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Screening Bioactive Nanoparticles in Phagocytic Immune Cells for Inhibitors of Toll-like Receptor Signaling
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TIRAP, an adaptor protein for TLR2/4, transduces a signal from RAGE phosphorylated upon ligand binding

Masakiyo Sakaguchi1, Hitoshi Murata, Ken-ichi Yamamoto

  • 1Department of Cell Biology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Kita-ku, Okayama, Japan.

Plos One
|August 11, 2011
PubMed

Insights

The receptor for advanced glycation end products (RAGE) is phosphorylated upon ligand binding, activating downstream signaling. This involves Toll-like receptor adaptors TIRAP and MyD88, revealing a novel RAGE-TLR interaction in cellular regulation.

Area of Science:

  • Molecular biology
  • Cellular signaling
  • Immunology

Background:

  • The receptor for advanced glycation end products (RAGE) is implicated in numerous inflammatory and degenerative diseases.
  • RAGE binds diverse ligands, activating intracellular pathways, but downstream molecular events remain unclear.

Purpose of the Study:

  • To elucidate the immediate molecular events following ligand binding to RAGE.
  • To identify key proteins involved in RAGE-mediated intracellular signaling.

Main Methods:

  • Investigated the phosphorylation of RAGE's cytoplasmic domain using PKCζ.
  • Examined the interaction of RAGE with adaptor proteins TIRAP and MyD88.
  • Assessed the impact of blocking TIRAP and MyD88 on RAGE signaling.

Main Results:

  • Ligand binding induced phosphorylation of RAGE at Ser391 by PKCζ.
  • Phosphorylated RAGE recruited adaptor proteins TIRAP and MyD88.
  • Inhibition of TIRAP and MyD88 significantly blocked intracellular signaling from ligand-activated RAGE.

Conclusions:

  • RAGE signaling is initiated by ligand-induced phosphorylation.
  • TIRAP and MyD88 act as crucial adaptors linking RAGE to downstream signaling pathways.
  • Functional interaction between RAGE and Toll-like receptors (TLRs) coordinates inflammatory and immune responses.

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