Journal
MOLECULAR AND CELLULAR BIOLOGY
Volume 29, Issue 12, Pages 3401-3412Publisher
AMER SOC MICROBIOLOGY
DOI: 10.1128/MCB.00880-08
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Funding
- Canadian Institutes for Health Research
- National Cancer Institute of Canada
- Canadian Foundation for AIDS Research
- L' Agence Nationale de la Recherche contre le SIDA
- FRSQ Bourse de Troisieme Cycle
- FRM Bourse de Fin de These
- CIHR
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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.
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