Protein prenylation restrains innate immunity by inhibiting Rac1 effector interactions.,Nature Communications

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Protein prenylation restrains innate immunity by inhibiting Rac1 effector interactions.
Nature Communications ( IF 14.7 ) Pub Date : 2019-09-04 , DOI: 10.1038/s41467-019-11606-x
Murali K Akula _{1,

2} , Mohamed X Ibrahim ₁ , Emil G Ivarsson ₁ , Omar M Khan _{3,

4} , Israiel T Kumar ₁ , Malin Erlandsson ₅ , Christin Karlsson ₁ , Xiufeng Xu ₆ , Mikael Brisslert ₅ , Cord Brakebusch ₇ , Donghai Wang ₈ , Maria Bokarewa ₅ , Volkan I Sayin _{2,

9} , Martin O Bergo _{1,

6}

Affiliation

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.

中文翻译：

蛋白质异戊二烯化通过抑制 Rac1 效应子相互作用来抑制先天免疫。

Rho 家族蛋白被 I 型香叶基香叶基转移酶 (GGTase-I) 异戊二烯化，其通常将蛋白质靶向膜以装载 GTP。然而，小鼠巨噬细胞中 GGTase-I 的条件性缺失会增加 Rho 蛋白的 GTP 负载，导致炎症反应增强和严重的类风湿性关节炎。在这里，我们显示 Rho 家族基因 Rac1 的杂合缺失，而不是 Rhoa 和 Cdc42，可逆转 GGTase-I 缺陷小鼠的炎症和关节炎。非异戊二烯化 Rac1 对接头蛋白 Ras GTPase 激活样蛋白 1 (Iqgap1) 具有高亲和力，这有助于 GTP 交换和泛素化介导的 Rac1 降解。一致地，失活 Iqgap1 使 Rac1 GTP 负载正常化，并减少 GGTase-I 缺陷小鼠的炎症和关节炎，以及防止他汀类药物增加巨噬细胞中 Rac1 GTP 的负载和细胞因子的产生。我们得出结论，阻断异戊烯化会刺激 Rac1 效应相互作用并释放促炎信号。因此，我们的研究结果表明，异戊二烯化通常通过阻止 Rac1 效应器相互作用来抑制先天免疫反应。

更新日期：2019-09-04

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