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Phosphatidic acid is required for the constitutive ruffling and macropinocytosis of phagocytes

Michal Bohdanowicz1, Daniel Schlam, Martin Hermansson

  • 1Division of Cell Biology, Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.

Molecular Biology of the Cell
|April 12, 2013
PubMed

Insights

Immune cells like macrophages use phosphatidic acid (PA) to remodel their actin cytoskeleton for surveillance. This process involves specific enzymes and signaling proteins, enabling pathogen detection and uptake.

Area of Science:

  • Immunology
  • Cell Biology
  • Biochemistry

Background:

  • Macrophages and dendritic cells constantly scan their surroundings for foreign substances.
  • This immune surveillance relies on actin-rich cell protrusions and the formation of phagosomes and macropinosomes.
  • The specific signals driving this continuous cytoskeletal remodeling remain largely undefined.

Purpose of the Study:

  • To identify the molecular signals that induce constitutive cytoskeletal remodeling in macrophages and dendritic cells.
  • To elucidate the pathway responsible for the elevated levels of phosphatidic acid (PA) in the plasma membrane of these immune cells.

Main Methods:

  • Investigated the role of phosphatidic acid (PA) synthesis and its regulation in immune cells.
  • Utilized inhibitors of diacylglycerol kinase and phosphatidylinositol-4,5-bisphosphate 3-kinase.
  • Assessed the impact on T-cell lymphoma invasion and metastasis-inducing protein 1 (TIAM1) localization and Rac activity.
  • Monitored actin remodeling, ruffling, and macropinocytosis.

Main Results:

  • Macrophages and immature dendritic cells exhibit higher plasma membrane phosphatidic acid (PA) levels compared to nonphagocytic cells.
  • PA is synthesized via G protein-coupled phospholipase C and diacylglycerol kinase.
  • Inhibiting diacylglycerol kinase disrupts TIAM1 membrane binding, reduces Rac activity, and abolishes constitutive cell ruffling and macropinocytosis.
  • Phosphatidylinositol-4,5-bisphosphate 3-kinase activity is essential for PA accumulation and TIAM1 membrane association.

Conclusions:

  • A distinct, constitutive pathway of phosphatidic acid (PA) biosynthesis is identified as a key regulator of actin remodeling in immune surveillance.
  • This pathway involves the interplay of G protein-coupled phospholipase C, diacylglycerol kinase, phosphatidylinositol-4,5-bisphosphate 3-kinase, and TIAM1-Rac signaling.
  • The findings provide novel insights into the molecular mechanisms underlying the continuous immune surveillance capabilities of macrophages and dendritic cells.

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