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Interleukin-1 receptor-associated kinase (IRAK) -1-mediated NF-B activation requires cytosolic and nuclear activity

Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA

¹Correspondence: Department of Medicine, University of Alabama at Birmingham School of Medicine, 420 Boshell Bldg., 1808 7th Ave., South, Birmingham, AL 35294, USA. E-mail: eabraham{at}uab.edu

Interleukin-1 receptor-associated kinase (IRAK) -1 plays an essential role in Toll-like receptor/interleukin-1 receptor (TLR/IL-1R) -associated NF-B activation through its involvement in IKK activation, which then leads to subsequent IB degradation and NF-B nuclear translocation. In the present studies, we demonstrate a novel pathway in which IRAK-1 present in the nucleus participates in NF-B-dependent gene expression. Nuclear localization of IRAK-1 is increased on cellular stimulation with IL-1 and LPS, or CRM-1-dependent nuclear export blockade. Induction of IRAK-1 produces enhanced NF-B transcriptional activity that precedes IB- degradation and nuclear translocation of NF-B. IRAK-1 binds to the promoter of NF-B-regulated gene, IB-, and enhances binding of the NF-B p65 subunit to NF-B responsive elements within the IB- promoter. IRAK-1 phosphorylates histone H3 in vitro and is required for IL-1-induced phosphorylation of histone H3 at serine 10 in vivo. These data indicate that both cytosolic and nuclear actions of IRAK-1 participate in the activation of NF-B-dependent transcriptional events.—Liu, G., Park, Y.-J., Abraham, E. Interleukin-1 receptor-associated kinase (IRAK) -1-mediated NF-B activation requires cytosolic and nuclear activity.

Key Words: transcription • histone H3 • nuclear translocation • Toll-like receptor