Research Centre for Infectious Diseases (ZINF), University of Würzburg, Würzburg 97080, Germany; Institute for Molecular Infection Biology (IMIB), University of Würzburg, Würzburg 97080, Germany.
National Centre for Biotechnology (CNB), Spanish Research Council (CSIC), Darwin 3, Madrid 28049, Spain.
Cell Chem Biol. 2017 Jul 20;24(7):845-857.e6. doi: 10.1016/j.chembiol.2017.05.027. Epub 2017 Jun 29.
Scaffold proteins are ubiquitous chaperones that bind proteins and facilitate physical interaction of multi-enzyme complexes. Here we used a biochemical approach to dissect the scaffold activity of the flotillin-homolog protein FloA of the multi-drug-resistant human pathogen Staphylococcus aureus. We show that FloA promotes oligomerization of membrane protein complexes, such as the membrane-associated RNase Rny, which forms part of the RNA-degradation machinery called the degradosome. Cells lacking FloA had reduced Rny function and a consequent increase in the targeted sRNA transcripts that negatively regulate S. aureus toxin expression. Small molecules that altered FloA oligomerization also reduced Rny function and decreased the virulence potential of S. aureus in vitro, as well as in vivo, using invertebrate and murine infection models. Our results suggest that flotillin assists in the assembly of protein complexes involved in S. aureus virulence, and could thus be an attractive target for the development of new antimicrobial therapies.
支架蛋白是普遍存在的伴侣蛋白，可结合蛋白质并促进多酶复合物的物理相互作用。在这里，我们使用生化方法来剖析多药耐药人类病原体金黄色葡萄球菌中 flotillin 同源蛋白 FloA 的支架活性。我们表明 FloA 促进膜蛋白复合物的寡聚化，例如膜相关 RNase Rny，其形成称为降解体的 RNA 降解机制的一部分。缺乏 FloA 的细胞的 Rny 功能降低，并且靶向 sRNA 转录物的含量增加，这些转录物负调控金黄色葡萄球菌毒素的表达。改变 FloA 寡聚化的小分子也降低了 Rny 的功能，并降低了金黄色葡萄球菌在体外和体内的毒力潜能，使用无脊椎动物和鼠类感染模型。我们的结果表明 flotillin 有助于参与金黄色葡萄球菌毒力的蛋白质复合物的组装，因此可能是开发新的抗菌治疗方法的有吸引力的靶标。
