Abstract：
Statins are used to treat hypercholesterolemia and function by inhibiting the production of the rate-limiting metabolite mevalonate. As such, statin treatment not only inhibits de novo synthesis of cholesterol but also isoprenoids that are involved in prenylation, the posttranslational lipid modification of proteins. The immunomodulatory effects of statins are broad and often conflicting. Previous work demonstrated that statins increased survival and inhibited myeloid cell trafficking in a murine model of sepsis, but the exact mechanisms underlying this phenomenon were unclear. Herein, we investigated the role of prenylation in chemoattractant responses. We found that simvastatin treatment abolished chemoattractant responses induced by stimulation by C5a and FMLP. The inhibitory effect of simvastatin treatment was unaffected by the addition of either farnesyl pyrophosphate (FPP) or squalene but was reversed by restoring geranylgeranyl pyrophosphate (GGPP). Treatment with prenyltransferase inhibitors showed that the chemoattractant response to both chemoattractants was dependent on geranylgeranylation. Proteomic analysis of C15AlkOPP-prenylated proteins identified several geranylgeranylated proteins involved in chemoattractant responses, including RHOA, RAC1, CDC42, and GNG2. Chemoattractant responses in THP-1 human macrophages were also geranylgeranylation dependent. These studies provide data that help clarify paradoxical findings on the immunomodulatory effects of statins. Furthermore, they establish the role of geranylgeranylation in mediating the morphological response to chemoattractant C5a.NEW & NOTEWORTHY The immunomodulatory effect of prenylation is ill-defined. We investigated the role of prenylation on the chemoattractant response to C5a. Simvastatin treatment inhibits the cytoskeletal remodeling associated with a chemotactic response. We showed that the chemoattractant response to C5a was dependent on geranylgeranylation, and proteomic analysis identified several geranylgeranylated proteins that are involved in C5a receptor signaling and cytoskeletal remodeling. Furthermore, they establish the role of geranylgeranylation in mediating the response to chemoattractant C5a.
摘要：
他汀类药物用于治疗高胆固醇血症，并通过抑制限速代谢物甲羟戊酸的产生而发挥作用。因此，他汀类药物治疗不仅抑制胆固醇的从头合成，而且抑制参与异戊二烯化的类异戊二烯，蛋白质的翻译后脂质修饰。他汀类药物的免疫调节作用是广泛的，通常是相互矛盾的。以前的研究表明，他汀类药物在脓毒症小鼠模型中增加存活率并抑制骨髓细胞运输，但这种现象的确切机制尚不清楚。在这里，我们研究了异戊二烯化在化学引诱物反应中的作用。我们发现辛伐他汀治疗消除了C5a和FMLP刺激引起的化学引诱物反应。辛伐他汀治疗的抑制作用不受添加焦磷酸法尼酯（FPP）或角鲨烯的影响，但通过恢复香叶基香叶基焦磷酸(GGMP)逆转了。用异戊二烯基转移酶抑制剂处理表明，对两种化学引诱物的化学引诱物反应取决于香叶基香叶酰化。C15AlkOPP-异戊二烯化蛋白的蛋白质组学分析鉴定了几种参与化学引诱反应的香叶基香叶化蛋白，包括RHOA,RAC1、CDC42和GNG2。THP-1人巨噬细胞中的趋化因子反应也是香叶基香叶化依赖性的。这些研究提供的数据有助于澄清他汀类药物免疫调节作用的矛盾发现。此外，他们确定了香叶基香叶化在介导对化学引诱物C5a的形态学反应中的作用。
