nemo binds ubiquitinated tank-binding kinase 1 (tbk1) to regulate innate immune responses to rna viruses尼莫结合ubiquitinated tank-binding激酶1(tbk1)先天免疫反应调节rna病毒.pdfVIP

NEMO Binds Ubiquitinated TANK-Binding Kinase 1 (TBK1) to Regulate Innate Immune Responses to RNA Viruses . . Lingyan Wang , Shitao Li* , Martin E. Dorf* Department of Microbiology Immunobiology, Harvard Medical School, Boston, Massachusetts, United States of America 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. Citation: Wang L, Li S, Dorf ME (2012) NEMO Binds Ubiquitinated TANK-Binding Kinase 1 (TBK1) to Regulate Innate Immune Responses to RNA Viruses. PLoS ONE 7(9): e43756. doi:10.1371/journal.pone.0043756 Editor: Eliane F. Meurs, Institut Pasteur, France Received June 14, 2012; Accepted July 25, 2012; Published September 18, 2012 Copyright: 2012 Wang et al. This is an open-access