Stem-Loop Recognition by DDX17 Facilitates miRNA Processing and Antiviral Defense

• Published in: Cell Vol. 158; no. 4; pp. 764 - 777
• Main Authors: Moy, Ryan H., Cole, Brian S., Yasunaga, Ari, Gold, Beth, Shankarling, Ganesh, Varble, Andrew, Molleston, Jerome M., tenOever, Benjamin R., Lynch, Kristen W., Cherry, Sara
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 14-08-2014
• Subjects: Animals; Cell Line, Tumor; DEAD-box RNA Helicases - immunology; DEAD-box RNA Helicases - metabolism; Drosophila melanogaster - immunology; Drosophila melanogaster - metabolism; Drosophila melanogaster - virology; Drosophila Proteins - immunology; Drosophila Proteins - metabolism; Humans; Immunity, Innate; Inverted Repeat Sequences; MicroRNAs - metabolism; Rift Valley fever virus - physiology; RNA, Viral - chemistry; Virus Replication
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2014.06.023

DEAD-box helicases play essential roles in RNA metabolism across species, but emerging data suggest that they have additional functions in immunity. Through RNAi screening, we identify an evolutionarily conserved and interferon-independent role for the DEAD-box helicase DDX17 in restricting Rift Valley fever virus (RVFV), a mosquito-transmitted virus in the bunyavirus family that causes severe morbidity and mortality in humans and livestock. Loss of Drosophila DDX17 (Rm62) in cells and flies enhanced RVFV infection. Similarly, depletion of DDX17 but not the related helicase DDX5 increased RVFV replication in human cells. Using crosslinking immunoprecipitation high-throughput sequencing (CLIP-seq), we show that DDX17 binds the stem loops of host pri-miRNA to facilitate their processing and also an essential stem loop in bunyaviral RNA to restrict infection. Thus, DDX17 has dual roles in the recognition of stem loops: in the nucleus for endogenous microRNA (miRNA) biogenesis and in the cytoplasm for surveillance against structured non-self-elements.
[Display omitted]
•DDX17 (Rm62) restricts RVFV infection in Drosophila•DDX17 controls RVFV replication in human cells•DDX17 CLIP-seq demonstrates binding at pri-miRNA stem loops•DDX17 directly binds to a structured viral RNA element
DDX17, an evolutionarily conserved member of the DEAD-box family, has a dual role in the recognition of RNA stem loops. Whereas in the nucleus it binds the stem loops of host pri-miRNA and facilitates miRNA biogenesis, in the cytoplasm, it binds virally encoded stem loops to restrict infection in an interferon-independent manner.