H-Ras Distribution and Signaling in Plasma Membrane Microdomains Are Regulated by Acylation and Deacylation Events
H-Ras Distribution and Signaling in Plasma Membrane Microdomains Are Regulated by Acylation and Deacylation Events
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DOI：
10.1128/mcb.01398-14
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发表时间：
2015-06-01
影响因子：
5.3
通讯作者：
Crespo, Piero
中科院分区：
文献类型：
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作者：
Agudo-Ibanez, Lorena;Herrero, Ana;Crespo, Piero
H-RAS必须附着在质膜上才能发挥作用。这是通过翻译后修饰完成的，包括棕榈酰化，这是一个可逆的过程，H-RAS在质膜和高尔基复合体之间进行运输。在质膜上，H-RAS被认为占据了不同的亚组分，这取决于它的激活状态：脂筏/抗洗剂膜组分与GDP结合，在GTP负荷下扩散到无序的膜/可溶性组分。在这里，我们证明了H-RAS的亚区块化是由其棕榈酰化程度以细胞类型特异性的方式决定的。虽然H-RAS定位于棕榈酰化活性低的细胞中的抗洗涤剂膜组分，但它定位于棕榈酰化程度较高的谱系中的可溶性膜组分。有趣的是，在这两种情况下，GTP负载都会导致H-RAS从原来的亚区块化扩散出去。此外，倾斜棕榈酸化和脱醛酸化过程之间的平衡可以显著改变H-RAS的分离，从而改变其生化和生物学功能。因此，棕榈酰化/去脂酰化平衡不仅调节着膜和质膜之间的H-RAS循环，而且是H-RAS在不同类型质膜之间横向扩散的关键协调者，从而也是H-RAS信号转导的关键。
H-Ras must adhere to the plasma membrane to be functional. This is accomplished by posttranslational modifications, including palmitoylation, a reversible process whereby H-Ras traffics between the plasma membrane and the Golgi complex. At the plasma membrane, H-Ras has been proposed to occupy distinct sublocations, depending on its activation status: lipid rafts/detergent-resistant membrane fractions when bound to GDP, diffusing to disordered membrane/soluble fractions in response to GTP loading. Herein, we demonstrate that H-Ras sublocalization is dictated by its degree of palmitoylation in a cell type-specific manner. Whereas H-Ras localizes to detergent-resistant membrane fractions in cells with low palmitoylation activity, it locates to soluble membrane fractions in lineages where it is highly palmitoylated. Interestingly, in both cases GTP loading results in H-Ras diffusing away from its original sublocalization. Moreover, tilting the equilibrium between palmitoylation and depalmitoylation processes can substantially alter H-Ras segregation and, subsequently, its biochemical and biological functions. Thus, the palmitoylation/depalmitoylation balance not only regulates H-Ras cycling between endomembranes and the plasma membrane but also serves as a key orchestrator of H-Ras lateral diffusion between different types of plasma membrane and thereby of H-Ras signaling.