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 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, and García-Sastre A
- Subjects
- Animals, Antiviral Agents, Cells, Cultured, Enzyme Activation immunology, Humans, Janus Kinase 1, Mice, Phosphorylation immunology, RNA Interference, RNA, Small Interfering, STAT1 Transcription Factor immunology, Signal Transduction immunology, Tripartite Motif Proteins, Ubiquitin-Conjugating Enzymes immunology, Ubiquitin-Protein Ligases genetics, I-kappa B Kinase immunology, Interferon Type I immunology, Polyubiquitin biosynthesis, Ubiquitin-Protein Ligases immunology
- 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., (Copyright © 2014 Elsevier Inc. All rights reserved.)
- Published
- 2014
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