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, Anna; Beermann, Sandra; Cicco, Giulia di; Dietrich, Ursula; Maga, Giovanni

doi:10.1371/journal.pone.0019810

Cited by 79 publications

(89 citation statements)

References 24 publications

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“…Genetic studies have begun to address the role of altered RH function in human disease (e.g., DHX37 and DHX30 ) 16, 1718, 19. In a diagnostic laboratory referral cohort of 4839 subjects with DD and/or ID, we have identified 26 postnatal individuals (24 females, 2 males) with syndromic ID or DD carrying pathogenic or likely pathogenic variants in DDX3X , and one fetus with abnormal ultrasound findings carrying a de novo variant of unknown significance in DDX3X ; an additional four females were identified through research WES at BHCMG.…”

Section: Discussionmentioning

confidence: 99%

Phenotypic expansion in DDX3X – a common cause of intellectual disability in females

Wang

Posey

Rosenfeld

et al. 2018

Ann Clin Transl Neurol

117

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De novo variants in DDX3X account for 1–3% of unexplained intellectual disability (ID) cases and are amongst the most common causes of ID especially in females. Forty‐seven patients (44 females, 3 males) have been described. We identified 31 additional individuals carrying 29 unique DDX3X variants, including 30 postnatal individuals with complex clinical presentations of developmental delay or ID, and one fetus with abnormal ultrasound findings. Rare or novel phenotypes observed include respiratory problems, congenital heart disease, skeletal muscle mitochondrial DNA depletion, and late‐onset neurologic decline. Our findings expand the spectrum of DNA variants and phenotypes associated with DDX3X disorders.

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Section: Discussionmentioning

confidence: 99%

Phenotypic expansion in DDX3X – a common cause of intellectual disability in females

Wang

Posey

Rosenfeld

et al. 2018

Ann Clin Transl Neurol

117

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“…The core-helicase domain in human DDX3 comprises residues 168 to 582, while the flanking N-and C-terminal regions comprise residues 1 to 167 and 583 to 662, respectively (41). Based on sequence alignment with other DEAD box helicases, the core-helicase domain contains the nine conserved motifs involved in ATPase, helicase, and RNA binding activity (42). The N-terminal region contains a conserved leucine-rich nuclear export signal and is critical for CRM1-mediated nuclear export and eIF4E binding (3,23,36), while an SR-rich region in the C terminus is associated in an interaction with the nuclear export receptor NXF1/TAP (43).…”

Section: Ddx3mentioning

confidence: 99%

DDX3 Interacts with Influenza A Virus NS1 and NP Proteins and Exerts Antiviral Function through Regulation of Stress Granule Formation

Raman

Liu

Pyo

et al. 2016

J Virol

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DDX3 belongs to the DEAD box RNA helicase family and is a multifunctional protein affecting the life cycle of a variety of viruses. However, its role in influenza virus infection is unknown. In this study, we explored the potential role of DDX3 in influenza virus life cycle and discovered that DDX3 is an antiviral protein. Since many host proteins affect virus life cycle by interacting with certain components of the viral machinery, we first verified whether DDX3 has any viral interaction partners. Immunoprecipitation studies revealed NS1 and NP as direct interaction partners of DDX3. Stress granules (SGs) are known to be antiviral and do form in influenza virus-infected cells expressing defective NS1 protein. Additionally, a recent study showed that DDX3 is an important SG-nucleating factor. We thus explored whether DDX3 plays a role in influenza virus infection through regulation of SGs. Our results showed that SGs were formed in infected cells upon infection with a mutant influenza virus lacking functional NS1 (del NS1) protein, and DDX3 colocalized with NP in SGs. We further determined that the DDX3 helicase domain did not interact with NS1 and NP; however, it was essential for DDX3 localization in virus-induced SGs. Knockdown of DDX3 resulted in impaired SG formation and led to increased virus titers. Taken together, our results identified DDX3 as an antiviral protein with a role in virus-induced SG formation. IMPORTANCEDDX3 is a multifunctional RNA helicase and has been reported to be involved in regulating various virus life cycles. However, its function during influenza A virus infection remains unknown. In this study, we demonstrated that DDX3 is capable of interacting with influenza virus NS1 and NP proteins; DDX3 and NP colocalize in the del NS1 virus-induced SGs. Furthermore, knockdown of DDX3 impaired SG formation and led to a decreased virus titer. Thus, we provided evidence that DDX3 is an antiviral protein during influenza virus infection and its antiviral activity is through regulation of SG formation. Our findings provide knowledge about the function of DDX3 in the influenza virus life cycle and information for future work on manipulating the SG pathway and its components to fight influenza virus infection.

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“…The human UAP56 and P. falciparum UAP56 were also reported to interact with RNA (Shen et al 2007;Shankar et al 2008). Earlier, the yeast DBP9p and human DDX3 DEAD-box proteins have been reported to interact with both RNA and DNA (Kikuma et al 2004;Garbelli et al 2011).…”

Section: Discussionmentioning

confidence: 99%

Stress-induced Oryza sativa BAT1 dual helicase exhibits unique bipolar translocation

et al. 2015

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HLA-B associated transcript 1 (BAT1) protein, also named as spliceosome RNA helicase UAP56, is a member of the DExD/H-box family of helicases. However, regulation under stress, biochemical properties, and functions of plant homologue of BAT1 are poorly understood. Here, we report the purification and detailed biochemical characterization of the Oryza sativa homologue of BAT1 (OsBAT1/UAP56) protein (52 kDa) and regulation of its transcript under abiotic stress. OsBAT1 transcript levels are enhanced in rice seedlings in response to abiotic stress including salt stress and abscisic acid. Purified OsBAT1 protein exhibits the DNA- and RNA-dependent ATPase, RNA helicase, and DNA- and RNA-binding activities. Interestingly OsBAT1 also exhibits unique DNA helicase activity, which has not been reported so far in any BAT1 homologue. Moreover, OsBAT1 translocates in both the 3' to 5' and 5' to 3' directions, which is also a unique property. The K m value for OsBAT1 DNA helicase is 0.9753 nM and for RNA helicase is 1.7536 nM, respectively. This study demonstrates several unique characteristics of OsBAT1 especially its ability to unwind both DNA and RNA duplexes; bipolar translocation and its transcript upregulation under abiotic stresses indicate that it is a multifunctional protein. Overall, this study represents significant contribution in advancing our knowledge regarding functions of OsBAT1 in RNA and DNA metabolism and its putative role in abiotic stress signaling in plants.

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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

Cited by 79 publications

References 24 publications

Phenotypic expansion in DDX3X – a common cause of intellectual disability in females

Phenotypic expansion in DDX3X – a common cause of intellectual disability in females

DDX3 Interacts with Influenza A Virus NS1 and NP Proteins and Exerts Antiviral Function through Regulation of Stress Granule Formation

Stress-induced Oryza sativa BAT1 dual helicase exhibits unique bipolar translocation

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