Gardner R G, Hampton R Y
Department of Biology, University of California, San Diego, La Jolla, California 92093, USA.
J Biol Chem. 1999 Oct 29;274(44):31671-8. doi: 10.1074/jbc.274.44.31671.
Sterol synthesis by the mevalonate pathway is modulated, in part, through feedback-regulated degradation of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGR). In both mammals and yeast, a non-sterol isoprenoid signal positively regulates the rate of HMGR degradation. To define more precisely the molecule that serves as the source of this signal, we have conducted both pharmacological and genetic manipulations of the mevalonate pathway in yeast. We now demonstrate that farnesyl diphosphate (FPP) is the source of the positive signal for Hmg2p degradation in yeast. This FPP-derived signal does not act by altering the endoplasmic reticulum degradation machinery in general. Rather, the FPP-derived signal specifically modulates Hmg2p stability. In mammalian cells, an FPP-derived molecule also serves as a positive signal for HMGR degradation. Thus, both yeast and mammalian cells employ the same strategy for regulation of HMGR degradation, perhaps by conserved molecular processes.
甲羟戊酸途径的甾醇合成部分通过3-羟基-3-甲基戊二酰辅酶A还原酶（HMGR）的反馈调节降解来调控。在哺乳动物和酵母中，一种非甾醇类异戊二烯信号正向调节HMGR的降解速率。为了更精确地确定作为该信号来源的分子，我们对酵母中的甲羟戊酸途径进行了药理学和遗传学操作。我们现在证明，法尼基二磷酸（FPP）是酵母中Hmg2p降解正向信号的来源。这种源自FPP的信号一般不会通过改变内质网降解机制来发挥作用。相反，源自FPP的信号特异性地调节Hmg2p的稳定性。在哺乳动物细胞中，一种源自FPP的分子也作为HMGR降解的正向信号。因此，酵母和哺乳动物细胞可能通过保守的分子过程采用相同的策略来调节HMGR的降解。
