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Lymphoid susceptibility to the Aggregatibacter actinomycetemcomitans cytolethal distending toxin is dependent upon baseline levels of the signaling lipid, phosphatidylinositol‐3,4,5‐triphosphate
Author(s) -
Shenker B.J.,
Walker L.P.,
Zekavat A.,
BoeszeBattaglia K.
Publication year - 2016
Publication title -
molecular oral microbiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.18
H-Index - 77
eISSN - 2041-1014
pISSN - 2041-1006
DOI - 10.1111/omi.12127
Subject(s) - cytolethal distending toxin , jurkat cells , phosphatidylinositol , biology , signal transduction , microbiology and biotechnology , cancer research , t cell , toxin , immunology , microbial toxins , immune system
Summary The Aggregatibacter actinomycetemcomitans cytolethal distending toxin (Cdt) induces G2 arrest and apoptosis in lymphocytes and other cell types. We have shown that the active subunit, CdtB, exhibits phosphatidylinositol‐3,4,5‐triphosphate ( PIP 3) phosphatase activity and depletes lymphoid cells of PIP 3. Hence we propose that Cdt toxicity results from depletion of this signaling lipid and perturbation of phosphatidylinositol‐3‐kinase ( PI ‐3K)/ PIP 3/Akt signaling. We have now focused on the relationship between cell susceptibility to CdtB and differences in the status of baseline PIP 3 levels. Our studies demonstrate that the baseline level of PIP 3, and likely the dependence of cells on steady‐state activity of the PI ‐3K signaling pathway for growth and survival, influence cell susceptibility to the toxic effects of Cdt. Jurkat cells with known defects in both PIP 3 degradative enzymes, PTEN and SHIP 1, not only contain high baseline levels of PIP 3, pA kt, and pGSK 3β, but also exhibit high sensitivity to Cdt. In contrast, HUT 78 cells, with no known defects in this pathway, contain low levels of PIP 3, pA kt, and pGSK 3β and likely minimal dependence on the PI ‐3K signaling pathway for growth and survival, and exhibit reduced susceptibility to Cdt. These differences in susceptibility to Cdt cannot be explained by differential toxin binding or internalization of the active subunit. Indeed, we now demonstrate that Jurkat and HUT 78 cells bind toxin at comparable levels and internalize relatively equal amounts of CdtB. The relevance of these observations to the mode of action of Cdt and its potential role as a virulence factor is discussed.