IRAK1 and IRAK4 promote phosphorylation, ubiquitination, and degradation of MyD88 adaptor-like (Mal)

J Biol Chem. 2010 Jun 11;285(24):18276-82. doi: 10.1074/jbc.M109.098137. Epub 2010 Apr 16.

Abstract

Signal transduction by Toll-like receptor 2 (TLR2) and TLR4 requires the adaptors MyD88 and Mal (MyD88 adaptor-like) and serine/threonine kinases, interleukin-1 receptor-associated kinases IRAK1 and IRAK4. We have found that both IRAK1 and IRAK4 can directly phosphorylate Mal. In addition, co-expression of Mal with either IRAK resulted in depletion of Mal from cell lysates. This is likely to be due to Mal phosphorylation by the IRAKs because kinase-inactive forms of either IRAK had no effect. Furthermore, lipopolysaccharide stimulation resulted in ubiquitination and degradation of Mal, which was inhibited using an IRAK1/4 inhibitor or by knocking down expression of IRAK1 and IRAK4. MyD88 is not a substrate for either IRAK and did not undergo degradation. We therefore conclude that Mal is a substrate for IRAK1 and IRAK4 with phosphorylation promoting ubiquitination and degradation of Mal. This process may serve to negatively regulate signaling by TLR2 and TLR4.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line
  • Gene Expression Regulation*
  • Humans
  • Interleukin-1 Receptor-Associated Kinases / metabolism*
  • Lipopolysaccharides / chemistry
  • Mass Spectrometry / methods
  • Membrane Transport Proteins / metabolism*
  • Models, Biological
  • Myelin Proteins / metabolism*
  • Myelin and Lymphocyte-Associated Proteolipid Proteins
  • Myeloid Differentiation Factor 88 / metabolism*
  • Phosphorylation
  • Proteolipids / metabolism*
  • Signal Transduction
  • Toll-Like Receptor 2 / metabolism
  • Toll-Like Receptor 4 / metabolism
  • Ubiquitin / chemistry

Substances

  • Lipopolysaccharides
  • MAL protein, human
  • MYD88 protein, human
  • Membrane Transport Proteins
  • Myelin Proteins
  • Myelin and Lymphocyte-Associated Proteolipid Proteins
  • Myeloid Differentiation Factor 88
  • Proteolipids
  • TLR2 protein, human
  • TLR4 protein, human
  • Toll-Like Receptor 2
  • Toll-Like Receptor 4
  • Ubiquitin
  • IRAK1 protein, human
  • IRAK4 protein, human
  • Interleukin-1 Receptor-Associated Kinases