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 (IEL-M) and triggers a number of intracellular signaling cascade s leading to activation of transcription factors, transcriptional up-regula tion of target genes, and mRNA stabilization. IL-1RI-associated kinase-1 (I RAK1) is a membrane proximal serine-threonine kinase involved in IL-1 signa ling 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 spli ce site defined by sequence within exon 12 of IRAK1. IRAK1b mRNA exhibits w ide tissue expression and is evolutionarily conserved in both mouse and hum an. IRAK1b can activate the transcription factor nuclear factor KB and inte racts with the IL-1 signaling factors Toll-interacting protein and tumor ne crosis factor receptor-associated factor 6. It forms homodimers and heterod imers with the previously described isoform of IRAK1. We show that the IRAK 1b protein is kinase-inactive and that, unlike IRAK1, its levels remain con stant after IL-1 induction. The presence of an alternative splice variant o f IRAK1, which is functionally active and highly stable following IL-1 stim ulation, adds further complexity to the control mechanisms that govern IL-1 signaling.