NEMO recruitment of polyubiquitinated TBK1 to MAVS builds signalosome to regulate innate anti-viral immunity

RIG-I-like receptors (RLRs) 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. The E3 ligases Mind bomb 1 (MIB1) and Mind bomb 2 (MIB2) conjugate TBK1 with K63-linked polyubiquitin on residues K69 and K154. TBK1 polyubiquitination is critical for recruitment of the downstream adaptor, NEMO. After viral infection NEMO and IRF3 are independently recruited to MAVS. NEMO bridges TBK1 to MAVS through ubiquitin binding domains. The assembly of the NEMO/TBK1 complex on MAVS leads to activation of TBK1 kinase activity and phosphorylation of the transcription factor, IRF3. In contrast, activation of NF-kB is not impaired by MIB deficiency. The combined results refine current views of RLR signaling, define the role of TBK1 polyubiquitination and detail the assembly of the MAVS signalosome.