Sahlgrenska Cancer Center, Department of Molecular and Clinical Medicine, Institute of Medicine, University of Gothenburg, SE-405 30, Gothenburg, Sweden.
Wallenberg Centre for Molecular and Translational Medicine, University of Gothenburg, SE-405 30, Gothenburg, Sweden.
Nat Commun. 2019 Sep 4;10(1):3975. doi: 10.1038/s41467-019-11606-x.
Rho family proteins are prenylated by geranylgeranyltransferase type I (GGTase-I), which normally target proteins to membranes for GTP-loading. However, conditional deletion of GGTase-I in mouse macrophages increases GTP-loading of Rho proteins, leading to enhanced inflammatory responses and severe rheumatoid arthritis. Here we show that heterozygous deletion of the Rho family gene Rac1, but not Rhoa and Cdc42, reverses inflammation and arthritis in GGTase-I-deficient mice. Non-prenylated Rac1 has a high affinity for the adaptor protein Ras GTPase-activating-like protein 1 (Iqgap1), which facilitates both GTP exchange and ubiquitination-mediated degradation of Rac1. Consistently, inactivating Iqgap1 normalizes Rac1 GTP-loading, and reduces inflammation and arthritis in GGTase-I-deficient mice, as well as prevents statins from increasing Rac1 GTP-loading and cytokine production in macrophages. We conclude that blocking prenylation stimulates Rac1 effector interactions and unleashes proinflammatory signaling. Our results thus suggest that prenylation normally restrains innate immune responses by preventing Rac1 effector interactions.
Rho 家族蛋白由法尼基转移酶 I（GGTase-I）进行异戊烯基化修饰，该酶通常将蛋白质靶向到细胞膜以进行 GTP 加载。然而，条件性敲除小鼠巨噬细胞中的 GGTase-I 会增加 Rho 蛋白的 GTP 加载，导致炎症反应增强和严重的类风湿性关节炎。在这里，我们发现 Rac1（Rho 家族基因）的杂合缺失可逆转 GGTase-I 缺陷型小鼠的炎症和关节炎，而 Rhoa 和 Cdc42 的缺失则无此作用。非异戊烯基化的 Rac1 与衔接蛋白 Ras GTP 酶激活样蛋白 1（Iqgap1）具有高亲和力，这促进了 Rac1 的 GTP 交换和泛素化介导的降解。一致地，失活 Iqgap1 可使 Rac1 的 GTP 加载正常化，降低 GGTase-I 缺陷型小鼠的炎症和关节炎，并防止他汀类药物增加巨噬细胞中 Rac1 的 GTP 加载和细胞因子产生。我们得出结论，阻断异戊烯基化可刺激 Rac1 效应物相互作用并释放促炎信号。因此，我们的研究结果表明，异戊烯基化通常通过阻止 Rac1 效应物相互作用来抑制先天免疫反应。
