TANK-Binding Kinase 1 (TBK1): Structure, Function, and Regulation

Abstract

Synopsis Originally discovered as a kinase that interacted with the effector proteins TANK and TRAF2 in a ternary complex that could activate NF-kB, TANK-binding kinase 1 (TBK1) has since been characterized as a key regulator of substrates ranging from cell proliferation and vesicle transport to xenophagic elimination of bacteria and antiviral immune response. Also known as NAK (NF-kB-activating kinase) or T2K (TRAF2-associated kinase), TBK1 is a ubiquitously expressed 729-amino-acid serine/threonine kinase that is a noncanonical IkB kinase family member, targeting the transcription factors IRF3 and IRF7 in the type I interferon response. TBK1 is composed of an N-terminal kinase domain (KD), which contains an activation loop between subdomains VII and VIII controlling its catalytic activity, and three C-terminal regulatory domains: a ubiquitin-like domain (ULD), which interacts with the KD rather than the known ubiquitin-binding proteins and appears to be necessary for substrate presentation and full activation of the kinase, a leucine zipper-containing dimerization domain (DD), and a small helix-loop-helix protein interaction module that has been termed the adaptor-binding (AB) motif. From TBK1 structural studies, the kinase has been shown to be a dimmer with the KD, ULD, and DD forming a three-way interface to position the kinase active sites away from one another and prevent productive autophosphorylation events required for TBK1 activation. Upon recognition of an upstream signal and recruitment to signaling complexes via its AB motif, TBK1 becomes activated either through local clustering of TBK1 molecules (mediates transactivation by autophosphorylation), or by IKKb phosphorylation of TBK1 serine residue 172 within its KD activation loop, both of which lead to the formation of a productive active site center. TBK1 has been shown to phosphorylate several substrates involved in a multitude of molecular events. Best understood today for its role in the induction of type I interferons, activated TBK1 has been shown to target two sites (seven serine/threonine residues) near the C-terminus of the transcription factor IRF3, which induces the production of type I interferons and facilitates an immediate inflammatory response; TBK1 also participates in vesicle transport and xenophagic elimination of bacteria. While TBK1 activation can promote host survival during infection, an unchecked TBK1 response can lead to detrimental effects ranging from cellular proliferation in transformed cells and insulin resistance to numerous autoimmune disorders, obesity, and glaucoma. For this reason, effector molecules have been sought and identified that control TBK1 activation and prevent its rampant activation from negating its beneficial effects.