GTPase activating protein function of p85 facilitates uptake and recycling of the beta1 integrin.
GTPase activating protein function of p85 facilitates uptake and recycling of the beta1 integrin.
复制标题
p85 的 GTP 酶激活蛋白功能促进 β1 整合素的摄取和再循环。
DOI：
10.1016/j.bbrc.2009.11.077
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发表时间：
2010
影响因子：
3.1
通讯作者：
McDowell,SusanA
中科院分区：
文献类型：
--
作者：
Stankiewicz,TraciE;Haaning,KelseyL;Owens,JanelleM;Jordan,AlysS;Gammon,Kelly;Bruns,HeatherA;McDowell,SusanA
在细胞膜上含有β-1的粘附物作为动态复合体在细胞和环境之间提供双向通信，但通常被病原体用来获得宿主细胞的进入。最近，降胆固醇药物辛伐他汀被发现通过含有β-1的黏附复合体抑制宿主的侵袭。为了更好地了解控制黏附形成和摄取的调节机制以及金黄色葡萄球菌对这些复合体的使用，我们研究了辛伐他汀的抑制机制。金黄色葡萄球菌是败血症、菌血症和心内膜炎的主要病原体。对辛伐他汀的反应是，黏附复合体减少，β-1转运到启动黏附形成所需的质膜。辛伐他汀刺激CDC42活化并与小鸟苷三磷酸酶激活蛋白(GAP)P85偶联，但将CDC42偶联到P85胞浆中。通过使用遗传策略失去P85 GAP活性，减少了宿主细胞的入侵和β1的运输。根据这些发现，我们提出了一种机制，即P85间隙活性定位于膜间隔内，促进β1的运输。辛伐他汀通过将P85隔离在胞浆中，限制了病原菌用来获得宿主细胞进入的受体的可用性和摄取。
β1-containing adhesions at the plasma membrane function as dynamic complexes to provide bidirectional communication between the cell and its environment, yet commonly are used by pathogens to gain host cell entry. Recently, the cholesterol-lowering drug simvastatin was found to inhibit host invasion through β1-containing adhesion complexes. To better understand the regulatory mechanisms controlling adhesion formation and uptake and the use of these complexes by Staphylococcus aureus, the primary etiologic agent in sepsis, bacteremia and endocarditis, we investigated the mechanism of inhibition by simvastatin. In response to simvastatin, adhesion complexes diminished as well as β1 trafficking to the plasma membrane required to initiate adhesion formation. Simvastatin stimulated CDC42 activation and coupling to p85, a small-guanosine triphosphatase (GTPase) activating protein (GAP), yet sequestered CDC42 coupled to p85 within the cytosol. Loss of p85 GAP activity through use of genetic strategies decreased host cell invasion as well as β1 trafficking. From these findings, we propose a mechanism whereby p85 GAP activity localized within membrane compartments facilitates β1 trafficking. By sequestering p85 within the cytosol, simvastatin restricts the availability and uptake of the receptor used by pathogenic strains to gain host cell entry.