| First Author | Bakshi S | Year | 2017 |
| Journal | Biochem J | Volume | 474 |
| Issue | 7 | Pages | 1163-1174 |
| PubMed ID | 28159912 | Mgi Jnum | J:246386 |
| Mgi Id | MGI:5925198 | Doi | 10.1042/BCJ20160992 |
| Citation | Bakshi S, et al. (2017) Identification of TBK1 complexes required for the phosphorylation of IRF3 and the production of interferon beta. Biochem J 474(7):1163-1174 |
| abstractText | The double-stranded RNA mimetic poly(I:C) and lipopolysaccharide (LPS) activate Toll-like receptors 3 (TLR3) and TLR4, respectively, triggering the activation of TANK (TRAF family member-associated NF-kappaB activator)-binding kinase 1 (TBK1) complexes, the phosphorylation of interferon regulatory factor 3 (IRF3) and transcription of the interferon beta (IFNbeta) gene. Here, we demonstrate that the TANK-TBK1 and optineurin (OPTN)-TBK1 complexes control this pathway. The poly(I:C)- or LPS-stimulated phosphorylation of IRF3 at Ser396 and production of IFNbeta were greatly reduced in bone marrow-derived macrophages (BMDMs) from TANK knockout (KO) mice crossed to knockin mice expressing the ubiquitin-binding-defective OPTN[D477N] mutant. In contrast, IRF3 phosphorylation and IFNbeta production were not reduced significantly in BMDM from OPTN[D477N] knockin mice and only reduced partially in TANK KO BMDM. The TLR3/TLR4-dependent phosphorylation of IRF3 and IFNbeta gene transcription were not decreased in macrophages from OPTN[D477N] crossed to mice deficient in IkappaB kinase epsilon, a TANK-binding kinase related to TBK1. In contrast with the OPTN-TBK1 complex, TBK1 associated with OPTN[D477N] did not undergo phosphorylation at Ser172 in response to poly(I:C) or LPS, indicating that the interaction of ubiquitin chains with OPTN is required to activate OPTN-TBK1 in BMDM. The phosphorylation of IRF3 and IFNbeta production induced by Sendai virus infection were unimpaired in BMDM from TANK KO x OPTN[D477N] mice, suggesting that other/additional TBK1 complexes control the RIG-I-like receptor-dependent production of IFNbeta. Finally, we present evidence that, in human HACAT cells, the poly(I:C)-dependent phosphorylation of TBK1 at Ser172 involves a novel TBK1-activating kinase(s). |
