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Treponema denticola major outer sheath protein impairs the cellular phosphoinositide balance that regulates

Michelle B Visser1, Chun-Xiang Sun, Adeline Koh

  • 1Matrix Dynamics Group, Dental Research Institute, University of Toronto, Toronto, Ontario, Canada. michelle.visser@utoronto.ca

Plos One
|June 12, 2013
PubMed

Insights

Treponema denticola's Msp protein disrupts neutrophil chemotaxis by altering phosphoinositide balance, inhibiting PI3-kinase and activating PTEN. Restoring PIP3 signaling with PTEN inhibition reverses these effects.

Area of Science:

  • Immunology
  • Microbiology
  • Cell Biology

Background:

  • The major outer sheath protein (Msp) from Treponema denticola interferes with neutrophil functions like polarization and chemotaxis.
  • Msp's mechanism involves inhibiting a Rac1-dependent pathway, but upstream regulators remain unclear.

Purpose of the Study:

  • To investigate the role of phospholipid-modifying enzymes in Msp's disruption of neutrophil chemotaxis and actin dynamics.
  • To elucidate the upstream signaling events affected by Msp in response to N-formyl-methionine-leucine-phenylanine (fMLP).

Main Methods:

  • Murine bone marrow neutrophils were stimulated with Msp and fMLP.
  • Phosphoinositide levels, including phosphatidylinositol (3,4,5)-triphosphate (PIP3), were analyzed.
  • Activation of downstream mediators like Akt and Rac1 was assessed.
  • Actin dynamics, including the release of gelsolin and CapZ, were monitored.
  • The effects of PTEN inhibition and active Rac1 transduction were evaluated.

Main Results:

  • Msp inhibited phosphatidylinositol 3-kinase (PI3-kinase) and activated PTEN, leading to reduced PIP3 levels.
  • Decreased PIP3 impaired Akt recruitment and activation.
  • Msp inhibited the fMLP-induced release of actin-capping proteins gelsolin and CapZ.
  • Inhibition of PTEN restored PIP3 signaling, Akt and Rac1 activation, actin uncapping, polarization, and chemotaxis.
  • Active Rac1 transduction also restored fMLP-mediated actin uncapping.

Conclusions:

  • Msp disrupts neutrophil chemotaxis by altering the phosphoinositide balance, specifically by inhibiting PI3-kinase and activating PTEN.
  • This leads to reduced PIP3 levels, impairing downstream signaling pathways crucial for cell polarization and directed movement.
  • Msp's action occurs upstream of Rac1 activation, within the feedback loop regulating PIP3 and Rac1.
  • Restoring PIP3 levels via PTEN inhibition effectively counteracts Msp's inhibitory effects on neutrophil chemotaxis.

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