title: NEMO binds ubiquitinated TANK-binding kinase 1 (TBK1) to regulate innate immune responses to RNA viruses.
abstract: RIG-I-like receptors (RLR) are intracellular sensors utilized by nearly all cell types for recognition of viral RNA, initiation of antiviral defense, and induction of type I interferons (IFN). TBK1 is a critical kinase implicated in RLR-dependent IFN transcription. Posttranslational modification of TBK1 by K63-linked ubiquitin is required for RLR driven signaling. However, the TBK1 ubiquitin acceptor sites and the function of ubiquitinated TBK1 in the signaling cascade are unknown. We now show that TBK1 is ubiquitinated on residues K69, K154, and K372 in response to infection with RNA virus. The K69 and K154 residues are critical for innate antiviral responses and IFN production. Ubiquitinated TBK1 recruits the downstream adaptor NEMO through ubiquitin binding domains. The assembly of the NEMO/TBK1 complex on the mitochondrial protein MAVS leads to activation of TBK1 kinase activity and phosphorylation of the transcription factor, interferon response factor 3. The combined results refine current views of RLR signaling, define the role of TBK1 polyubiquitination, and detail the mechanisms involved in signalosome assembly.
authors.affiliation: Department of Microbiology & Immunobiology, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Lingyan
authors.initials: L
authors.lastname: Wang
authors.forename: Shitao
authors.initials: S
authors.lastname: Li
authors.forename: Martin E
authors.initials: ME
authors.lastname: Dorf
mesh_terms: D000818:Animals; D002460:Cell Line; D004789:Enzyme Activation; D006801:Humans; D007113:Immunity, Innate; D056747:Immunomodulation; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D051379:Mice; D009154:Mutation; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D012328:RNA Viruses / Q000276:immunology*; D054875:Ubiquitination
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; C514981:NEMO protein, mouse; C498588:Tbk1 protein, mouse; D017346:Protein Serine-Threonine Kinases