title: DEAD-box RNA helicase DDX3 connects CRM1-dependent nuclear export and translation of the HIV-1 unspliced mRNA through its N-terminal domain.
abstract: DEAD-box RNA helicase DDX3 is a host factor essential for HIV-1 replication and thus, a potential target for novel therapies aimed to overcome viral resistance. Previous studies have shown that DDX3 promotes nuclear export and translation of the HIV-1 unspliced mRNA. Although the function of DDX3 during both processes requires its catalytic activity, it is unknown whether other domains surrounding the helicase core are involved. Here, we show the involvement of the N- and C-terminal domains of DDX3 in the regulation of HIV-1 unspliced mRNA translation. Our results suggest that the intrinsically disordered N-terminal domain of DDX3 regulates its functions in translation by acting prior to the recruitment of the 43S pre-initiation complex onto the viral 5'-UTR. Interestingly, this regulation was conserved in HIV-2 and was dependent on the CRM1-dependent nuclear export pathway suggesting a role of the RNA helicase in interconnecting nuclear export with ribosome recruitment of the viral unspliced mRNA. This specific function of DDX3 during HIV gene expression could be exploited as an alternative target for pharmaceutical intervention.
authors.affiliation: Molecular and Cellular Virology Laboratory, Virology Program, Institute of Biomedical Sciences, Faculty of Medicine, Universidad de Chile, Independencia 834100, Santiago, Chile.
authors.forename: Alvaro
authors.initials: A
authors.lastname: Fröhlich
authors.affiliation: Molecular and Cellular Virology Laboratory, Virology Program, Institute of Biomedical Sciences, Faculty of Medicine, Universidad de Chile, Independencia 834100, Santiago, Chile.
authors.forename: Bárbara
authors.initials: B
authors.lastname: Rojas-Araya
authors.affiliation: Molecular and Cellular Virology Laboratory, Virology Program, Institute of Biomedical Sciences, Faculty of Medicine, Universidad de Chile, Independencia 834100, Santiago, Chile.
authors.forename: Camila
authors.initials: C
authors.lastname: Pereira-Montecinos
authors.affiliation: Molecular and Cellular Virology Laboratory, Virology Program, Institute of Biomedical Sciences, Faculty of Medicine, Universidad de Chile, Independencia 834100, Santiago, Chile.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Dellarossa
authors.affiliation: Molecular and Cellular Virology Laboratory, Virology Program, Institute of Biomedical Sciences, Faculty of Medicine, Universidad de Chile, Independencia 834100, Santiago, Chile.
authors.forename: Daniela
authors.initials: D
authors.lastname: Toro-Ascuy
authors.affiliation: Molecular and Cellular Virology Laboratory, Virology Program, Institute of Biomedical Sciences, Faculty of Medicine, Universidad de Chile, Independencia 834100, Santiago, Chile.
authors.forename: Yara
authors.initials: Y
authors.lastname: Prades-Pérez
authors.affiliation: Molecular and Cellular Virology Laboratory, Virology Program, Institute of Biomedical Sciences, Faculty of Medicine, Universidad de Chile, Independencia 834100, Santiago, Chile.
authors.forename: Francisco
authors.initials: F
authors.lastname: García-de-Gracia
authors.affiliation: Molecular and Cellular Virology Laboratory, Virology Program, Institute of Biomedical Sciences, Faculty of Medicine, Universidad de Chile, Independencia 834100, Santiago, Chile.
authors.forename: Andrea
authors.initials: A
authors.lastname: Garcés-Alday
authors.affiliation: CIRI, International Center for Infectiology Research, Université de Lyon, Lyon, France; Inserm, U1111 Lyon, France; Ecole Normale Supérieure de Lyon, Lyon, France.
authors.forename: Paulina S
authors.initials: PS
authors.lastname: Rubilar
authors.affiliation: Molecular and Cellular Virology Laboratory, Virology Program, Institute of Biomedical Sciences, Faculty of Medicine, Universidad de Chile, Independencia 834100, Santiago, Chile.
authors.forename: Fernando
authors.initials: F
authors.lastname: Valiente-Echeverría
authors.affiliation: CIRI, International Center for Infectiology Research, Université de Lyon, Lyon, France; Inserm, U1111 Lyon, France; Ecole Normale Supérieure de Lyon, Lyon, France.
authors.forename: Théophile
authors.initials: T
authors.lastname: Ohlmann
authors.affiliation: Molecular and Cellular Virology Laboratory, Virology Program, Institute of Biomedical Sciences, Faculty of Medicine, Universidad de Chile, Independencia 834100, Santiago, Chile. Electronic address: rsotorifo@med.uchile.cl.
authors.forename: Ricardo
authors.initials: R
authors.lastname: Soto-Rifo
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000235:genetics; D053487:DEAD-box RNA Helicases / Q000235:genetics*; D015967:Gene Expression Regulation, Viral; D015658:HIV Infections / Q000235:genetics* / Q000628:therapy / Q000821:virology; D015497:HIV-1 / Q000235:genetics* / Q000472:pathogenicity; D054884:Host-Pathogen Interactions / Q000235:genetics; D006801:Humans; D028884:Karyopherins / Q000235:genetics*; D014176:Protein Biosynthesis; D017434:Protein Structure, Tertiary; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D012367:RNA, Viral / Q000235:genetics; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics*; D014779:Virus Replication / Q000235:genetics; D000097606:Exportin 1 Protein
chemical_list: D053487:DEAD-box RNA Helicases; D028884:Karyopherins; D012333:RNA, Messenger; D012367:RNA, Viral; D018160:Receptors, Cytoplasmic and Nuclear; D000097606:Exportin 1 Protein; C119332:DDX3X protein, human
keywords: CRM1; DDX3; HIV-1; Intrinsic disorder; Nuclear export; Translation; Unspliced mRNA