Veterinary and Biomedical Sciences, Department of


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Date of this Version



JVI Accepts, published online ahead of print on 26 December 2013 J. Virol. doi:10.1128/JVI.03202-13


Copyright © 2013, American Society for Microbiology. All Rights Reserved.


In a genome-wide siRNA screen, we recently identified the interferon (IFN) inducible protein 35 (IFI35, also known as IFP35) as a factor required for VSV infection. Studies reported here were conducted to further understand the role and requirement of IFI35 in VSV infection. Consistent with the siRNA screening data, we found that depletion of IFI35 led to reduced VSV replication at the level of viral gene expression. Although no direct interaction of IFI35 with the viral replication machinery was observed, we found that IFI35 negatively regulated the host innate immune response and rescued poly(I:C)-induced inhibition of VSV replication. Promoter-driven reporter gene assays demonstrated that IFI35 overexpression suppressed the activation of IFNβ and ISG56 promoters, whereas its depletion had opposite effect. Further investigation revealed that IFI35 specifically interacted with RIG-I and negatively regulated its activation through mechanisms that include: (i) suppression of dephosphorylation (activation) of RIG-I and (ii) proteasome-mediated degradation of RIG-I via K48-linked ubiquitination. Overall, the results presented here suggest a novel role for IFI35 in negative regulation of RIG-I mediated antiviral signaling, which will have implications for diseases associated with excessive immune signaling.