Tollip, a new component of the IL-1RI pathway, links IRAK to the IL-1 receptor

Nat Cell Biol. 2000 Jun;2(6):346-51. doi: 10.1038/35014038.

Abstract

Interleukin-1 (IL-1) is a proinflammatory cytokine that elicits its pleiotropic effects through activation of the transcription factors NF-kappaB and AP-1. Binding of IL-1 to its receptor results in rapid assembly of a membrane-proximal signalling complex that consists of two different receptor chains (IL-1Rs), IL-1RI and IL-1RAcP, the adaptor protein MyD88, the serine/threonine kinase IRAK and a new protein, which we have named Tollip. Here we show that, before IL-1beta treatment, Tollip is present in a complex with IRAK, and that recruitment of Tollip-IRAK complexes to the activated receptor complex occurs through association of Tollip with IL-1RAcP. Co-recruited MyD88 then triggers IRAK autophosphorylation, which in turn leads to rapid dissociation of IRAK from Tollip (and IL-1Rs). As overexpression of Tollip results in impaired NF-kappaB activation, we conclude that Tollip is an important constituent of the IL-1R signalling pathway.

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Amino Acid Sequence
  • Animals
  • Antigens, Differentiation / chemistry
  • Antigens, Differentiation / genetics
  • Antigens, Differentiation / metabolism
  • Carrier Proteins / chemistry
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism*
  • Cell Line
  • Conserved Sequence / genetics
  • Enzyme Activation / drug effects
  • Humans
  • Interleukin-1 / pharmacology
  • Interleukin-1 Receptor-Associated Kinases
  • Intracellular Signaling Peptides and Proteins*
  • JNK Mitogen-Activated Protein Kinases
  • Kinetics
  • Mitogen-Activated Protein Kinases / metabolism
  • Models, Biological
  • Molecular Sequence Data
  • Mutation / genetics
  • Myeloid Differentiation Factor 88
  • NF-kappa B / metabolism
  • Phosphoprotein Phosphatases / metabolism
  • Phosphorylation / drug effects
  • Precipitin Tests
  • Protein Binding / drug effects
  • Protein Kinases / genetics
  • Protein Kinases / metabolism*
  • RNA, Messenger / analysis
  • RNA, Messenger / genetics
  • Receptors, Immunologic*
  • Receptors, Interleukin-1 / genetics
  • Receptors, Interleukin-1 / metabolism*
  • Sequence Alignment
  • Signal Transduction* / drug effects
  • Two-Hybrid System Techniques

Substances

  • Adaptor Proteins, Signal Transducing
  • Antigens, Differentiation
  • Carrier Proteins
  • Interleukin-1
  • Intracellular Signaling Peptides and Proteins
  • MYD88 protein, human
  • Myeloid Differentiation Factor 88
  • NF-kappa B
  • RNA, Messenger
  • Receptors, Immunologic
  • Receptors, Interleukin-1
  • TOLLIP protein, human
  • Protein Kinases
  • Interleukin-1 Receptor-Associated Kinases
  • JNK Mitogen-Activated Protein Kinases
  • Mitogen-Activated Protein Kinases
  • Phosphoprotein Phosphatases

Associated data

  • GENBANK/AJ242971
  • GENBANK/AJ242972