TANK-binding kinase 1 as a novel therapeutic target for viral diseases

Abstract

Introduction: TANK-binding kinase 1 (TBK1) is vital for the induction of antiviral innate immune responses. Both RNA and DNA viral infection induces TBK1 activation, triggers phosphorylation of interferon regulatory factor (IRF) 3 and subsequent expression of type I interferons (IFNs; IFN-α/β). Type I IFNs can induce the expression of numerous antiviral genes called interferon-stimulated genes (ISGs) to build a remarkable antiviral state and limit viral replication. Thus, optimal TBK1 activity is crucial for IRF3-induced type I IFNs expression and ISGs-mediated viral elimination. Areas covered: This review provides an overview of the diverse roles of TBK1 in antiviral innate immune responses, the regulatory mechanisms of TBK1 activity and the implication in antiviral development. Expert opinion: TBK1 is a key kinase against antiviral infection via inducing type I IFNs expression. Multiple types of post-translational modifications of TBK1 tightly regulate TBK1 activity and subsequent TBK1-dependent antiviral responses. The identified regulators of TBK1 unveil regulatory mechanisms of host antiviral innate immunity and immuno-escape mechanism of virus provide strategies to control viral diseases by modulating TBK1 activity.

Enteroviruses and T1D: Is It the Virus, the Genes or Both which Cause T1D

“…In the largely non-replicative β-cells, such an increase in the IFN response seems deleterious. The intracellular antiviral defence is initiated by TBK1-IRF3-mediated interferon production (see Section 6 and Section 7 above) [ 134 ] and controlled by the Hippo terminators and transcriptional regulators YAP and TAZ [ 135 , 136 , 137 ], which negatively regulate and thus balance the antiviral immune response. Recent studies have linked YAP/TAZ with antiviral sensing [ 135 , 136 , 137 ].…”

A Novel Transcript Isoform of TBK1 Negatively Regulates Type I IFN Production by Promoting Proteasomal Degradation of TBK1 and Lysosomal Degradation of IRF3

“…When ectopically expressed TBK1_tv3 was immunoprecipitated by FLAG, the ubiquitination of TBK1 was obviously increased in the presence of TBK1_tv3 ( Figure 6A ). It has been documented that the accumulation and function of TBK1 is regulated by both K48-linked and K63-linked ubiquitination ( 8 , 9 ). To determine the specific ubiquitination type of TBK1, we transfected HEK 293T cells with FLAG-TBK1, TBK1_tv3-GFP, HA-tagged K48-linked ubiquitin (Ub-HA K48), or K63-linked ubiquitin (Ub-HA K63).…”

“…TBK1 is regulated by adaptor proteins and many other molecules, which control its activation and participation in different signaling pathways. In mammals, multiple mechanisms including posttranslational modification of TBK1, kinase activity modulation, and prevention of functional TBK1-containing complexes formation are associated with the regulation of TBK1 activity ( 8 , 9 ). For example, DYRK2 promotes proteasomal degradation of TBK1 to attenuate antiviral responses by phosphorylating TBK1 at Ser527 ( 10 ).…”

Systems vaccinology analysis of a recombinant vaccinia-based vector reveals diverse innate immune signatures at the injection site

“…IL-1 receptor signaling (see below) also involves many of the same signaling molecules as TLR signaling (Rhyasen et al ., 2015). The dominance of TBK1 may reflect its involvement in a series of signaling pathways; specifically, TLRs (including TLR3), STING and MDA5/MAVS (Zhao et al ., 2019) that were illustrated in Fig. 2.…”