The ubiquitin-proteasome pathway mediates the regulated degradation of mammalian 3-hydroxy-3-methylglutaryl-coenzyme A reductase

3-Hydroxy-3-methylglutaryl-coenzyme A reductase (HMGR), the key regulatory enzyme in the mevalonate (MVA) pathway, is rapidly degraded in mammalian ce lls supplemented with sterols or MVA This accelerated turnover was blocked by N-acetyl-leucyl-leucyl-nor-leucinal (ALLN), MG-132, and lactacystin, and to a lesser extent by N-acetyl-leucyl-leucyl-methional (ALLM), indicating the involvement of the 26 S proteasome. Proteasome inhibition led to enhanc ed accumulation of high:molecular weight polyubiquitin conjugates of HMGR a nd of HMGal, a chimera between the membrane domain of HMGR and beta -galact osidase. Importantly, increased amounts of polyubiquitinated HMGR and HMGal were observed upon treating cells with sterols or MVA. Cycloheximide inhib ited the sterol-stimulated degradation of HMGR concomitantly with a marked reduction in polyubiquitination of the enzyme, Inhibition of squalene synth ase with zaragozic acid blocked the MVA- but not sterol-stimulated ubiquiti nation and degradation of HMGR, Thus, similar to yeast, the ubiquitin-prote asome pathway is involved in the metabolically regulated turnover of mammal ian HMGR, Yet, the data indicate divergence between yeast and mammals and s uggest distinct roles for sterol and nonsterol metabolic signals in the reg ulated ubiquitination and degradation of mammalian HMGR.