A novel regulatory step in cholesterol biosynthesis reveals a potentially crucial E3 ligase in cholesterol metabolism and stabilization of mammalian sterol reductases
School of Biotechnology and Biomolecular Sciences, UNSW Sydney, NSW 2052, Australia.
Cholesterol homeostasis requires a careful balance of cholesterol uptake, efflux and synthesis. The biosynthesis of cholesterol consists of over 20 enzymes and is tightly regulated at the gene and protein level. Here we investigated the post-translational regulation of two enzymes involved in cholesterol biosynthesis that share a high level of sequence identity – 14-Dehydrocholesterol Reductase (DHCR14) and the Lamin-B Receptor (LBR). These enzymes are 3β-hydroxysterol Δ14-reductases, which catalyse the same reaction in the pathway. These enzymes also share a high level of homology with one of the terminal enzymes of cholesterol biosynthesis, DHCR7. Loss of function mutations in DHCR7 lead to the devastating developmental disorder Smith-Lemmli-Opitz Syndrome (SLOS) We found that despite the high similarities between these enzymes, LBR protein levels were stable over time, whereas DHCR14 protein was rapidly turned over. We establish that the cholesterol mediated degradation of DHCR14 occurs via the proteasome and is triggered by cholesterol, as well as sterol intermediates.