Unanchored K48-linked polyubiquitin synthesized by the E3-ubiquitin ligase TRIM6 stimulates the interferon-IKKε kinase-mediated antiviral response

  • Immunity. 2014 Jun 19;40(6):880-95. doi: 10.1016/j.immuni.2014.04.018.
Ricardo Rajsbaum  1 ,  Gijs A Versteeg  2 ,  Sonja Schmid  3 ,  Ana M Maestre  3 ,  Alan Belicha-Villanueva  1 ,  Carles Martínez-Romero  1 ,  Jenish R Patel  1 ,  Juliet Morrison  1 ,  Giuseppe Pisanelli  4 ,  Lisa Miorin  1 ,  Maudry Laurent-Rolle  1 ,  Hong M Moulton  5 ,  David A Stein  5 ,  Ana Fernandez-Sesma  3 ,  Benjamin R tenOever  1 ,  Adolfo García-Sastre  6
Affiliations
  • 1. Department of Microbiology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA; Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA.
  • 2. Department of Microbiology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA; Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA; Max F. Perutz Laboratories, University of Vienna, Dr. Bohr-Gasse 9/4, 1030 Vienna, Austria.
  • 3. Department of Microbiology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA.
  • 4. Department of Microbiology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA; Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA; Department of Veterinary Medicine and Animal Production, University of Naples Federico II, Via Federico Delpino 1, 80137 Naples, Italy.
  • 5. Department of Biomedical Sciences, College of Veterinary Medicine, Oregon State University, Corvallis, OR 97331, USA.
  • 6. Department of Microbiology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA; Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA; Department of Medicine, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA. Electronic address: [email protected].
PMID: 24882218 DOI: 10.1016/j.immuni.2014.04.018
Abstract

Type I interferons (IFN-I) are essential Antiviral cytokines produced upon microbial Infection. IFN-I elicits this activity through the upregulation of hundreds of IFN-I-stimulated genes (ISGs). The full breadth of ISG induction demands activation of a number of cellular factors including the IκB kinase epsilon (IKKε). However, the mechanism of IKKε activation upon IFN receptor signaling has remained elusive. Here we show that TRIM6, a member of the E3-ubiquitin Ligase tripartite motif (TRIM) family of proteins, interacted with IKKε and promoted induction of IKKε-dependent ISGs. TRIM6 and the E2-ubiquitin conjugase UbE2K cooperated in the synthesis of unanchored K48-linked polyubiquitin chains, which activated IKKε for subsequent STAT1 phosphorylation. Our work attributes a previously unrecognized activating role of K48-linked unanchored polyubiquitin chains in kinase activation and identifies the UbE2K-TRIM6-ubiquitin axis as critical for IFN signaling and Antiviral response.