Actinobacillus actinomycetemcomitans leukotoxin and

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We propose that toxin-induced Ca 2 + 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.

SummaryAggregatibacter actinomycetemcomitans leukotoxin (Ltx) is a repeats-in-toxin (RTX) cytolysin that kills human leukocyte function-associated antigen-1 (LFA-1; aL/b2)-bearing cells. In order to determine whether the aL portion of the heterodimer is involved in Ltx recognition, we transfected human, mouse and bovine aL cDNAs into J-b2.7, an aL-deficient cell line, and looked for restoration of Ltx susceptibility. Cells expressing either bovine or human aL in conjunction with human b2 were efficiently killed by Ltx, an indication that bovine aL could substitute for its human counterpart in critical regions used by Ltx for attachment to LFA-1. On the other hand, cells expressing murine aL and human b2 were not susceptible to the lethal effects of Ltx indicating that the toxin recognition sites are not present in the corresponding mouse sequence. To further identify the region(s) of aL recognized by Ltx, we constructed and evaluated a panel of chimeric human/murine aL genes in J-b2.7 cells. Analysis of the aL mutant panel showed that the presence of human N-terminal 128 amino acids on a mouse CD11a background, a region that includes b-sheets 1 and 2 of the b-propeller of the human aL chain, was sufficient for Ltx cytolysis.