Abstract
We have previously identified integrin alpha(v)beta(3) and Fas as receptors for the streptococcal pyrogenic exotoxin B (SPE B), and G308S, a mutant of SPE B that binds to Fas only. In the current study we found that after binding to alpha(v)beta(3), SPE B stimulated the tyrosine phosphorylation of JAK2 and STAT1. STAT1 tyrosine phosphorylation was inhibited by a JAK2 inhibitor, AG490, short interfering RNA (siRNA) silencing of JAK2, and anti-alpha(V)beta(3) antibody. AG490 also decreased the binding of tyrosine-phosphorylated STAT1 to the procaspase 8 promoter, decreasing procaspase 8 expression, suggesting that SPE B up-regulates procaspase 8 expression via the JAK2/STAT1 pathway. Alternatively, both SPE B and G308S increased STAT1 phosphorylation at serine 727, which was inhibited by anti-Fas antibody, a p38 inhibitor, SB203580, and siRNA silencing of p38. In addition, SPE B and G308S increased binding of serine-phosphorylated STAT1 to the Bax promoter and Bax expression, which was decreased by SB203580. SPE B and G308S-stimulated Bax expression was also inhibited by anti-Fas antibody. These findings suggest that Fas mediate SPE B-induced Bax expression through p38. Silencing of JAK2 or p38 by siRNA blocked procaspase 8 expression, whereas only p38 siRNA decreased Bax expression. Furthermore, JAK2 inhibition and p38 inhibition reduced SPE B-induced apoptosis, but only p38 inhibition blocked G308S-induced apoptosis.
Highlights
Our presented evidence indicates that (i) streptococcal pyrogenic exotoxin B (SPE B) triggers the integrin ␣V3-mediated JAK2/STAT1 signal pathway to induce the expression of procaspase 8 and (ii) SPE B binds to the Fas receptor to activate p38 mitogen-activated protein kinases (MAPKs) that phosphorylates STAT1 at serine 727 and increases expression of Bax
SPE B, but Not G308S, Up-regulates Procaspase 8 Expression— We previously found that caspase 8 was activated first during SPE B-induced apoptosis (8)
To determine whether STAT1 activation is a key event in SPE B-induced expression of procaspase 8, we evaluated the involvement of JAK2
Summary
Our presented evidence indicates that (i) SPE B triggers the integrin ␣V3-mediated JAK2/STAT1 signal pathway to induce the expression of procaspase 8 and (ii) SPE B binds to the Fas receptor to activate p38 MAPK that phosphorylates STAT1 at serine 727 and increases expression of Bax. Preparation of Recombinant SPE B and Its Mutant G308S— The expression and purification of recombinant SPE B (rSPE B) have been previously described (5). Levels of STAT1 phosphorylated at serine 727 were increased both in SPE B- and G308S-treated cells. To investigate the molecular basis of SPE B-induced up-regulation of procaspase 8, we studied whether the expression of procaspase 8 mRNA depends on STAT1 transcriptional activity.
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