Unanchored K48-Linked Polyubiquitin Synthesized by the E3-Ubiquitin Ligase TRIM6 Stimulates the Interferon-IKKε Kinase-Mediated Antiviral Response

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

Research output: Contribution to journalArticle

71 Scopus citations

Abstract

Type I interferons (IFN-I) are essential antiviral cytokines produced upon microbial infection. IFN-I elicits this activity through the upregulation of hundreds ofIFN-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.

Original languageEnglish (US)
Pages (from-to)880-895
Number of pages16
JournalImmunity
Volume40
Issue number6
DOIs
StatePublished - Jun 19 2014
Externally publishedYes

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Infectious Diseases

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    Rajsbaum, R., Versteeg, G. A., Schmid, S., Maestre, A. M., Belicha-Villanueva, A., Martínez-Romero, C., Patel, J. R., Morrison, J., Pisanelli, G., Miorin, L., Laurent-Rolle, M., Moulton, H. M., Stein, D. A., Fernandez-Sesma, A., tenOever, B. R., & García-Sastre, A. (2014). Unanchored K48-Linked Polyubiquitin Synthesized by the E3-Ubiquitin Ligase TRIM6 Stimulates the Interferon-IKKε Kinase-Mediated Antiviral Response. Immunity, 40(6), 880-895. https://doi.org/10.1016/j.immuni.2014.04.018