Abstract
Viral infection causes activation of the transcription factor IRF3, which is critical for production of type I interferons (IFNs) and innate antiviral immune response. How virus-induced type I IFN signaling is controlled is not fully understood. Here we identified the transcription factor FoxO1 as a negative regulator for virus-triggered IFN-β induction. Overexpression of FoxO1 inhibited virus-triggered ISRE activation, IFN-β induction as well as cellular antiviral response, whereas knockdown of FoxO1 had opposite effects. FoxO1 interacted with IRF3 in a viral infection-dependent manner and promoted K48-linked polyubiquitination and degradation of IRF3 in the cytosol. Furthermore, FoxO1-mediated degradation of IRF3 was independent of the known E3 ubiquitin ligases for IRF3, including RBCK1 and RAUL. Our findings thus suggest that FoxO1 negatively regulates cellular antiviral response by promoting IRF3 ubiquitination and degradation, providing a previously unknown mechanism for control of type I IFN induction and cellular antiviral response.
Highlights
The transcription factor IRF3 is critical for type I interferon induction and innate antiviral immune response
Overexpression of FoxO1 Inhibits Virus-triggered IFN- Induction—To identify candidate molecules involved in virustriggered IFN- induction, we screened ϳ15,000 independent human and mouse cDNA expression plasmids by IFN- promoter luciferase reporter assays and found that human FoxO1 inhibited Sendai virus (SeV)-induced activation of the IFN- promoter
We found that overexpression of FoxO1 potently inhibited poly(I:C)-triggered both RLR (Fig. 1C) and TLR3 (Fig. 1D) -mediated activation of the IFN- promoter and ISRE
Summary
The transcription factor IRF3 is critical for type I interferon induction and innate antiviral immune response. Viral infection causes activation of the transcription factor IRF3, which is critical for production of type I interferons (IFNs) and innate antiviral immune response. Upon the recognition of viral RNA, RIG-I and MDA5 undergo conformational changes and interact with downstream mitochondrial-localized adapter protein VISA ( known as MAVS, Cardif, and IPS-1) via their N-terminal CARD domains (6 –9) Another mitochondrial- and endoplasmic reticulum (ER)-localized adapter protein MITA ( known as STING) interacts with VISA and recruits the downstream kinase TBK1 and transcription factor IRF3 to the VISA-associated complex, thereby promoting activation of IRF3 and expression of type I IFNs [10, 11]. FoxO1 was associated with IRF3 in a viral infection-dependent manner and promoted K48-linked polyubiquitination and degradation of IRF3, thereby inhibiting excessive expression of IFN- and cellular antiviral response. Our findings uncovered a negative feedback regulatory mechanism of cellular antiviral response by FoxO1
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