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  • As suggested by previous data we identified that


    As suggested by previous data [45], we identified that the N-terminal and C-terminal domains of DDX3 were enriched in intrinsically disordered regions (Fig. 6). We also found that this characteristic was conserved in the external domains of several homologs of DDX3 (from yeast to human) and all described human DEAD-box proteins. DEAD-box helicases play pleiotropic functions within the cell by remodeling RNA:RNA and RNA:protein complexes or by functioning as RNA clamps for the assembly of large macromolecular complexes. Despite the high degree of conservation of the catalytic core and the mechanisms of RNA binding and ATP binding/hydrolysis in several members of the family, their functions are rather non-redundant probably due to the substrate specificity conferred by the N- and/or C-terminal domains surrounding the helicase core. Interestingly, several RNA helicases, including DDX3, have been identified as components of different RNP complexes and thus, associated with different biological processes involving RNA [2], [15]. The presence of intrinsically disordered regions within the N- and C-termini may confer DEAD-box proteins the flexibility needed to interact with different partners in different RNP complexes in a spatiotemporal manner. In the case of DDX3, the N-terminal domain allows interaction with the VACV K7 protein [35], eIF4E [36], IRF3 [38] and to be included in a complex together with CRM1 (Fig. 5), indicating an important role of this domain in establishing multiple interactions. Moreover, the N-terminal domain regulates the RNA-stimulated ATPase activity [11], stress granule assembly [37] and HIV-1 unspliced mRNA translation (Fig. 1) also indicating an important role of the N-terminal domain in regulating biological processes driven by this enzyme. Given the fact that neither the NES nor the eIF4E-binding domain seems to be involved in DDX3 function during HIV-1 gene prostaglandin e1 australia (Fig. 6) [5], [6], it is tempting to speculate that the intrinsically disordered N-terminal domain of DDX3 may first confer the ability to be incorporated into the CRM1-exported viral mRNP at the nuclear envelope and then the flexibility to promote the transition from an export mRNP to a translation one. In this work we provide evidence for the interconnection between CRM1-dependent nuclear export and translation of the HIV-1 unspliced mRNA, two processes previously shown to require the catalytic activity of DDX3 [3], [6]. This occurs through the intrinsically disordered N-terminal domain of DDX3, which allows the RNA helicase to be incorporated into the viral mRNP in a CRM1-dependent manner. Targeting the function of the N-terminal of DDX3 rather than its catalytic activity must be considered as a potential target for novel therapies against HIV. Further work is needed to unveil the mechanisms involved in these processes. The following are the supplementary data related to this article.
    Conflict of interest
    Transparency document
    Acknowledgments The following material was obtained through the NIH AIDS Reagent Program, Division of AIDS, NIAD, NIH: H9 cells from Dr. Robert Gallo and Jurkat Clone E-61 from Dr. Arthur Weiss. This work was supported by CONICYT Chile through the FONDECYT Initiation Into Research Program N° 11121339 to RSR and N° 11140502 to FVE. This work was also supported by a grant from ANRS to TO. YPP and AGA are recipients of a Doctoral fellowship from the Graduate Program in Biomedical Sciences, Faculty of Medicine, Universidad de Chile. FGG is a recipient of a National Doctoral fellowship from CONICYT and PSR was a recipient of a Becas Chile Doctoral fellowship.
    Introduction Post-transcriptional processes play a crucial role in the regulation of many oncogenes, cytokines and pro-inflammatory genes (like TNF-α, COX-2 or iNOS) whose expression has to be tightly controlled [1], [2], [3]. One post-transcriptional mechanism is the modulation of mRNA stability of these genes involving a network of RNA binding proteins (RNA-BPs). These RNA-BPs bind to distinct cis-acting elements mainly located in the 3′-untranslated region of the mRNA. The most important cis-acting elements in the 3′-UTR of many unstable mRNAs are the AU-rich elements (AREs), which mediate rapid decay of the corresponding mRNA [4].