The roles of two IκB kinase-related kinases in lipopolysaccharide and double stranded RNA signaling and viral infection

H Hemmi, O Takeuchi, S Sato, M Yamamoto… - The Journal of …, 2004 - rupress.org
H Hemmi, O Takeuchi, S Sato, M Yamamoto, T Kaisho, H Sanjo, T Kawai, K Hoshino…
The Journal of experimental medicine, 2004rupress.org
Viral infection and stimulation with lipopolysaccharide (LPS) or double stranded RNA
(dsRNA) induce phosphorylation of interferon (IFN) regulatory factor (IRF)-3 and its
translocation to the nucleus, thereby leading to the IFN-β gene induction. Recently, two IκB
kinase (IKK)–related kinases, inducible IκB kinase (IKK-i) and TANK-binding kinase 1
(TBK1), were suggested to act as IRF-3 kinases and be involved in IFN-β production in Toll-
like receptor (TLR) signaling and viral infection. In this work, we investigated the …
Viral infection and stimulation with lipopolysaccharide (LPS) or double stranded RNA (dsRNA) induce phosphorylation of interferon (IFN) regulatory factor (IRF)-3 and its translocation to the nucleus, thereby leading to the IFN-β gene induction. Recently, two IκB kinase (IKK)–related kinases, inducible IκB kinase (IKK-i) and TANK-binding kinase 1 (TBK1), were suggested to act as IRF-3 kinases and be involved in IFN-β production in Toll-like receptor (TLR) signaling and viral infection. In this work, we investigated the physiological roles of these kinases by gene targeting. TBK1-deficient embryonic fibroblasts (EFs) showed dramatic decrease in induction of IFN-β and IFN-inducible genes in response to LPS or dsRNA as well as after viral infection. However, dsRNA-induced expression of these genes was residually detected in TBK1-deficient cells and intact in IKK-i–deficient cells, but completely abolished in IKK-i/TBK1 doubly deficient cells. IRF-3 activation, in response not only to dsRNA but also to viral infection, was impaired in TBK1-deficient cells. Together, these results demonstrate that TBK1 as well as, albeit to a lesser extent, IKK-i play a crucial role in the induction of IFN-β and IFN-inducible genes in both TLR-stimulated and virus-infected EFs.
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