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St. Jude finds mechanism for faulty protein disposal

A discovery by St. Jude Childrens Research Hospital scientists offers new insights into how myeloma cells dispose of defective or excess proteins and could lead to new cancer treatments.

The researchers identified key cellular components that carry out protein disposal, a finding that helps to explain how cancer drugs called proteasome inhibitors interfere with this process. The discovery is important because the newly identified components of the protein disposal mechanism could be targets for novel cancer drugs designed to kill the cell by blocking this mechanism. A report on this work appears in the Nov. 30 issue of Molecular Cell.

Myelomas are cancers of plasma cells, which are the activated form of B lymphocytesimmune system cells that respond to infection by temporarily producing extremely large amounts of proteins called antibodies that attack the target. The rapidly multiplying cancer cells continually make large numbers of new antibodies, which increases the chance for errors in the production process, resulting in the accumulation of defective proteins that must be degraded.

Proteasome inhibitors are currently being used to treat some types of cancer including multiple myelomas, although many aspects of this cellular process remain poorly understood, said Linda Hendershot, Ph.D., a member of the St. Jude Department of Genetics and Tumor Cell Biology, and the papers senior author. Our study sheds new light on how that process works.

The St. Jude team focused their investigation on special channels called retrotranslocons in the membrane of the cells protein factory. The researchers also studied a small collection of molecules that pull defective proteins out of the factory through the retrotranslocon so they can be delivered to the cells protein shreddera structure called the proteasome.

The protein factory, called the endoplasmic reticulum, is somewhat like an origami workshop: In the endoplasmic reticulum, molecules called chaperones help to fold up newly made proteins into the exact shape that enables that particular protein to perform its assigned task. Successfully folded proteins are transported to the cell surface or into the blood stream where they do their job. But if the folding does not occur or is faulty, defective proteins are ejected from the endoplasmic reticulum through channels called retrotranslocons and put into the proteasome, where they get degraded. This process, called endoplasmic reticulum-associated degradation, ensures that defective proteins do not accumulate in the endoplasmic reticulum and kill the cell by disrupting the vital process of protein folding.

Previous research identified a channel out of the endoplasmic reticulum for glycosylated proteins, or proteins tagged with sugar molecules. The channel relies on the detection of the sugar molecules to identify the proteins and send them to the proteasome. However, nothing was known about the disposal of non-glycosylated proteins (proteins with few or no sugar molecules attached). The St. Jude team found that this group of proteins exits the endoplasmic reticulum through a channel that is similar to the one used for glycoproteins but that has different components. The team focused the study on non-glycosylated proteins called light chains and heavy chains, which are the building blocks for antibodies made by plasma cells.

We wanted to determine what happens to defective heavy and light chains in plasma cells so we could get a better understanding of the molecules and channels that allow these cells to get rid of defective proteins that cant be used to make antibodies, Hendershot said. When plasma cells become cancerous, they multiply rapidly and continue to produce large amounts of antibodies, some of which are not folded properly. These cells depend on endoplasmic reticulum-associated degradation to dispose of unwanted proteins before they clog up the endoplasmic reticulum and eventually kill the cells.

The class of cancer drugs called proteasome inhibitors block endoplasmic reticulum-associated degradation as well as the destruction of proteins from other parts of the cells and cause defective proteins to overload this system, she said. We want to fully understand how endoplasmic reticulum-associated degradation works for antibodies made by plasma cells, so we can design more specific ways to block this process in myelomas.

The St. Jude team first demonstrated that defective light chain and heavy chain proteins in plasma cells are degraded by the proteasome after being ejected from the endoplasmic reticulum and tagged with molecules called ubiquitina standard way the cell flags an unwanted protein for destruction.

The researchers then examined the menagerie of molecules that collaborate to pull defective proteins out of the endoplasmic reticulum and hand it over to the proteasome. Hendershots team showed previously that one of those molecules, a chaperone called BiP, initially helps newly made proteins undergo folding. If the folding operation fails, however, BiP becomes a conspirator with Herp, another member of the menagerie, to send the defective protein to the proteasome. Based on a series of detailed biochemical studies, the team showed that Herp binds to both the ubiquitinated protein and the proteasome, apparently serving as a bridge to direct the protein to the shredder.

In addition to BiP and Herp, three other members of the menagerie, Derlin-1, p97 and Hrd 1 collaborate with Herp to extract defective proteins from the retrotranslocon so Herp can hand it over to the proteasome.

Our study shows for the first time the role Herp plays at the retrotranslocon, said Yuki Okuda-Shimizu, Ph.D. a postdoctoral fellow in Hendershots laboratory who contributed significantly to the project. The study also describes how non-glycosylated proteins are removed from the endoplasmic reticulum and disposed of. This information helps to explain how the process works and how we might design ways to block it in cancer cells.


Contact: Summer Freeman
St. Jude Children's Research Hospital

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