Overmeyer J H, Maltese W A
Weis Center for Research, Geisinger Clinic, Danville, Pennsylvania 17822.
J Biol Chem. 1992 Nov 5;267(31):22686-92.
Lovastatin blocks the biosynthesis of the isoprenoid precursor, mevalonate. When Friend murine erythroleukemia (MEL) cells are cultured in medium containing lovastatin, the precursor of murine leukemia virus envelope glycoprotein (gPr90env) fails to undergo proteolytic processing, which normally occurs in the Golgi complex. Consequently, newly synthesized envelope proteins are not incorporated into viral particles that are shed into the culture medium. gPr90env appears to be localized in a pre-Golgi membrane compartment, based on its enrichment in subcellular fractions containing NADPH-cytochrome c reductase activity and the sensitivity of its carbohydrate chains to digestion with endoglycosidase H. Arrest of gPr90env processing occurs at concentrations of lovastatin that are not cytostatic, and the effect of the inhibitor is prevented by addition of mevalonate to the medium. The low molecular mass GTP-binding proteins, rab1p and rab6p, which are believed to function in early steps of the exocytic pathway, are normally modified posttranslationally by geranylgeranyl isoprenoids. However, in MEL cells treated with 1 microM lovastatin, nonisoprenylated forms of these proteins accumulate in the cytosol prior to arrest of gPr90env processing. These observations suggest that lovastatin may prevent viral envelope precursors from reaching the Golgi compartment by blocking the isoprenylation of rab proteins required for ER to Golgi transport.
洛伐他汀可阻断类异戊二烯前体甲羟戊酸的生物合成。当将弗瑞德小鼠红白血病（MEL）细胞培养在含有洛伐他汀的培养基中时，鼠白血病病毒包膜糖蛋白（gPr90env）的前体无法进行蛋白水解加工，而这种加工通常发生在高尔基体复合体中。因此，新合成的包膜蛋白不会被整合到释放到培养基中的病毒颗粒中。基于gPr90env在含有NADPH - 细胞色素c还原酶活性的亚细胞组分中的富集以及其糖链对内切糖苷酶H消化的敏感性，gPr90env似乎定位于高尔基体前膜区室。gPr90env加工的阻滞发生在洛伐他汀的非细胞毒性浓度下，并且通过向培养基中添加甲羟戊酸可防止抑制剂的作用。低分子量GTP结合蛋白rab1p和rab6p被认为在胞吐途径的早期步骤中发挥作用，它们通常在翻译后被香叶基香叶基类异戊二烯修饰。然而，在用1 microM洛伐他汀处理的MEL细胞中，这些蛋白的非异戊二烯化形式在gPr90env加工阻滞之前在细胞质中积累。这些观察结果表明，洛伐他汀可能通过阻断内质网到高尔基体运输所需的rab蛋白的异戊二烯化来阻止病毒包膜前体到达高尔基体区室。
