Selective inhibition of cotranslational translocation of vascular cell adhesion molecule 1
Selective inhibition of cotranslational translocation of vascular cell adhesion molecule 1
复制标题
DOI：
10.1038/nature03670
复制
发表时间：
2005-07-14
期刊：
影响因子：
64.8
通讯作者：
Lindley, IJD
中科院分区：
文献类型：
--
作者：
Besemer, J;Harant, H;Lindley, IJD
血管细胞粘附分子1（VCAM 1）的表达增加与多种慢性炎症相关，使其表达和功能成为治疗干预的靶点（1-3）。我们最近已经确定了CAM 741，一种真菌衍生的cyclopeptolide的衍生物，可作为内皮细胞中VCAM 1合成的选择性抑制剂。在这里，我们表明，该化合物抑制VCAM 1的生物合成在细胞中通过阻断共翻译易位，这是依赖于VCAM 1的信号肽的过程。CAM 741不抑制VCAM 1新生链靶向于易位子通道，但通过涉及易位子组分Sec 61 β的过程阻止易位至内质网（ER）的腔侧。因此，VCAM 1前体蛋白向细胞的胞质区室合成，在那里它被降解。我们的研究结果表明，低分子量化合物的共翻译易位的抑制，利用信号肽赋予的特异性，可以调节某些分泌和/或膜蛋白的生物合成。此外，他们强调ER膜的共翻译易位作为药物发现的潜在靶点。
Increased expression of vascular cell adhesion molecule 1 (VCAM1) is associated with a variety of chronic inflammatory conditions, making its expression and function a target for therapeutic intervention(1-3). We have recently identified CAM741, a derivative of a fungus-derived cyclopeptolide that acts as a selective inhibitor of VCAM1 synthesis in endothelial cells. Here we show that the compound represses the biosynthesis of VCAM1 in cells by blocking the process of cotranslational translocation, which is dependent on the signal peptide of VCAM1. CAM741 does not inhibit targeting of the VCAM1 nascent chains to the translocon channel but prevents translocation to the luminal side of the endoplasmic reticulum ( ER), through a process that involves the translocon component Sec61 beta. Consequently, the VCAM1 precursor protein is synthesized towards the cytosolic compartment of the cells, where it is degraded. Our results indicate that the inhibition of cotranslational translocation with low-molecular-mass compounds, using specificity conferred by signal peptides, can modulate the biosynthesis of certain secreted and/or membrane proteins. In addition, they highlight cotranslational translocation at the ER membrane as a potential target for drug discovery.