Lysine-11 ubiquitination drives type-I/III interferon induction by cGAS–STING and Toll-like receptors 3 and 4

Pattern recognition receptor (PRR)-induced interferon (IFN) is critical for effective immunity. The PRRs Toll-Like Receptor (TLR) 3, TLR4 and the cyclic GMP-AMP synthase (cGAS) signal through TANK-binding kinase 1 (TBK1), which phosphorylates and activates the type-I- and type-III-IFN-inducing transcription factor interferon-response factor 3 (IRF3). The mechanism by which these PRRs activate TBK1 remain unresolved. Here, we show that lysine 11 (K11)- linked ubiquitin chains drive TBK1 activation by these PRRs. The E3 ligase ANKIB1 attaches K11-linked ubiquitin chains to components of the TLR3- and cGAS-induced signalosomes. This facilitates recruitment of Optineurin (OPTN) to these complexes which, in turn, enables recruitment and activation of TBK1, defining a novel signalling axis. In mice, ANKIB1 deficiency dampens IFN induction via TLR3 and cGAS, reducing interferonopathy and compromising protection against HSV-1, respectively. Together, our results demonstrate an unanticipated and critical role for K11-linked ubiquitin in PRR-activated immune responses