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Journal of Biochemistry Advance Access originally published online on December 13, 2007
Journal of Biochemistry 2008 143(3):295-302; doi:10.1093/jb/mvm234
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© 2007 The Japanese Biochemical Society.

IRAK-4-dependent Degradation of IRAK-1 is a Negative Feedback Signal for TLR-mediated NF-{kappa}B Activation

Miho Kubo-Murai1, Kaoru Hazeki1,*, Kiyomi Nigorikawa1, Takatoshi Omoto1, Norimitsu Inoue2 and Osamu Hazeki1

1Division of Molecular Medical Science, Graduate School of Biomedical Sciences, Hiroshima University, Minami-ku, Hiroshima 734-8553; and 2Department of Immunology, Osaka Medical Center for Cancer and Cardiovascular Diseases, Higashinari-ku, Osaka 537-8511, Japan

*To whom correspondence should be addressed. Tel: +8182 257 5308, Fax: +81 82 257 5309, E-mail: khazeki{at}hiroshima-u.ac.jp

Received August 20, 2007; Accepted November 3, 2007


  Abstract

The activation of interleukin 1 receptor-associated kinase (IRAK)-1 is a key event in the transmission of signals from Toll-like receptors (TLRs). The catalytic activity of the protein kinase is not essential for its ability to activate nuclear factor (NF) {kappa}B, because transfection of a kinase-dead mutant of IRAK-1 (IRAK-1KD) is able to activate NF-{kappa}B in HEK293T cells. In the present study, we observed that the effect of IRAK-1KD was impaired by simultaneous expression of IRAK-4. The effect of IRAK-4 was accompanied by the phosphorylation and degradation of IRAK-1KD. Expression of IRAK-4KD instead of IRAK-4 did not cause these events. In IRAK-4-deficient Raw264.7 macrophages that were prepared by introducing short-hairpin RNA probes, the basal level of IRAK-1 was increased markedly. Stimulation of these cells with TLR ligands did not cause the degradation of IRAK-1, which was clearly observed in the parent cells. These results suggested that the expression of IRAK-4 alone is sufficient to cause the degradation of IRAK-1; the autophosphorylation of IRAK-1 is not necessary to terminate the TLR-induced activation of NF-{kappa}B. IRAK-4 has an ability to induce the degradation of IRAK-1 in addition to its role as an activator of IRAK-1.

Key Words: IRAK, LPS, NF-{kappa}B, phosphorylation, TLR

Abbreviations: IFN, interferon; IRF, IFN regulatory factor; IKK, I{kappa}B kinase; IL, interleukin; IRAK, IL-1R-associated kinase; LPS, lipopolysaccharide; MAPK, mitogen-activated protein kinase; NEMO, NF-{kappa}B essential modulator; shRNA, short-hairpin RNA; TIR, Toll-IL1 receptor homology domain; TLR, Toll-like receptor; TNF, tumour necrosis factor; TRAF, TNF receptor-associated factor; TRIF, TIR domain-containing adaptor inducing IFN-β


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