IRAK1b, a novel alternative splice variant of interleukin-1 receptor-associated kinase (IRAK), mediates interleukin-1 signaling and has prolonged stability.
Interleukin-1 (IL-1) is a pleiotropic cytokine essential for initiation of the immune response to infections and stress. IL-1 interacts with its type I receptor (IL-1RI) and triggers a number of intracellular signaling cascades leading to activation of transcription factors, transcriptional up-regulation of target genes, and mRNA stabilization. IL-1RI-associated kinase-1 (IRAK1) is a membrane proximal serine-threonine kinase involved in IL-1 signaling that becomes phosphorylated and progressively degraded in response to IL-1 induction. We have identified a novel variant of IRAK1, which we have named IRAK1b, that arises from the use of an alternative 5'-acceptor splice site defined by sequence within exon 12 of IRAK1. IRAK1b mRNA exhibits wide tissue expression and is evolutionarily conserved in both mouse and human. IRAK1b can activate the transcription factor nuclear factor kappaB and interacts with the IL-1 signaling factors Toll-interacting protein and tumor necrosis factor receptor-associated factor 6. It forms homodimers and heterodimers with the previously described isoform of IRAK1. We show that the IRAK1b protein is kinase-inactive and that, unlike IRAK1, its levels remain constant after IL-1 induction. The presence of an alternative splice variant of IRAK1, which is functionally active and highly stable following IL-1 stimulation, adds further complexity to the control mechanisms that govern IL-1 signaling.
Jensen
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Department of Pharmacology and Center for Pharmacogenetics, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. jensen@pharm.med.upenn.edu
Whitehead
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D017398:Alternative Splicing; D000595:Amino Acid Sequence; D001483:Base Sequence; D006528:Carcinoma, Hepatocellular; D002460:Cell Line; D003001:Cloning, Molecular; D005091:Exons; D014644:Genetic Variation; D006207:Half-Life; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology / Q000502:physiology*; D053592:Interleukin-1 Receptor-Associated Kinases; D007668:Kidney; D007700:Kinetics; D008113:Liver Neoplasms; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000378:metabolism; D020033:Protein Isoforms / Q000378:metabolism; D011494:Protein Kinases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D011994:Recombinant Proteins / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D014162:Transfection; D014407:Tumor Cells, Cultured
D007375:Interleukin-1; D016328:NF-kappa B; D020033:Protein Isoforms; D012333:RNA, Messenger; D011994:Recombinant Proteins; D011494:Protein Kinases; C507768:IRAK1 protein, human; D053592:Interleukin-1 Receptor-Associated Kinases; C507769:Irak1 protein, mouse