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

  • Author(s): Rajsbaum, Ricardo
  • Versteeg, Gijs A
  • Schmid, Sonja
  • Maestre, Ana M
  • Belicha-Villanueva, Alan
  • Martínez-Romero, Carles
  • Patel, Jenish R
  • Morrison, Juliet
  • Pisanelli, Giuseppe
  • Miorin, Lisa
  • Laurent-Rolle, Maudry
  • Moulton, Hong M
  • Stein, David A
  • Fernandez-Sesma, Ana
  • tenOever, Benjamin R
  • García-Sastre, Adolfo
  • et al.
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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