title: Interleukin-1 receptor-associated kinase (IRAK) -1-mediated NF-kappaB activation requires cytosolic and nuclear activity.
abstract: Interleukin-1 receptor-associated kinase (IRAK) -1 plays an essential role in Toll-like receptor/interleukin-1 receptor (TLR/IL-1R) -associated NF-kappaB activation through its involvement in IKK activation, which then leads to subsequent IkappaB degradation and NF-kappaB nuclear translocation. In the present studies, we demonstrate a novel pathway in which IRAK-1 present in the nucleus participates in NF-kappaB-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-kappaB transcriptional activity that precedes IkappaB-alpha degradation and nuclear translocation of NF-kappaB. IRAK-1 binds to the promoter of NF-kappaB-regulated gene, IkappaB-alpha, and enhances binding of the NF-kappaB p65 subunit to NF-kappaB responsive elements within the IkappaB-alpha 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-kappaB-dependent transcriptional events.
authors.affiliation: Department of Medicine, University of Alabama at Birmingham School of Medicine, Birmingham, AL 35294, USA.
authors.forename: Gang
authors.initials: G
authors.lastname: Liu
authors.forename: Young-Jun
authors.initials: YJ
authors.lastname: Park
authors.forename: Edward
authors.initials: E
authors.lastname: Abraham
mesh_terms: D000818:Animals; D001483:Base Sequence; D001943:Breast Neoplasms; D002460:Cell Line; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000201:enzymology*; D003600:Cytosol / Q000201:enzymology*; D017931:DNA Primers; D005260:Female; D006801:Humans; D053592:Interleukin-1 Receptor-Associated Kinases / Q000235:genetics* / Q000378:metabolism*; D007668:Kidney / Q000196:embryology; D008264:Macrophages / Q000502:physiology; D051379:Mice; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics
chemical_list: D017931:DNA Primers; D016328:NF-kappa B; D012333:RNA, Messenger; D053592:Interleukin-1 Receptor-Associated Kinases