Ubiquitin-regulated recruitment of IkappaB kinase epsilon to the MAVS interferon signaling adapter
Authors: Judith Lacoste
John Hiscott
Qiang Sun
Meztli Arguello
Elena A Shestakova
Suzanne Paz
Thi Lien-Anh Nguyen
Marc J Servant
Scott Zaari
Myriam Vilasco
Tiejun Zhao
Annie Bibeau-Poirier
Eliane F Meurs
Rongtuan Lin
Journal: Molecular and Cellular Biology (2009)
Discipline: MOLECULAR BIOLOGY & GENETICS
Keywords: antiviral interferon response; RIG-I; Mda-5; DEX(D/H) helicases; signaling cascade
Affiliations: Lady Davis Institute for Medical Research, Jewish General Hospital, 3755 Cote Ste. Catherine, Montreal, Quebec, Canada H3T 1E2., Department of Virology, Institut Pasteur, Paris, France, Terry Fox Molecular Oncology Group, Lady Davis Institute, Jewish General Hospital, Montreal, Canada H3T 1E2, Departments of Microbiology &amp; Immunology, Faculté de Pharmacie, Université de Montréal, Montreal, Canada, Medicine, McGill University, Montreal, Canada

Abstract:  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-kappaB transcription factors and the induction of interferon gene expression. We have previously shown that MAVS recruits IkappaB kinase epsilon (IKKepsilon) but not TBK-1 to the mitochondria following viral infection. Here we map the interaction of MAVS and IKKepsilon 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 IKKepsilon 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-kappaB activation. Thus, recruitment of IKKepsilon to the mitochondria upon MAVS K500 ubiquitination plays a modulatory role in the cascade leading to NF-kappaB activation and expression of inflammatory and antiviral genes. These results provide further support for the differential role of IKKepsilon and TBK-1 in the RIG-I/Mda5 pathway. 

Retracted: No

PubPeer comments:
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