TitleUnanchored K48-linked polyubiquitin synthesized by the E3-ubiquitin ligase TRIM6 stimulates the interferon-IKKε kinase-mediated antiviral response.
Publication TypeJournal Article
Year of Publication2014
AuthorsRajsbaum, R, Versteeg, GA, Schmid, S, Maestre, AM, Belicha-Villanueva, A, Martínez-Romero, C, Patel, JR, Morrison, J, Pisanelli, G, Miorin, L, Laurent-Rolle, M, Moulton, HM, Stein, DA, Fernandez-Sesma, A, tenOever, BR, García-Sastre, A
Date Published2014 Jun 19
KeywordsUbiquitin-Protein Ligases

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.