive regulation of protein acetylation; ISS:UniProtKB.
DR GO; GO:0031954; P:positive regulation of protein autophosphorylation; ISS:UniProtKB.
DR GO; GO:1902523; P:positive regulation of protein K63-linked ubiquitination; ISS:UniProtKB.
DR GO; GO:0071902; P:positive regulation of protein serine/threonine kinase activity; ISS:UniProtKB.
DR GO; GO:0034157; P:positive regulation of toll-like receptor 7 signaling pathway; ISS:UniProtKB.
DR GO; GO:0034161; P:positive regulation of toll-like receptor 8 signaling pathway; ISS:UniProtKB.
DR GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; ISS:UniProtKB.
DR GO; GO:0045727; P:positive regulation of translation; ISS:UniProtKB.
DR GO; GO:0036493; P:positive regulation of translation in response to endoplasmic reticulum stress; ISS:UniProtKB.
DR GO; GO:0045948; P:positive regulation of translational initiation; ISS:UniProtKB.
DR GO; GO:0045070; P:positive regulation of viral genome replication; ISO:MGI.
DR GO; GO:0031053; P:primary miRNA processing; IDA:MGI.
DR GO; GO:1903608; P:protein localization to cytoplasmic stress granule; ISO:MGI.
DR GO; GO:0009615; P:response to virus; ISS:UniProtKB.
DR GO; GO:0010501; P:RNA secondary structure unwinding; ISS:UniProtKB.
DR GO; GO:0034063; P:stress granule assembly; IMP:UniProtKB.
DR GO; GO:0006413; P:translational initiation; ISO:MGI.
DR GO; GO:0016055; P:Wnt signaling pathway; ISO:MGI.
DR Gene3D; 3.40.50.300; -; 2.
DR InterPro; IPR011545; DEAD/DEAH_box_helicase_dom.
DR InterPro; IPR014001; Helicase_ATP-bd.
DR InterPro; IPR001650; Helicase_C.
DR InterPro; IPR027417; P-loop_NTPase.
DR InterPro; IPR000629; RNA-helicase_DEAD-box_CS.
DR InterPro; IPR014014; RNA_helicase_DEAD_Q_motif.
DR Pfam; PF00270; DEAD; 1.
DR Pfam; PF00271; Helicase_C; 1.
DR SMART; SM00487; DEXDc; 1.
DR SMART; SM00490; HELICc; 1.
DR SUPFAM; SSF52540; SSF52540; 1.
DR PROSITE; PS00039; DEAD_ATP_HELICASE; 1.
DR PROSITE; PS51192; HELICASE_ATP_BIND_1; 1.
DR PROSITE; PS51194; HELICASE_CTER; 1.
DR PROSITE; PS51195; Q_MOTIF; 1.
PE 1: Evidence at protein level;
KW Acetylation; Apoptosis; ATP-binding; Cell membrane; Cell projection;
KW Chromosome partition; Cytoplasm; Direct protein sequencing; DNA-binding;
KW Helicase; Hydrolase; Immunity; Inflammasome; Inflammatory response;
KW Innate immunity; Isopeptide bond; Membrane; Methylation;
KW Nucleotide-binding; Nucleus; Phosphoprotein; Reference proteome;
KW Ribosome biogenesis; RNA-binding; Transcription; Transcription regulation;
KW Translation regulation; Ubl conjugation.
