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Infect Immun. 2008 Apr;76(4):1349-57. doi: 10.1128/IAI.01162-07. Epub 2008 Jan 28.

Streptococcal pyrogenic exotoxin B-induced apoptosis in A549 cells is mediated through alpha(v)beta(3) integrin and Fas.

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  • 1Institute of Medical Sciences, School of Medicine, Tzu Chi University, Hualien 970, Taiwan.


Our previous work suggested that streptococcal pyrogenic exotoxin (SPE) B-induced apoptosis is mediated through a receptor-like mechanism. In this study, we have identified alpha(v)beta(3) and Fas as the SPE B receptors for this function. The SPE B fragment without the RGD motif and G308S, a SPE B mutant with the RSD motif, induced less apoptosis than did native SPE B, suggesting that the RGD motif is critical for SPE B-induced apoptosis. Fluorescein isothiocyanate-SPE B binding assays and immunoprecipitation analysis showed that SPE B specifically interacted with alpha(v)beta(3). Anti-alpha(v)beta(3) antibody partially inhibited SPE B-induced apoptosis but had no effect on G308S-induced apoptosis. In addition, Fas binding to SPE B was verified in an affinity column and an immunoprecipitation analysis. Anti-Fas antibody inhibited SPE B- and G308S-induced apoptosis in a dose-dependent manner, suggesting that Fas-mediated SPE B-induced apoptosis also occurs RGD independently. Both anti-alpha(v)beta(3) and anti-Fas antibodies synergistically inhibited SPE B-induced apoptosis. The apoptotic cascades were activated by SPE B and G308S, with a little delay by the latter. After SPE B binding, the cell surface level of alpha(v)beta(3), but not of Fas, was decreased. The decreased alpha(v)beta(3) level was restored by treatment with the proteasome inhibitor MG132, suggesting a SPE B-mediated endocytosis of integrin alpha(v)beta(3) via the ubiquitin-proteasome system. Taken together, our results demonstrate that SPE B-induced apoptosis is mediated through alpha(v)beta(3) integrin and Fas in a synergistic manner.

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