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Rab8a localisation and activation by Toll-like receptors on macrophage macropinosomes

Adam A Wall1, Nicholas D Condon1, Lin Luo1

  • 1Institute for Molecular Bioscience (IMB) and IMB Centre for Inflammation and Disease Research, University of Queensland , Brisbane, Queensland 4072 , Australia.

Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences
|April 11, 2019
PubMed

Insights

Macropinocytosis in macrophages is upregulated by Toll-like receptors (TLRs). Rab8a GTPase is activated on macropinosomes, regulating innate immune responses via effectors OCRL and PI3Kγ.

Area of Science:

  • Cell Biology
  • Immunology
  • Macrophage Biology

Background:

  • Macropinocytosis is crucial for macrophage functions, including antimicrobial responses and environmental sampling.
  • Cell surface ruffles form macropinosomes, which are dynamic compartments involved in pathogen entry and signaling.
  • Toll-like receptor (TLR) activation by pathogens upregulates macropinocytosis in macrophages.

Purpose of the Study:

  • To investigate the role of Rab8a GTPase in TLR-induced macropinocytosis.
  • To identify the localization and activation site of Rab8a during macropinosome formation.
  • To elucidate the downstream effectors of Rab8a in regulating macrophage innate immunity.

Main Methods:

  • High-resolution lattice light sheet imaging of live macrophages.
  • Fluorescently tagging and tracking of membrane-associated Rab8a.
  • Development and use of a novel biosensor for quantitative Förster Resonance Energy Transfer (FRET) analysis.
  • Microscopy and cell marker analysis to determine Rab8a localization.

Main Results:

  • Rab8a localizes to and enriches on early macropinosomes in live macrophages.
  • TLR-induced activation of Rab8a occurs specifically on macropinosomes.
  • Rab8a interacts with effectors PI3Kγ and OCRL on macropinosomes, modulating phosphoinositide levels.
  • Rab8a regulates TLR signaling, cytokine production, and macrophage programming.

Conclusions:

  • Macropinosomes act as regulatory compartments for innate immune functions in macrophages.
  • Rab8a plays a central role in integrating TLR signaling with macropinocytosis.
  • Rab8a's interaction with OCRL and PI3Kγ highlights its multi-level regulation of phosphoinositides in macropinosomes.
Keywords:
FRETRab GTPaseToll-like receptorsmacropinocytosisphosphoinositidesruffles

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