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A promiscuous lipid-binding protein diversifies the subcellular sites of toll-like receptor signal transduction

Kevin S Bonham1, Megan H Orzalli2, Kachiko Hayashi3

  • 1Division of Gastroenterology, Boston Children's Hospital and Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA.

Cell
|February 18, 2014
PubMed

Insights

Toll-like receptors (TLRs) signal from various cell parts. The adaptor protein TIRAP enables this by binding to different lipids, allowing TLRs to activate immune responses from the plasma membrane and endosomes.

Area of Science:

  • Immunology
  • Cell Biology

Background:

  • Toll-like receptors (TLRs) are key components of the innate immune system.
  • TLRs reside on different organelles but converge on a common signaling pathway.
  • How TLRs activate common pathways from diverse locations is not fully understood.

Purpose of the Study:

  • To investigate the mechanism by which TLRs activate common signaling pathways from multiple subcellular locations.
  • To identify the role of the sorting adaptor TIRAP in TLR signaling regulation.

Main Methods:

  • Investigated TIRAP's function in regulating TLR signaling.
  • Examined TIRAP's interaction with phosphoinositides and its localization.
  • Analyzed the assembly of the myddosome complex and its role in cytokine expression.

Main Results:

  • TIRAP regulates TLR signaling from both the plasma membrane and endosomes.
  • TIRAP-dependent myddosome assembly is crucial for proinflammatory cytokine expression.
  • TIRAP's promiscuous phosphoinositide-binding domain allows it to survey multiple cellular compartments for activated TLRs.

Conclusions:

  • Promiscuity in TIRAP's lipid-binding domain facilitates TLR signal transduction from diverse subcellular sites.
  • This mechanism allows for effective innate immune responses despite varied TLR localization.
  • The findings provide insight into the adaptability of innate immunity signaling.

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