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Treponema denticola major outer sheath protein impairs the cellular phosphoinositide balance that regulates neutrophil chemotaxis. - PubMed - NCBI
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PLoS One. 2013 Jun 3;8(6):e66209. doi: 10.1371/journal.pone.0066209. Print 2013.

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

Author information

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

Abstract

The major outer sheath protein (Msp) of Treponema denticola inhibits neutrophil polarization and directed chemotaxis together with actin dynamics in vitro in response to the chemoattractant N-formyl-methionine-leucine-phenylanine (fMLP). Msp disorients chemotaxis through inhibition of a Rac1-dependent signaling pathway, but the upstream mechanisms are unknown. We challenged murine bone marrow neutrophils with enriched native Msp to determine the role of phospholipid modifying enzymes in chemotaxis and actin assembly downstream of fMLP-stimulation. Msp modulated cellular phosphoinositide levels through inhibition of phosphatidylinositol 3-kinase (PI3-kinase) together with activation of the lipid phosphatase, phosphatase and tensin homolog deleted on chromosome 10 (PTEN). Impaired phosphatidylinositol[(3,4,5)]-triphosphate (PIP3) levels prevented recruitment and activation of the downstream mediator Akt. Release of the actin capping proteins gelsolin and CapZ in response to fMLP was also inhibited by Msp exposure. Chemical inhibition of PTEN restored PIP3 signaling, as measured by Akt activation, Rac1 activation, actin uncapping, neutrophil polarization and chemotaxis in response to fMLP-stimulation, even in the presence of Msp. Transduction with active Rac1 also restored fMLP-mediated actin uncapping, suggesting that Msp acts at the level of PIP3 in the hierarchical feedback loop of PIP3 and Rac1 activation. Taken together, Msp alters the phosphoinositide balance in neutrophils, impairing the cell "compass", which leads to inhibition of downstream chemotactic events.

PMID:
23755300
PMCID:
PMC3670873
DOI:
10.1371/journal.pone.0066209
[Indexed for MEDLINE]
Free PMC Article

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