2. Academic Validation
  3. Unanchored K48-linked polyubiquitin synthesized by the E3-ubiquitin ligase TRIM6 stimulates the interferon-IKKε kinase-mediated antiviral response

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

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: adolfo.garcia-sastre@mssm.edu.
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.

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