An amino-terminal signal peptide of Vfr protein negatively influences RopB-dependent SpeB expression and attenuates virulence in Streptococcus pyogenes.
An amino-terminal signal peptide of Vfr protein negatively influences RopB-dependent SpeB expression and attenuates virulence in Streptococcus pyogenes.
复制标题
DOI：
10.1111/j.1365-2958.2011.07902.x
复制
发表时间：
2011-12
影响因子：
3.6
通讯作者：
Kumaraswami M
中科院分区：
文献类型：
--
作者：
Shelburne SA 3rd;Olsen RJ;Makthal N;Brown NG;Sahasrabhojane P;Watkins EM;Palzkill T;Musser JM;Kumaraswami M
链球菌热原外毒素B(SpeB)是一种胞外半胱氨酸蛋白酶，是由人类主要致病菌A组链球菌(GAS)产生的关键毒力因子。SpeB的表达依赖于蛋白酶B(RopB)的调节，并随着细胞密度的增加和感染过程中的上调而上调。由于计算机模拟表明RopB与其他革兰氏阳性细菌产生的多肽敏感调节蛋白具有显著的结构相似性，我们假设SpeB的表达受到RopB-多肽相互作用的影响。在指数生长期，毒力因子相关蛋白(Vfr)编码基因(Vfr)的失活导致SpeB转录水平增加，而只提供Vfr的氨基末端区域(包括反式分泌信号序列)，则恢复了野生型SpeB的表达。加入表达Vfr信号肽的GAS菌株的培养上清液，将野生型SpeB转录水平恢复到Vfr失活的等基因突变菌株。Vfr分泌信号序列中与重组RopB特异结合的一种独特的多肽。最后，在两种侵袭性感染的小鼠模型中，Vfr分泌信号序列的过表达显著降低了SpeB转录水平和减弱了GAS毒力。综上所述，这些数据描绘了一个以前未知的小肽介导的调控系统，该系统控制气体毒力因子的产生。
Streptococcal pyrogenic exotoxin B (SpeB) is an extracellular cysteine protease that is a critical virulence factor made by the major human pathogen group A Streptococcus (GAS). speB expression is dependent on the regulator of proteinase B (RopB) and is upregulated with increasing cell density and during infection. Because computer modeling suggested significant structural similarity between RopB and peptide-sensing regulatory proteins made by other Gram-positive bacteria, we hypothesized that speB expression is influenced by RopB-peptide interactions. Inactivation of the gene (vfr) encoding the virulence factor related (Vfr) protein resulted in increased speB transcript level during the exponential growth phase, whereas provision of only the amino-terminal region of Vfr comprising the secretion signal sequence in trans restored a wild-type speB expression profile. Addition of the culture supernatant from a Vfr signal peptide-expressing GAS strain restored wild-type speB transcript level to a vfr-inactivated isogenic mutant strain. A distinct peptide in the Vfr secretion signal sequence specifically bound to recombinant RopB. Finally, overexpression of the Vfr secretion signal sequence significantly decreased speB transcript level and attenuated GAS virulence in two mouse models of invasive infection. Taken together, these data delineate a previously unknown small peptide-mediated regulatory system that controls GAS virulence factor production.