Ubiquitin-Regulated Recruitment Of I Kappa B Kinase E To The Mavs Interferon Signaling Adapter

Induction of the antiviral interferon response is initiated upon recognition of viral RNA structures by the RIG-I or Mda-5 DEX(D/H) helicases. A complex signaling cascade then converges at the mitochondrial adapter MAVS, culminating in the activation of the IRF and NF-kappa B transcription factors and the induction of interferon gene expression. We have previously shown that MAVS recruits I kappa B kinase epsilon (IKK epsilon) but not TBK-1 to the mitochondria following viral infection. Here we map the interaction of MAVS and IKK epsilon to the C-terminal region of MAVS and demonstrate that this interaction is ubiquitin dependent. MAVS is ubiquitinated following Sendai virus infection, and K63-linked ubiquitination of lysine 500 (K500) of MAVS mediates recruitment of IKK epsilon to the mitochondria. Real-time PCR analysis reveals that a K500R mutant of MAVS increases the mRNA level of several interferon-stimulated genes and correlates with increased NF-kappa B activation. Thus, recruitment of IKK epsilon to the mitochondria upon MAVS K500 ubiquitination plays a modulatory role in the cascade leading to NF-kappa B activation and expression of inflammatory and antiviral genes. These results provide further support for the differential role of IKK epsilon and TBK-1 in the RIG-I/Mda5 pathway.