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, H, Stein, DA, Fernandez-Sesma, A, tenOever, BR, García-Sastre, A
JournalImmunity
Volume40
Issue6
Pagination880-95
Date Published2014 Jun 19
ISSN1097-4180
KeywordsAnimals, 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, Signal Transduction, STAT1 Transcription Factor, 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.

DOI10.1016/j.immuni.2014.04.018
Alternate JournalImmunity
PubMed ID24882218
PubMed Central IDPMC4114019
Grant List1R01AI073450 / AI / NIAID NIH HHS / United States
P01AI090935 / AI / NIAID NIH HHS / United States
HHSN272201000054C / AI / NIAID NIH HHS / United States
U19AI106754 / AI / NIAID NIH HHS / United States
U01AI095611 / AI / NIAID NIH HHS / United States
U19 AI083025 / AI / NIAID NIH HHS / United States
1P01AI90935 / AI / NIAID NIH HHS / United States
HHSN272201000054C / / PHS HHS / United States
U19 AI106754 / AI / NIAID NIH HHS / United States
R01 AI073450 / AI / NIAID NIH HHS / United States
U01 AI095611 / AI / NIAID NIH HHS / United States
R01AI080624 / AI / NIAID NIH HHS / United States
R01 AI080624 / AI / NIAID NIH HHS / United States
R01 DA033773 / DA / NIDA NIH HHS / United States
HHSN266200700010C / / PHS HHS / United States
HHSN266200700010C / AI / NIAID NIH HHS / United States
P01 AI090935 / AI / NIAID NIH HHS / United States