A discovery by St. Jude Children’s 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 lymphocytes—immune 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 paper’s 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 cell’s 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 cell’s protein shredder—a 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 can’t 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 ubiquitin—a 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. Hendershot’s 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 Hendershot’s 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.”
Summer Freeman | EurekAlert!
Cancer diagnosis: no more needles?
25.05.2018 | Christian-Albrechts-Universität zu Kiel
Less is more? Gene switch for healthy aging found
25.05.2018 | Leibniz-Institut für Alternsforschung - Fritz-Lipmann-Institut e.V. (FLI)
The more electronics steer, accelerate and brake cars, the more important it is to protect them against cyber-attacks. That is why 15 partners from industry and academia will work together over the next three years on new approaches to IT security in self-driving cars. The joint project goes by the name Security For Connected, Autonomous Cars (SecForCARs) and has funding of €7.2 million from the German Federal Ministry of Education and Research. Infineon is leading the project.
Vehicles already offer diverse communication interfaces and more and more automated functions, such as distance and lane-keeping assist systems. At the same...
A research team led by physicists at the Technical University of Munich (TUM) has developed molecular nanoswitches that can be toggled between two structurally different states using an applied voltage. They can serve as the basis for a pioneering class of devices that could replace silicon-based components with organic molecules.
The development of new electronic technologies drives the incessant reduction of functional component sizes. In the context of an international collaborative...
At the LASYS 2018, from June 5th to 7th, the Laser Zentrum Hannover e.V. (LZH) will be showcasing processes for the laser material processing of tomorrow in hall 4 at stand 4E75. With blown bomb shells the LZH will present first results of a research project on civil security.
At this year's LASYS, the LZH will exhibit light-based processes such as cutting, welding, ablation and structuring as well as additive manufacturing for...
There are videos on the internet that can make one marvel at technology. For example, a smartphone is casually bent around the arm or a thin-film display is rolled in all directions and with almost every diameter. From the user's point of view, this looks fantastic. From a professional point of view, however, the question arises: Is that already possible?
At Display Week 2018, scientists from the Fraunhofer Institute for Applied Polymer Research IAP will be demonstrating today’s technological possibilities and...
So-called quantum many-body scars allow quantum systems to stay out of equilibrium much longer, explaining experiment | Study published in Nature Physics
Recently, researchers from Harvard and MIT succeeded in trapping a record 53 atoms and individually controlling their quantum state, realizing what is called a...
25.05.2018 | Event News
02.05.2018 | Event News
13.04.2018 | Event News
25.05.2018 | Event News
25.05.2018 | Machine Engineering
25.05.2018 | Life Sciences