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

• Published in: Immunity (Cambridge, Mass.) Mass.), 2014-06, Vol.40 (6), p.880-895
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: Animals; Antiviral Agents; Cells, Cultured; Enzyme Activation - immunology; Humans; I-kappa B Kinase - immunology; Interferon Type I - immunology; Janus Kinase 1; Mice; Phosphorylation - immunology; Polyubiquitin - biosynthesis; RNA Interference; RNA, Small Interfering; Signal Transduction - immunology; STAT1 Transcription Factor - immunology; Tripartite Motif Proteins; Ubiquitin-Conjugating Enzymes - immunology; Ubiquitin-Protein Ligases - genetics; Ubiquitin-Protein Ligases - immunology
• ISSN: 1074-7613; 1097-4180
• DOI: 10.1016/j.immuni.2014.04.018

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. [Display omitted] •TRIM6 plays a critical role in innate immune activation•TRIM6 and the E2 conjugase UbE2K synthesize unanchored K48-linked ubiquitin chains•Unanchored K48-linked ubiquitin chains activate the IKKε kinase•TRIM6 couples IFNαR engagement to activation of the IKKε kinase for ISG induction Type I interferons elicit antiviral activity through the activation of signaling molecules such as the IKKε kinase. Rajsbaum et al. report that the E3-ubiquitin ligase TRIM6 synthesizes unanchored K48-linked polyubiquitin, which activates IKKε for phosphorylation of the STAT1 signaling molecule, resulting in the induction of an antiviral response.