DDX17 Specifically, and Independently of DDX5, Controls Use of the HIV A4/5 Splice Acceptor Cluster and Is Essential for Efficient Replication of HIV.
Williams, Claire A
Vaughan, Aisling M
Journal of molecular biology
18 Pt B
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Sithole, N., Williams, C. A., Vaughan, A. M., Kenyon, J., & Lever, A. (2018). DDX17 Specifically, and Independently of DDX5, Controls Use of the HIV A4/5 Splice Acceptor Cluster and Is Essential for Efficient Replication of HIV.. Journal of molecular biology, 430 (18 Pt B), 3111-3128. https://doi.org/10.1016/j.jmb.2018.06.052
HIV splicing involves 5 splice donor and 8 splice acceptor sequences which, together with cryptic splice sites, generate over 100 mRNA species. 90% of both partially spliced and fully spliced transcripts utilise the intrinsically weak A4/A5 3’ splice site cluster. We show that DDX17, but not its close paralog DDX5, specifically controls the usage of this splice acceptor group. In its absence production of the viral envelope protein and other regulatory and accessory proteins are grossly reduced whilst Vif, which uses the A1 splice acceptor is unaffected. This is associated with a profound decrease in viral export from the cell. Loss of Vpu expression causing upregulation of cellular Tetherin compounds the phenotype. DDX17 utilises distinct RNA binding motifs for its role in efficient HIV replication and we identify RNA binding motifs essential for its role whilst the Walker A, Walker B (DEAD), Q motif and the glycine doublet motif are all dispensable. We show that DDX17 interacts with SRSF1/SF2 and the heterodimeric auxiliary factor U2AF65/35 which are essential splicing factors in the generation of Rev and Env/Vpu transcripts.
Cells, Cultured, Cell Line, Tumor, Humans, HIV-1, HIV Infections, RNA Splice Sites, Gene Expression Regulation, Viral, Alternative Splicing, Amino Acid Motifs, Protein Binding, DEAD-box RNA Helicases, Protein Interaction Domains and Motifs, Gene Knockdown Techniques
Wellcome Trust , Cambridge Biomedical Research Centre and Clinical Academic Reserve
Wellcome Trust (097223/Z/11/Z)
External DOI: https://doi.org/10.1016/j.jmb.2018.06.052
This record's URL: https://www.repository.cam.ac.uk/handle/1810/280044
Attribution 4.0 International
Licence URL: http://creativecommons.org/licenses/by/4.0/