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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Cholesterol-dependent actin remodeling via RhoA and Rac1 activation by the Streptococcus pneumoniae toxin pneumolysin
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Cholesterol-dependent actin remodeling via RhoA and Rac1 activation by the Streptococcus pneumoniae toxin pneumolysin

机译：通过RhoA和Rac1激活的肺炎链球菌毒素肺炎球菌溶血素对胆固醇依赖性肌动蛋白的重塑

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摘要

The Streptococcus pneumoniae toxin pneumolysin belongs to the group of cholesterol-dependent cytolysins. It produces rapid cell lysis at higher concentrations or apoptosis at lower concentrations. In cell membranes, it forms prepores and pores. Here, we show that sublytic concentrations of pneumolysin produce rapid activation of Rho and Rac GTPases and formation of actin stress fibers, filopodia, and lamellipodia. That Rac1-specific and Rho-associated kinase (ROCK)-specific inhibitors reverted the formation of lamellipodia and stress fibers, respectively, identifies RhoA and Rac1 as key toxin effectors. Live imaging excluded macropore formation (as judged by membrane impermeability toward calcein) but indicated very early membrane depolarization [as judged by bis-(1,3-dibutylbarbituric acid)trime-thine oxanol staining], indicative of formation of micropores with ion channel properties. That Rac1-dependent lamellipodia formation was reverted by the voltage-gated calcium channel inhibitor SKF96365 and by toxin exposure in calcium-free medium suggests a role for calcium influx via endogenous calcium channels in the Rac1 activation. Cellular cholesterol depletion by methyl-β-cyclodextrin or incubation of the toxin with cholesterol before cell treatment eliminated its membrane binding and the subsequent GTPase activation. Thus, that our experiments show small GTPase activation by a cholesterol-dependent cytolysin suggests a membrane cholesterol-dependent activation mechanism.
机译：肺炎链球菌毒素肺炎球菌溶血素属于胆固醇依赖性溶血素。在较高浓度下会产生快速的细胞裂解，在较低浓度下会产生凋亡。在细胞膜中，它形成前孔和孔。在这里，我们显示肺炎球菌溶血素的溶解浓度产生Rho和Rac GTPases的快速激活，并形成肌动蛋白应激纤维，丝状伪足和片状脂蛋白。 Rac1特异性和Rho相关激酶（ROCK）特异性抑制剂分别逆转了片状脂蛋白和应激纤维的形成，从而确定RhoA和Rac1是关键的毒素效应物。实时成像排除了大孔的形成（如通过膜对钙黄绿素的不渗透性判断），但表明很早就出现了膜去极化（如双-（1,3-二丁基巴比妥酸）三甲胺-thin oxanol染色所判断），表明具有离子通道特性的微孔的形成。电压门控钙通道抑制剂SKF96365还原了Rac1依赖性的片状脂蛋白形成，并且无钙培养基中的毒素暴露逆转了钙通过内源性钙通道流入Rac1激活的作用。通过甲基-β-环糊精清除细胞胆固醇或在细胞处理之前将毒素与胆固醇一起孵育消除了其膜结合和随后的GTPase活化。因此，我们的实验表明胆固醇依赖性溶血素对GTP酶的激活很小，这提示了膜胆固醇依赖性激活机制。

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