A novel splice variant of mouse interleukin-1-receptor-associated kinase-1 (IRAK-1) activates nuclear factor-kappaB (NF-kappaB) and c-Jun N-terminal kinase (JNK)

Biochem J. 2003 Feb 15;370(Pt 1):159-66. doi: 10.1042/BJ20021218.

Abstract

Interleukin-1 (IL-1)-receptor-associated kinase (IRAK) is an indispensable signalling molecule for host-defence responses initiated by a variety of ligands that bind to members of the Toll/IL-1 receptor family. Here we report a novel splice variant of mouse IRAK-1, IRAK-1-S, which is generated by utilizing a new splicing acceptor site within exon 12. IRAK-1-S cDNA is shorter than the originally reported IRAK-1 (IRAK-1-W) cDNA by 271 nucleotides, and the subsequent frameshift causes a premature termination of translation after 23 amino acids, which are unique to the IRAK-1-S protein. To elucidate the physiological function of IRAK-1-S, we overexpressed it in 293T cells and studied the effects on the IL-1 signalling cascade. As it lacks the C-terminal region of IRAK-1-W that has been reported to contain the TRAF6 (tumour necrosis factor receptor-associated factor 6) binding domain, IRAK-1-S was unable to bind TRAF6 protein, which is a proposed downstream signalling molecule. However, IRAK-1-S overexpressed in 293T cells induced constitutive activation of nuclear factor-kappaB (NF-kappaB) and c-Jun N-terminal kinase (JNK) independent of stimulation by IL-1, as did IRAK-1-W. To clarify the mechanism of NF-kappaB activation by IRAK-1-S in the absence of binding to TRAF6, we demonstrated that IRAK-1-S binds to IRAK-1-W through its death domain; the findings suggested that overexpressed IRAK-1-S may bind endogenous IRAK-1-W and activate TRAF6 through IRAK-1-W. These results also indicate that this novel variant may play roles in the activation of NF-kappaB and JNK by IL-1 and other ligands whose signal transduction is dependent on IRAK-1 under physiological conditions.

MeSH terms

  • Alternative Splicing*
  • Animals
  • Base Sequence
  • Cloning, Molecular
  • DNA / metabolism
  • DNA, Complementary
  • Electrophoretic Mobility Shift Assay
  • Enzyme Activation
  • Exons
  • Interleukin-1 / pharmacology
  • Interleukin-1 Receptor-Associated Kinases
  • JNK Mitogen-Activated Protein Kinases
  • Mice
  • Mitogen-Activated Protein Kinases / metabolism*
  • Molecular Sequence Data
  • NF-kappa B / metabolism*
  • Protein Kinases / genetics
  • Protein Kinases / metabolism
  • Protein Kinases / physiology*
  • RNA, Messenger / genetics
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction

Substances

  • DNA, Complementary
  • Interleukin-1
  • NF-kappa B
  • RNA, Messenger
  • DNA
  • Protein Kinases
  • Interleukin-1 Receptor-Associated Kinases
  • JNK Mitogen-Activated Protein Kinases
  • Mitogen-Activated Protein Kinases

Associated data

  • GENBANK/AB088370
  • GENBANK/AB088390