Subcellular localization of sterol biosynthesis enzymes

Abstract

Cholesterol synthesis is a complex, coordinated process involving a series of enzymes. As of today, our understanding of subcellular localization of cholesterol biosynthesis enzymes is far from complete. Considering the complexity and intricacies of this pathway and the importance of functions of DHCR7, DHCR24 and EBP enzymes for human health, we undertook a study to determine their subcellular localization and co-localization. Using expression constructs and antibody staining in cell cultures and transgenic mice, we found that all three enzymes are expressed in ER and nuclear envelope. However, their co-localization was considerably different across the cellular compartments. Furthermore, we observed that in the absence of DHCR7 protein, DHCR24 shows a compensatory upregulation in a Dhcr −/− transgenic mouse model. The overall findings suggest that the sterol biosynthesis enzymes might not always work in a same functional complex, but that they potentially have different, multifunctional roles that go beyond the sterol biosynthesis pathway. Furthermore, the newly uncovered compensatory mechanism between DHCR7 and DHCR24 could be of importance for designing medications that would improve cholesterol production in patients with desmosterolosis and Smith-Lemli-Opitz syndrome.

Sterol and oxysterol synthases near the ciliary base activate the Hedgehog pathway

“…S1 D ), which was also the case for the majority of overexpressed DHCR7 with a Myc tag. These data are consistent with previous reports ( Koczok et al, 2019 ), but contrast with our results for endogenous DHCR7, underscoring the importance of localization studies that focus on endogenous gene products rather than on overexpression of exogenous constructs that may be influenced by expression conditions or epitope tags.…”

Enzymes in the Cholesterol Synthesis Pathway: Interactomics in the Cancer Context

“…Protein interactions between human DHCR24 and DHCR7 [ 169 ], in part, favor in the cholesterol “metabolone” hypothesis. On the other hand, DHCR7, DHCR24 and EBP enzymes might not always combine in a functional complex because they potentially play different roles that go beyond the cholesterol biosynthesis pathway [ 170 ]. Thus, an existence of multiprotein cholesterol “metabolon” in human cells is a subject for future investigations.…”

Post-translational control of the long and winding road to cholesterol

“…There is some suggestion from work both in yeast (93) and mammalian cells (94), that lipid droplet formation could sequester these enzymes and shut down cholesterol synthesis, maybe as a feedback response opposing excess lipid synthesis and storage. Interestingly, DHCR7 has also been observed in the Golgi, whilst DHCR24 and EBP were not (95). All three enzymes were co-located in the ER along with the earlier enzyme SC5D, which was additionally localised to the nucleus which may suggest it has additional functions beyond sterol synthesis (95).…”

“…Interestingly, DHCR7 has also been observed in the Golgi, whilst DHCR24 and EBP were not (95). All three enzymes were co-located in the ER along with the earlier enzyme SC5D, which was additionally localised to the nucleus which may suggest it has additional functions beyond sterol synthesis (95). Under what physiological conditions DHCR7 and SC5D may be relocated needs to be established.…”