Twin enzymes, divergent control: The cholesterogenic enzymes DHCR14 and LBR are differentially regulated transcriptionally and post-translationally
Autor: | Isabelle M. Capell-Hattam, Anika V. Prabhu, Andrew J. Brown, Lydia Qian, Gene Hart-Smith, Laura J. Sharpe |
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Rok vydání: | 2020 |
Předmět: |
0301 basic medicine
Oxidoreductases Acting on CH-CH Group Donors Ubiquitin-Protein Ligases Receptors Cytoplasmic and Nuclear Constitutively active CHO Cells Protein degradation Reductase Biology Biochemistry 03 medical and health sciences chemistry.chemical_compound Cricetulus Gene expression Genetics Transcriptional regulation Animals Humans Receptor Molecular Biology chemistry.chemical_classification 030102 biochemistry & molecular biology Protein Stability Cholesterol Cell Biology Lipids Sterol Cell biology 030104 developmental biology Enzyme Gene Expression Regulation chemistry Organ Specificity lipids (amino acids peptides and proteins) Oxidoreductases Protein Processing Post-Translational Biotechnology |
Zdroj: | J Biol Chem |
ISSN: | 0021-9258 |
Popis: | 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. |
Databáze: | OpenAIRE |
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