Abstract
Cholesterol synthesis is a tightly regulated process, both transcriptionally and post-translationally. Transcriptional control of cholesterol synthesis is relatively well-understood. However, of the ∼20 enzymes in cholesterol biosynthesis, post-translational regulation has only been examined for a small number. Three of the four sterol reductases in cholesterol production, 7-dehydrocholesterol reductase (DHCR7), 14-dehydrocholesterol reductase (DHCR14), and lamin-B receptor (LBR), share evolutionary ties with a high level of sequence homology and predicted structural homology. DHCR14 and LBR uniquely share the same Δ-14 reductase activity in cholesterol biosynthesis, yet little is known about their post-translational regulation. We have previously identified specific modes of post-translational control of DHCR7, but it is unknown whether these regulatory mechanisms are shared by DHCR14 and LBR. Using CHO-7 cells stably expressing epitope-tagged DHCR14 or LBR, we investigated the post-translational regulation of these enzymes. We found that DHCR14 and LBR undergo differential post-translational regulation, with DHCR14 being rapidly turned over, triggered by cholesterol and other sterol intermediates, whereas LBR remained stable. DHCR14 is degraded via the ubiquitin-proteasome system, and we identified several DHCR14 and DHCR7 putative interaction partners, including a number of E3 ligases that modulate DHCR14 levels. Interestingly, we found that gene expression across an array of human tissues showed a negative relationship between the C14-sterol reductases; one enzyme or the other tends to be predominantly expressed in each tissue. Overall, our findings indicate that whereas LBR tends to be the constitutively active C14-sterol reductase, DHCR14 levels are tunable, responding to the local cellular demands for cholesterol.
Highlights
Cholesterol synthesis is a tightly regulated process, both transcriptionally and post-translationally
We found that DHCR14 and lamin-B receptor (LBR) undergo differential post-translational regulation, with DHCR14 being rapidly turned over, triggered by cholesterol and other sterol intermediates, whereas LBR remained stable
We found that 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), a canonical sterol regulatory element– binding protein 2 (SREBP-2) target, follows this trend in expression
Summary
Divergent control: The cholesterogenic enzymes DHCR14 and LBR are differentially regulated transcriptionally and post-translationally. DHCR14 and LBR uniquely share the same ⌬-14 reductase activity in cholesterol biosynthesis, yet little is known about their post-translational regulation. In the cholesterol synthesis pathway, there are four sterol reductases that catalyze three distinct reductive steps on sterol intermediates [7] (Fig. 1) Two of these reductases, 7-dehydrocholesterol reductase (DHCR7) and 24-dehydrocholesterol reductase (DHCR24) (the terminal enzymes of cholesterol biosynthesis), have been relatively well-characterized, and their transcriptional [8, 9] and post-translational regulation has been studied (10 –14). 7-dehydrocholesterol reductase (DHCR7) and 24-dehydrocholesterol reductase (DHCR24) (the terminal enzymes of cholesterol biosynthesis), have been relatively well-characterized, and their transcriptional [8, 9] and post-translational regulation has been studied (10 –14) Whereas their transcriptional regulation is generally understood [15,16,17], little is known about the posttranslational regulation of the two remaining sterol reductases, lamin-B receptor (LBR) and 14-dehydrocholesterol reductase (DHCR14). We further identify a tissue-specific RNA expression pattern between TM7SF2 (the gene encoding DHCR14) and LBR, suggesting preferential use of particular C14-SRs in different tissues
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