FT INIT_MET 1
FT /note="Removed"
FT /evidence="ECO:0000269|PubMed:10859333"
FT CHAIN 2..662
FT /note="ATP-dependent RNA helicase DDX3X"
FT /id="PRO_0000055010"
FT DOMAIN 211..403
FT /note="Helicase ATP-binding"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00541"
FT DOMAIN 414..575
FT /note="Helicase C-terminal"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00542"
FT REGION 2..139
FT /note="Required for TBK1 and IKBKE-dependent IFNB1
FT activation"
FT /evidence="ECO:0000250|UniProtKB:O00571"
FT REGION 19..144
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 38..44
FT /note="Interaction with EIF4E"
FT /evidence="ECO:0000250|UniProtKB:O00571"
FT REGION 100..662
FT /note="Interaction with GSK3B"
FT /evidence="ECO:0000250|UniProtKB:O00571"
FT REGION 100..110
FT /note="Interaction with IKBKE"
FT /evidence="ECO:0000250|UniProtKB:O00571"
FT REGION 139..172
FT /note="Interaction with CHUK"
FT /evidence="ECO:0000250|UniProtKB:O00571"
FT REGION 250..259
FT /note="Involved in stimulation of ATPase activity by DNA
FT and RNA, nucleic acid binding and unwinding"
FT /evidence="ECO:0000250|UniProtKB:O00571"
FT REGION 536..661
FT /note="Interaction with NXF1"
FT /evidence="ECO:0000250|UniProtKB:O00571"
FT REGION 601..633
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOTIF 12..21
FT /note="Nuclear export signal"
FT /evidence="ECO:0000250|UniProtKB:O00571"
FT MOTIF 180..208
FT /note="Q motif"
FT MOTIF 347..350
FT /note="DEAD box"
FT COMPBIAS 19..34
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 55..69
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 91..142
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 603..626
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT BINDING 200..207
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00541"
FT BINDING 224..231
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00541"
FT MOD_RES 2
FT /note="N-acetylserine"
FT /evidence="ECO:0000269|PubMed:10859333"
FT MOD_RES 55
FT /note="N6-acetyllysine"
FT /evidence="ECO:0007744|PubMed:23806337"
FT MOD_RES 82
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:O00571"
FT MOD_RES 90
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:O00571"
FT MOD_RES 101
FT /note="Omega-N-methylarginine"
FT /evidence="ECO:0007744|PubMed:24129315"
FT MOD_RES 104
FT /note="Phosphotyrosine"
FT /evidence="ECO:0007744|PubMed:15592455"
FT MOD_RES 110
FT /note="Omega-N-methylarginine"
FT /evidence="ECO:0007744|PubMed:24129315"
FT MOD_RES 118
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000250|UniProtKB:O00571"
FT MOD_RES 131
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:17242355"
FT MOD_RES 183
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:O00571"
FT MOD_RES 456
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q62095"
FT MOD_RES 592
FT /note="Omega-N-methylarginine"
FT /evidence="ECO:0000250|UniProtKB:O00571"
FT MOD_RES 594
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:O00571"
FT MOD_RES 605
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:O00571"
FT MOD_RES 612
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:O00571"
FT MOD_RES 617
FT /note="Omega-N-methylarginine"
FT /evidence="ECO:0000250|UniProtKB:O00571"
FT MOD_RES 632
FT /note="Omega-N-methylarginine"
FT /evidence="ECO:0007744|PubMed:24129315"
FT CROSSLNK 215
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in SUMO2)"
FT /evidence="ECO:0000250|UniProtKB:O00571"
SQ SEQUENCE 662 AA; 73101 MW; 216515CB00324017 CRC64;
MSHVAVENAL GLDQQFAGLD LNSSDNQSGG STASKGRYIP PHLRNREATK GFYDKDSSGW
SSSKDKDAYS SFGSRGDSRG KSSFFGDRGS GSRGRFDDRG RGDYDGIGGR GDRSGFGKFE
RGGNSRWCDK SDEDDWSKPL PPSERLEQEL FSGGNTGINF EKYDDIPVEA TGNNCPPHIE
SFSDVEMGEI IMGNIELTRY TRPTPVQKHA IPIIKEKRDL MACAQTGSGK TAAFLLPILS
QIYADGPGEA LRAMKENGRY GRRKQYPISL VLAPTRELAV QIYEEARKFS YRSRVRPCVV
YGGAEIGQQI RDLERGCHLL VATPGRLVDM MERGKIGLDF CKYLVLDEAD RMLDMGFEPQ
IRRIVEQDTM PPKGVRHTMM FSATFPKEIQ MLARDFLDEY IFLAVGRVGS TSENITQKVV
WVEEIDKRSF LLDLLNATGK DSLTLVFVET KKGADSLEDF LYHEGYACTS IHGDRSQRDR
EEALHQFRSG KSPILVATAV AARGLDISNV KHVINFDLPS DIEEYVHRIG RTGRVGNLGL
ATSFFNERNI NITKDLLDLL VEAKQEVPSW LENMAFEHHY KGSSRGRSKS SRFSGGFGAR
DYRQSSGASS SSFSSSRASS SRSGGGGHGG SRGFGGGGYG GFYNSDGYGG NYNSQGVDWW
GN
