Mechanisms of statin-mediated inhibition of small G-protein function
Mechanisms of statin-mediated inhibition of small G-protein function
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DOI：
10.1074/jbc.m505268200
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发表时间：
2005-10-07
影响因子：
4.8
通讯作者：
Landreth, G
中科院分区：
文献类型：
--
作者：
Cordle, A;Koenigsknecht-Talboo, J;Landreth, G
据报道，3-羟基-3-甲基戊二酰辅酶A还原酶抑制剂（他汀类药物）可降低阿尔茨海默病的风险。我们先前已经证明他汀类药物通过独立于胆固醇降低的机制抑制β-淀粉样蛋白（A β）介导的炎症反应。具体而言，他汀类药物通过其防止小G蛋白Rho家族成员异戊二烯化的能力发挥抗炎作用，导致这些G蛋白的功能失活。我们报告说，他汀类药物治疗的小胶质细胞的结果在扰动的细胞骨架和形态学的变化，由于改变Rho家族功能。他汀类药物还通过抑制Rac作用阻断A β刺激的吞噬作用。巧合的是，他汀类药物介导的G蛋白功能失活与Rac和RhoA的GTP负载增加相关，并且在髓系细胞和其他细胞类型中观察到这种效应。他汀类药物治疗破坏了Rac与其负调节剂Rho鸟嘌呤核苷酸解离抑制剂（RhoGDI）的相互作用，这种相互作用依赖于蛋白质异戊二烯化。我们认为，缺乏负调控占GTP负载增加。Rac的异戊二烯化也是与质膜有效相互作用所必需的，我们报告他汀类药物治疗显著降低了Rac与膜相互作用的能力。这些结果提示了他汀类药物抑制Rho GTP酶的作用并减弱A β刺激的炎症的机制。
3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) have been reported to reduce the risk of Alzheimer disease. We have shown previously that statins inhibit a beta-amyloid (A beta)mediated inflammatory response through mechanisms independent of cholesterol reduction. Specifically, statins exert anti-inflammatory actions through their ability to prevent the isoprenylation of members of the Rho family of small G-proteins, resulting in the functional inactivation of these G-proteins. We report that statin treatment of microglia results in perturbation of the cytoskeleton and morphological changes due to alteration in Rho family function. Statins also block A beta-stimulated phagocytosis through inhibition of Rac action. Paradoxically, the statin-mediated inactivation of G-protein function was associated with increased GTP loading of Rac and RhoA, and this effect was observed in myeloid lineage cells and other cell types. Statin treatment disrupted the interaction of Rac with its negative regulator the Rho guanine nucleotide dissociation inhibitor ( RhoGDI), an interaction that is dependent on protein isoprenylation. We propose that lack of negative regulation accounts for the increased GTP loading. Isoprenylation of Rac is also required for efficient interaction with the plasma membrane, and we report that statin treatment dramatically reduces the capacity of Rac to interact with membranes. These results suggest amechanism by which statins inhibit the actions of Rho GTPases and attenuate A beta-stimulated inflammation.