A palmitoylation switch mechanism regulates Rac1 function and membrane organization
A palmitoylation switch mechanism regulates Rac1 function and membrane organization
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DOI：
10.1038/emboj.2011.446
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发表时间：
2012-02-01
期刊：
影响因子：
11.4
通讯作者：
Del Pozo, Miguel A.
中科院分区：
文献类型：
--
作者：
Navarro-Lerida, Inmaculada;Sanchez-Perales, Sara;Del Pozo, Miguel A.
小G蛋白Rac 1在许多过程中发挥重要作用，包括细胞骨架重组、细胞迁移、细胞周期进程和基因表达。Rac 1信号传导的启动需要至少两种机制：通过三磷酸鸟苷（GTP）/二磷酸鸟苷（GDP）循环的GTP负载，以及靶向富含胆固醇的液体有序质膜微区。很少有人知道的分子机制，这种特定的区室化。我们表明，Rac 1可以将棕榈酸在半胱氨酸178，这种翻译后修饰的目标Rac 1的稳定在肌动蛋白cytochrons连接有序的膜区域。棕榈酰化的Rac 1需要其事先异戊烯化和完整的C-末端的多元区域，并通过富三脯氨酸基序调节。非棕榈酰化的Rac 1显示出降低的GTP负载和与耐洗涤剂（液体有序）膜（DRM）的较低关联。不表达Rac 1或棕榈酰化缺陷突变体的细胞具有增加的无序膜结构域的含量，并且从Rac 1缺陷细胞分离的有序膜的标记物不能正确地分配在DRM中。重要的是，缺乏Rac 1棕榈酰化的细胞显示出扩散和迁移缺陷。这些数据确定棕榈酰化作为Rac 1功能的肌动蛋白细胞骨架重塑的机制，通过控制其膜分区，这反过来又调节膜组织。The EMBO Journal（2012）31，534-551. doi：10.1038/daj.2011.446; 2011年12月9日在线发布
The small GTPase Rac1 plays important roles in many processes, including cytoskeletal reorganization, cell migration, cell-cycle progression and gene expression. The initiation of Rac1 signalling requires at least two mechanisms: GTP loading via the guanosine triphosphate (GTP)/guanosine diphosphate (GDP) cycle, and targeting to cholesterol-rich liquid-ordered plasma membrane microdomains. Little is known about the molecular mechanisms governing this specific compartmentalization. We show that Rac1 can incorporate palmitate at cysteine 178 and that this post-translational modification targets Rac1 for stabilization at actin cytoskeleton-linked ordered membrane regions. Palmitoylation of Rac1 requires its prior prenylation and the intact C-terminal polybasic region and is regulated by the triproline-rich motif. Non-palmitoylated Rac1 shows decreased GTP loading and lower association with detergent-resistant (liquid-ordered) membranes (DRMs). Cells expressing no Rac1 or a palmitoylation-deficient mutant have an increased content of disordered membrane domains, and markers of ordered membranes isolated from Rac1-deficient cells do not correctly partition in DRMs. Importantly, cells lacking Rac1 palmitoylation show spreading and migration defects. These data identify palmitoylation as a mechanism for Rac1 function in actin cytoskeleton remodelling by controlling its membrane partitioning, which in turn regulates membrane organization. The EMBO Journal (2012) 31, 534-551. doi: 10.1038/emboj.2011.446; Published online 9 December 2011