The TBK1 binding domain of optineurin promotes type I interferon responses.

Pathogen-associated molecular pattern (PAMP) recognition leads to TANK-binding kinase (TBK1) polyubiquitination and activation by transautophosphorylation, resulting in IFN- production. Here, we describe a mouse model of optineurin insufficiency (Optn(157)) in which the TBK1-interacting N-terminus of optineurin was deleted. PAMP-stimulated cells from Optn(157) mice had reduced TBK1 activity, no phosphorylation of optineurin Ser(187), and mounted low IFN- responses. In contrast to pull-down assays where the presence of N-terminus was sufficient for TBK1 binding, both the N-terminal and the ubiquitin-binding regions of optineurin were needed for PAMP-induced binding. This report establishes optineurin as a positive regulator TBK1 via a bipartite interaction between these molecules.