Multivalent control of 3-hydroxy-3-methylglutaryl coenzyme A reductase. Mevalonate-derived product inhibits translation of mRNA and accelerates degradation of enzyme.

Abstract

The enzyme 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA reductase) is subject to multivalent feedback suppression mediated by sterols and non-sterol substances derived from mevalonate, the product of the enzyme. To dissect the mechanism for this multivalent effect, Chinese hamster ovary cells were incubated with sterols contained in plasma lipoproteins and with a high concentration (100 microM) of compactin, an inhibitor of the reductase. Under these conditions, the amounts of HMG-CoA reductase protein and catalytic activity were high, although the cells were saturated with sterols, as reflected by active synthesis of cholesteryl esters. The amount of enzyme fell by 99% when the cells received excess mevalonate in addition to sterols. This decline was not associated with a fall in levels of reductase messenger RNA (mRNA). Rather, it was attributable to an 80% decline in translation of the mRNA, coupled with a 5-fold increase in the rate of degradation of reductase protein, as revealed by pulse-chase experiments with [35S]methionine. Considered together with previous data, these findings suggest a multilevel mechanism for multivalent regulation of HMG-CoA reductase. We suggest that sterols suppress the enzyme incompletely by partially repressing transcription of the gene and that nonsterol products derived from mevalonate further reduce the enzyme by inhibiting translation of the mRNA. Sterols and non-sterol products, acting together, accelerate the degradation of reductase protein. This combination of transcriptional and posttranscriptional controls can regulate the amount of reductase protein over a several hundred-fold range in animal cells.