Control of the innate immune response by the mevalonate pathway.
Control of the innate immune response by the mevalonate pathway.
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DOI：
10.1038/ni.3487
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发表时间：
2016-08
影响因子：
30.5
通讯作者：
Wang D
中科院分区：
文献类型：
--
作者：
Akula MK;Shi M;Jiang Z;Foster CE;Miao D;Li AS;Zhang X;Gavin RM;Forde SD;Germain G;Carpenter S;Rosadini CV;Gritsman K;Chae JJ;Hampton R;Silverman N;Gravallese EM;Kagan JC;Fitzgerald KA;Kastner DL;Golenbock DT;Bergo MO;Wang D
甲羟戊酸激酶（MVK）的缺乏导致全身炎症。然而，连接甲羟戊酸途径与炎症的分子机制仍然不清楚。牛儿基牛儿基焦磷酸（GGPP）是甲羟戊酸途径的非固醇中间体，是蛋白牛儿基牛儿基化的底物，蛋白牛儿基牛儿基转移酶I（GGT酶I）催化蛋白质翻译后修饰。Pyrin是一种先天性免疫传感器，其响应于细菌毒素而形成活性炎性体。MEFV（编码人PYRIN）的突变导致自身炎症性家族性地中海热（FMF）综合征。在这里，我们发现蛋白质香叶基香叶基化通过促进小GT3-Kras和PI（3）K催化亚基p110δ之间的相互作用，使Toll样受体（TLR）诱导的磷脂酰肌醇-3-OH激酶PI（3）K）活化。缺乏GGT酶I或p110δ的巨噬细胞表现出MEFV依赖性的组成性白细胞介素-1 β释放，但不依赖于NLRP 3、AIM 2和NLRC 4炎性体。在不存在蛋白质香叶基香叶基化的情况下，受损的PI（3）K活性允许不受抑制的TLR诱导的炎症反应和组成型激活的Pyrin炎性体。
Deficiency of mevalonate kinase (MVK) causes systemic inflammation. However, the molecular mechanisms linking the mevalonate pathway to inflammation remain obscure. Geranylgeranyl pyrophosphate (GGPP), a non-sterol intermediate of the mevalonate pathway, is the substrate for protein geranylgeranylation, protein post-translational modification catalyzed by protein geranylgeranyl transferase I (GGTase I). Pyrin is an innate immune sensor that forms an active inflammasome in response to bacterial toxins. Mutations in MEFV (encoding human PYRIN) cause autoinflammatory Familial Mediterranean Fever (FMF) syndrome. Here, we show that protein geranylgeranylation enables Toll-like receptor (TLR)-induced phosphatidylinositol-3-OH kinase PI(3)K) activation by promoting the interaction between the small GTPase Kras and the PI(3)K catalytic subunit p110δ. Macrophages deficient for GGTase I or p110δ exhibited constitutive interleukin-1β release that was MEFV-dependent, but NLRP3-, AIM2- and NLRC4- inflammasome independent. In the absence of protein geranylgeranylation, compromised PI(3)K activity allows for an unchecked TLR-induced inflammatory responses and constitutive activation of the Pyrin inflammasome.