New Research: A Link between Cholesterol Metabolism and Lysosome Synthesis

In the immediately previous blog entry, we discussed how proteins are targeted to specific locations in the cell via zip-codes. One location is the lysosome, which functions as a recycling unit, containing enzymes that break apart portions of the cell marked for destruction. The lysosomal enzymes are brought to the lysosome using a specific zip-code, a chemical addition called mannose 6-phosphate (M6P).

One of the two proteins that adds M6P is made of two parts made from the same gene GNPTAB. Initially, a large premature protein is initially made, but it gets chopped into two pieces. Afterwards, the two products combine to form the functional M6P-adding enzyme. Patients with a disease called mucolipidosis II have mutations that prevents proper formation of the enzyme that adds M6P, leading to defective lysosomes and an inability to breakdown damaged portions of a cell. Ultimately, this leads to skeletal abnormalities and mental retardation, similar to Tays-Sachs disease which is also a disease of defective lysosomes.

Katrin Marschner of the Pohl lab wanted to find out what was the protein that caused the chopping of the premature protein. She found that a crucial part of the cleavage site was similar to the sites cut by the protein S1P. Further experiments revealed that S1P could also cleave the precursor to M6P-adding enzyme, creating a mature protein. Both mice with mutations in S1P and mice with mutations in M6P-adding enzyme had similar characteristics, such as defects in cartilage formation. Similar to when a pipe gets clogged, S1P-deficient cells had prominent accumulation of materials, further suggesting that S1P cleaves the M6P-adding enzyme.

S1P also known to be essential for regulating the body's cholesterol levels. At high levels of cholesterol, a molecular switch called SREBP gets anchored to the inside of the cell. However when cholesterol levels are low, S1P cuts off the anchor, freeing SREBP and allowing it to go to the nucleus where it turn on genes that make cholesterol.

As a result, drug companies have been investing money to find chemicals that can block S1P as a way to treat high blood cholesterol. Without S1P, SREBP cannot reach the nucleus and cholesterol is no longer made. However, this study suggests that such drugs would have the unwanted side effect of blocking proper lysosome function. This would lead to accumulation of garbage in the cell, something that is linked also to Alzheimer's and Parkinson's disease.


Marschner, K., et al (2011). A Key Enzyme in the Biogenesis of Lysosomes is a Protease that Regulates Cholesterol Metabolism. Science 33(6038):87-90. Paper