DOI: 10.1084/jem.20040520. The Roles of Two IκB Kinase-related Kinases in Lipopolysaccharide and Double Stranded RNA Signaling and Viral Infection

The Roles of Two IκB Kinase-related Kinases in Lipopolysaccharide and Double Stranded RNA Signaling and Viral Infection

10.1084/jem.20040520

Crossref journal-article

Rockefeller University Press

The Journal of Experimental Medicine (291)

Abstract

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.

Bibliography

Hemmi, H., Takeuchi, O., Sato, S., Yamamoto, M., Kaisho, T., Sanjo, H., Kawai, T., Hoshino, K., Takeda, K., & Akira, S. (2004). The Roles of Two IÎºB Kinase-related Kinases in Lipopolysaccharide and Double Stranded RNA Signaling and Viral Infection. The Journal of Experimental Medicine, 199(12), 1641â1650.

Authors 10

Hiroaki Hemmi (first)
Osamu Takeuchi (additional)
Shintaro Sato (additional)
Masahiro Yamamoto (additional)
Tsuneyasu Kaisho (additional)
Hideki Sanjo (additional)
Taro Kawai (additional)
Katsuaki Hoshino (additional)
Kiyoshi Takeda (additional)
Shizuo Akira (additional)

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Dates

Type	When
Created	21 years, 2 months ago (June 21, 2004, 2:43 p.m.)
Deposited	2 years, 1 month ago (July 25, 2023, 8:34 a.m.)
Indexed	1 month, 1 week ago (July 23, 2025, 8:26 a.m.)
Issued	21 years, 2 months ago (June 21, 2004)
Published	21 years, 2 months ago (June 21, 2004)
Published Online	21 years, 2 months ago (June 21, 2004)
Published Print	21 years, 2 months ago (June 21, 2004)

Funders 0

None

BibTeX

@article{Hemmi_2004, title={The Roles of Two IκB Kinase-related Kinases in Lipopolysaccharide and Double Stranded RNA Signaling and Viral Infection}, volume={199}, ISSN={0022-1007}, url={http://dx.doi.org/10.1084/jem.20040520}, DOI={10.1084/jem.20040520}, number={12}, journal={The Journal of Experimental Medicine}, publisher={Rockefeller University Press}, author={Hemmi, Hiroaki and Takeuchi, Osamu and Sato, Shintaro and Yamamoto, Masahiro and Kaisho, Tsuneyasu and Sanjo, Hideki and Kawai, Taro and Hoshino, Katsuaki and Takeda, Kiyoshi and Akira, Shizuo}, year={2004}, month=jun, pages={1641–1650} }

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  "abstract": "<jats:p>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-\u03b2 gene induction. Recently, two I\u03baB kinase (IKK)\u2013related kinases, inducible I\u03baB kinase (IKK-i) and TANK-binding kinase 1 (TBK1), were suggested to act as IRF-3 kinases and be involved in IFN-\u03b2 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-\u03b2 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\u2013deficient 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-\u03b2 and IFN-inducible genes in both TLR-stimulated and virus-infected EFs.</jats:p>",
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