1. Unanchored K48-Linked Polyubiquitin Synthesized by the E3-Ubiquitin Ligase TRIM6 Stimulates the Interferon-IKKε Kinase-Mediated Antiviral Response
- Author
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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, and García-Sastre, Adolfo
- Subjects
Biomedical and Clinical Sciences ,Immunology ,Infectious Diseases ,Genetics ,1.1 Normal biological development and functioning ,Underpinning research ,Animals ,Antiviral Agents ,Cells ,Cultured ,Enzyme Activation ,Humans ,I-kappa B Kinase ,Interferon Type I ,Janus Kinase 1 ,Mice ,Phosphorylation ,Polyubiquitin ,RNA Interference ,RNA ,Small Interfering ,STAT1 Transcription Factor ,Signal Transduction ,Tripartite Motif Proteins ,Ubiquitin-Conjugating Enzymes ,Ubiquitin-Protein Ligases - 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.
- Published
- 2014