DEAD-box RNA helicase 18 disrupts IRF3-binding to the interferon-β promoter

Abstract

AbstractThe production of type I interferons (IFN-α/β) requires strict control to avoid excessive activation during viral infections. The binding of interferon regulatory factor 3 (IRF3) to the IFN-β promoter region in the nucleus is essential for IFN-β transcription; however, whether nuclear factors have important negative-regulatory roles in this process is largely unknown. By screening for IRF3-interacting partners in the nucleus, we identified DEAD-box RNA helicase 18 (DDX18) as an important negative regulator of intranuclear IRF3. Overexpression of DDX18 suppressed virus- and IRF3-induced IFN-β production, whereas knockdown of DDX18 expression or knockout of the DDX18 gene had opposite effects. Mechanistically, DDX18 interacts with IRF3 and decreases the binding of IRF3 to the IFN-β promoter after viral infection. DDX18 knockdown mice (Ddx18+/-) further demonstrated that DDX18 suppressed antiviral innate immunity in vivo. Thus, despite many members of the DDX family act as important positive regulators in the cytoplasm, DDX18 plays a unique “braking” role in balancing virus-induced type I IFN production.