Mindbomb proteins are E3 ubiquitin ligases essential for TBK1-mediated antiviral activity (136.6)

Abstract

Abstract First line host defense against virus attack includes the innate immune system which recognizes and mounts rapid antiviral responses. An important aspect in defense against viral infections is the production of type 1 interferon which provides a protective state to surrounding cells. TBK1 is a critical kinase involved in cellular transcriptional responses to infection and production of type I interferon. We found that TBK1 undergoes Lys63 ubiquitination following viral infection. The E3 ligases Mindbomb 1 (MIB1) and Mindbomb 2 (MIB2) associate with the TBK1 complex and confer K63-linked ubiquitin to TBK1, resulting in activation of downstream IRF signaling. Two lysine residues on TBK1 are ubiquitin acceptor sites and critical for innate antiviral defense. Ectopic expression of MIB1 or MIB2 augments TBK1-induced antiviral responses. Deficiency of MIB1 and MIB2 demonstrates that these genes are critical for TBK1 ubiquitination, type 1 interferon production, and TBK1-mediated antiviral activity. These results identify MIB1 and MIB2 as positive regulators of antiviral responses through polyubiquitination of TBK1.