Journal
CELLULAR MICROBIOLOGY
Volume 8, Issue 11, Pages 1753-1767Publisher
BLACKWELL PUBLISHING
DOI: 10.1111/j.1462-5822.2006.00746.x
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Funding
- NCRR NIH HHS [S10 RR026365-01, S10 RR026365] Funding Source: Medline
- NEI NIH HHS [R01 EY010420-13A2, R01 EY010420-10A2, R01 EY010420-06, R29 EY010420-03, R01 EY010420-14, R01 EY010420-12, R01 EY010420-08, R01 EY010420, R29 EY010420, R01 EY010420-11, R01 EY010420-16, R01 EY010420-09, R21 EY018705, R21 EY018705-02, R21 EY018705-01A1, R01 EY010420-15, R01 EY010420-07] Funding Source: Medline
- NIDCR NIH HHS [DE12305, R01 DE009517, DE09517, R01 DE012305] Funding Source: Medline
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Actinobacillus actinomycetemcomitans produces a leukotoxin (Ltx) that kills leukocyte function-associated antigen-1 (LFA-1)-bearing cells from man, the Great Apes and Old World monkeys. The unique specificity of Ltx for the beta 2 integrin, LFA-1, suggests it is capable of providing insight into the pathogenic mechanisms of Ltx and other RTX toxins. Using the Jurkat T cell line and an LFA-1-deficient Jurkat mutant (J beta 2.7) as models, we found the initial effect of Ltx is to elevate cytosolic Ca2+ [Ca2+](c), an event that is independent of the Ltx/LFA-1 interaction. [Ca2+](c) increases initiate a series of events that involve the activation of calpain, talin cleavage, mobilization to, and subsequent clustering of, LFA-1 in cholesterol and sphingolipid-rich regions of the plasma membrane known as lipid rafts. The association of Ltx and LFA-1 within lipid rafts is essential for cell lysis. J beta 2.7 cells fail to accumulate Ltx in their raft fractions and are not killed, while cholesterol depletion experiments demonstrate the necessity of raft integrity for Ltx function. We propose that toxin-induced Ca2+ fluxes mobilize LFA-1 to lipid rafts where it associates with Ltx. These findings suggest that Ltx utilizes the raft to stimulate an integrin signalling pathway that leads to apoptosis of target cells.
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