TANK-binding kinase 1 (TBK1) and inducible IkappaB-kinase (IKK) are central regulators of type-I interferon induction. TANK (TRAF family member-associated NF-kappa-B activator) is aadaptor protein that connects IKK complexes with IKK epsilon and TBK1 kinases [, ]. It negatively regulates NF-kappaB activation by DNA damage via inhibiting ubiquitination of TRAF6 []. It is also a negative regulator of osteoclastogenesis and bone formation [].
This is the ubiquitin-like domain (ULD) found in TANK-binding kinase 1 (TBK1). TBK1 is a serine/threonine kinase and a noncanonical member of the IKK family implicated in diverse cellular functions, including innate immune response as well as tumorigenesis and development []. It has been reported that the ULD of TBK1 regulates kinase activity, playing an important role in signaling and mediating interactions with other molecules in the IFN pathway. Deletion of ULD indicates that it is required for the kinase domain to form an enzymatically active conformation. TBK1 ULD has a ubiquitin-like structure and an Ile44 hydrophobic patch, which is conserved among ULDs and IKK and IKK-related proteins. This hydrophobic patch is involved in ULD-SDD interactions in TBK1 and other IKK and IKK-related proteins [].
The Tbk1/Ikki binding domain (TBD) is a 40 amino acid domain able to bind kinases which is essential for poly(I:C)-induced IRF activation []. The domain is found in the SINTBAD, TANK and NAP1 proteins. This domain is predicted to form an α-helix with residues essential for kinase binding clustering on one side [].
This entry represents the non-structural protein 6 (NSP6) from betacoronavirus. Recently, it was reported that SARS-CoV-2 NSP6 binds TANK binding kinase 1 (TBK1) to suppress interferon regulatory factor 3 (IRF3) phosphorylation which suppresses IFN-I signalling and production more efficiently than SARS-CoV and MERS-CoV [].Coronaviruses (CoV) redirect and rearrange host cell membranes as part of the viral genome replication and transcription machinery; they induce the formation of double-membrane vesicles in infected cells. CoV non-structural protein 6 (NSP6), a transmembrane-containing protein, together with NSP3 and NSP4, have the ability to induce double-membrane vesicles that are similar to those observed in severe acute respiratory syndrome (SARS) coronavirus-infected cells []. By itself, NSP6 can generate autophagosomes from the endoplasmic reticulum. Autophagosomes are normally generated as a cellular response to starvation to carry cellular organelles and long-lived proteins to lysosomes for degradation. Degradation through autophagy may provide an innate defense against virus infection, or conversely, autophagosomes can promote infection by facilitating the assembly of replicase proteins []. In additionto initiating autophagosome formation, NSP6 also limits autophagosome expansion regardless of how they were induced, i.e. whether they were induced directly by NSP6, or indirectly by starvation or chemical inhibition of MTOR signalling. This may favour coronavirus infection by compromising the ability of autophagosomes to deliver viral components to lysosomes for degradation [].
