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Inactivation of Rho GTPases by Statins Attenuates Anthrax Lethal Toxin Activity

机译：他汀类药物对Rho GTPases的灭活作用减弱了炭疽致死毒素的活性。

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Anthrax lethal factor (LF), secreted by Bacillus anthracis, interacts with protective antigen to form a bipartite toxin (lethal toxin [LT]) that exerts pleiotropic biological effects resulting in subversion of the innate immune response. Although the mitogen-activated protein kinase kinases (MKKs) are the major intracellular protein targets of LF, the pathology induced by LT is not well understood. The statin family of HMG-coenzyme A reductase inhibitors have potent anti-inflammatory effects independent of their cholesterol-lowering properties, which have been attributed to modulation of Rho family GTPase activity. The Rho GTPases regulate vesicular trafficking, cytoskeletal dynamics, and cell survival and proliferation. We hypothesized that disruption of Rho GTPase function by statins might alter LT action. We show here that statins delay LT-induced death and MKK cleavage in RAW macrophages and that statin-mediated effects on LT action are attributable to disruption of Rho GTPases. The Rho GTPase-inactivating toxin, toxin B, did not significantly affect LT binding or internalization, suggesting that the Rho GTPases regulate trafficking and/or localization of LT once internalized. The use of drugs capable of inhibiting Rho GTPase activity, such as statins, may provide a means to attenuate intoxication during B. anthracis infection.
机译：炭疽芽孢杆菌分泌的炭疽致死因子（LF）与保护性抗原相互作用，形成二分毒素（致命毒素[LT]），该毒素发挥多效性生物学作用，导致先天免疫反应的颠覆。尽管有丝分裂原激活的蛋白激酶激酶（MKKs）是LF的主要细胞内蛋白靶标，但对LT诱导的病理学了解甚少。 HMG辅酶A还原酶抑制剂的他汀类家族具有独立于其降胆固醇特性的有效抗炎作用，这归因于Rho家族GTPase活性的调节。 Rho GTPases调节水泡运输，细胞骨架动力学以及细胞存活和增殖。我们假设他汀类药物破坏Rho GTPase功能可能会改变LT的作用。我们在这里显示他汀类药物延迟RAW巨噬细胞中LT诱导的死亡和MKK裂解，并且他汀类药物对LT作用的介导作用是Rho GTPases破坏的结果。 Rho GTPase失活毒素毒素B并未显着影响LT结合或内在化，这表明Rho GTPases一旦内在化，便调节LT的运输和/或定位。使用能够抑制Rho GTP酶活性的药物（如他汀类药物）可以提供减轻B期中毒的手段。炭疽感染。

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