Cholesterol synthesis: Regulation by destruction
-Dangsheng Li

AbstractScientists have found that the degradation of a key enzyme involved in cholesterol synthesis is regulated by a cofactor known as Ufd1

The endoplasmic reticulum (ER) is an organelle responsible for several specialized functions, including the synthesis of some proteins. As a quality control, ER destroys misfolded proteins through a process known as ER-associated degradation. Cells also use this process to degrade the key enzyme, HMG-CoA reductase (HMGCR), which is involved in cholesterol synthesis. Baoliang Song, Boliang Li at the Chinese Academy of Sciences in Shanghai and co-workers1 have found that the degradation of HMGCR is regulated by a cofactor, Ufd1.
An important step in HMGCR degradation is the attachment of a regulatory protein called ubiquitin — a unique tag which marks the HMGCR for destruction. This ubiquitin attachment is catalysed by an ER-residing enzyme. The researchers discovered that Ufd1 binds directly to this enzyme, enhances its ability to tag ubiquitin onto HMGCR, and consequently helps HMGCR degradation. As a result, cells with higher levels of Ufd1 produce less cholesterol and, to compensate, are able to take up more cholesterol from outside the cell.
A high cholesterol level is associated with medical conditions such as heart disease. The finding provides new strategies to lower cholesterol through regulating HMGCR degradation.
The authors of this work are from:
State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China; Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, Texas, USA.