Nuclear transcription of long hairpin RNA triggers innate immune responses.
RNA interference (RNAi) is one of the most promising tools for deciphering the human genome and has great therapeutic potential. However, its high target specificity limits its efficiency for therapeutic protection from viruses with high rates of genetic mutation. This limitation may be overcome by the expression of long hairpin RNAs (lhRNAs). Indeed, lhRNAs have been shown recently to have increased efficacy over short interfering RNAs (siRNAs) as protective antiviral agents. Here, we investigate the expression of lhRNAs and demonstrate unintended effects. We show that overexpressed lhRNAs are exported to the cytoplasm. As a consequence, we detect activation of innate immune signaling pathways by lhRNAs. With growing concerns about the complexity of cytoplasmic detection of dsRNAs by the innate immune machinery, this work highlights the need for closer scrutiny when using lhRNAs as potential antiviral agents.
Gantier
Michael P
MP
School of Medicine and Medical Science, UCD Conway Institute of Biomolecular and Biomedical Research, University College Dublin, and St. Vincent's University Hospital, Dublin, Ireland.
Baugh
John A
JA
Donnelly
Seamas C
SC
D048868:Adaptor Proteins, Signal Transducing / Q000276:immunology / Q000378:metabolism*; D000998:Antiviral Agents / Q000378:metabolism; D002460:Cell Line; D003593:Cytoplasm / Q000378:metabolism; D006801:Humans; D007113:Immunity, Innate; D016899:Interferon-beta / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D009690:Nucleic Acid Conformation; D034622:RNA Interference; D012320:RNA Polymerase III / Q000378:metabolism; D012330:RNA, Double-Stranded / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000276:immunology / Q000378:metabolism; D014158:Transcription, Genetic; D014162:Transfection
D048868:Adaptor Proteins, Signal Transducing; D000998:Antiviral Agents; D016328:NF-kappa B; D012330:RNA, Double-Stranded; D034741:RNA, Small Interfering; D016899:Interferon-beta; D012320:RNA Polymerase III