Division of Nutritional Sciences, University of Illinois at Urbana-Champaign, Urbana, Illinois, United States.
Department of Animal Sciences,University of Illinois at Urbana-Champaign, Urbana, Illinois, United States.
Am J Physiol Endocrinol Metab. 2024 Jul 1;327(1):E55-E68. doi: 10.1152/ajpendo.00359.2023. Epub 2024 May 8.
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. 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.
他汀类药物用于治疗高胆固醇血症，通过抑制限速代谢产物甲羟戊酸的产生而起作用。因此，他汀类药物治疗不仅抑制胆固醇的从头合成，还抑制参与翻译后脂质修饰的异戊烯基。他汀类药物的免疫调节作用广泛且常常相互矛盾。先前的工作表明，他汀类药物在脓毒症的小鼠模型中增加了存活率并抑制了髓样细胞的迁移，但这种现象的具体机制尚不清楚。在此，我们研究了 prenylation 在趋化因子反应中的作用。我们发现，辛伐他汀处理消除了 C5a 和 FMLP 刺激诱导的趋化因子反应。辛伐他汀处理的抑制作用不受法呢基焦磷酸（FPP）或角鲨烯的添加影响，但被恢复香叶基香叶基焦磷酸（GGPP）逆转。prenyltransferase 抑制剂的处理表明，两种趋化因子的趋化因子反应都依赖于 geranylgeranylation。C15AlkOPP-prenylated 蛋白的蛋白质组学分析鉴定了几种参与趋化因子反应的 geranylgeranylated 蛋白，包括 RHOA、RAC1、CDC42 和 GNG2。THP-1 人巨噬细胞的趋化因子反应也依赖于 geranylgeranylation。这些研究提供了有助于阐明他汀类药物免疫调节作用的矛盾发现的数据。此外，它们确立了 geranylgeranylation 在介导对趋化因子 C5a 的形态反应中的作用。prenylation 的免疫调节作用尚未明确。我们研究了 prenylation 在 C5a 趋化因子反应中的作用。辛伐他汀处理抑制与趋化反应相关的细胞骨架重塑。我们表明，C5a 的趋化因子反应依赖于 geranylgeranylation，蛋白质组学分析鉴定了几种参与 C5a 受体信号转导和细胞骨架重塑的 geranylgeranylated 蛋白。此外，它们确立了 geranylgeranylation 在介导对趋化因子 C5a 的反应中的作用。
