A highly conserved signal controls degradation of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase in eukaryotes

Sterol synthesis by the mevalonate pathway is modulated, in part, through f eedback-regulated degradation of 3-hydroxy-3-methylglutaryl-coenzyme A redu ctase (HMGR). In both mammals and yeast, a non-sterol isoprenoid signal pos itively regulates the rate of HMGR degradation. To define more precisely th e molecule that serves as the source of this signal, we have conducted both pharmacological and genetic manipulations of the mevalonate pathway in yea st. We now demonstrate that farnesyl diphosphate (FPP) is the source of the positive signal for Hmg2p degradation in yeast. This FPP-derived signal do es not act by altering the endoplasmic reticulum degradation machinery in g eneral. Rather, the FPP-derived signal specifically modulates Hmg2p stabili ty. In mammalian cells, an FPP-derived molecule also serves as a positive s ignal for HMGR degradation. Thus, both yeast and mammalian cells employ the same strategy for regulation of HMGR degradation, perhaps by conserved mol ecular processes.