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!
At last, butterflies get a bigger, better evolutionary tree
16.02.2018 | Florida Museum of Natural History
New treatment strategies for chronic kidney disease from the animal kingdom
16.02.2018 | Veterinärmedizinische Universität Wien
Breakthrough provides a new concept of the design of molecular motors, sensors and electricity generators at nanoscale
Researchers from the Institute of Organic Chemistry and Biochemistry of the CAS (IOCB Prague), Institute of Physics of the CAS (IP CAS) and Palacký University...
For photographers and scientists, lenses are lifesavers. They reflect and refract light, making possible the imaging systems that drive discovery through the microscope and preserve history through cameras.
But today's glass-based lenses are bulky and resist miniaturization. Next-generation technologies, such as ultrathin cameras or tiny microscopes, require...
Scientists from the University of Zurich have succeeded for the first time in tracking individual stem cells and their neuronal progeny over months within the intact adult brain. This study sheds light on how new neurons are produced throughout life.
The generation of new nerve cells was once thought to taper off at the end of embryonic development. However, recent research has shown that the adult brain...
Theoretical physicists propose to use negative interference to control heat flow in quantum devices. Study published in Physical Review Letters
Quantum computer parts are sensitive and need to be cooled to very low temperatures. Their tiny size makes them particularly susceptible to a temperature...
Let’s say the armrest is broken in your vintage car. As things stand, you would need a lot of luck and persistence to find the right spare part. But in the world of Industrie 4.0 and production with batch sizes of one, you can simply scan the armrest and print it out. This is made possible by the first ever 3D scanner capable of working autonomously and in real time. The autonomous scanning system will be on display at the Hannover Messe Preview on February 6 and at the Hannover Messe proper from April 23 to 27, 2018 (Hall 6, Booth A30).
Part of the charm of vintage cars is that they stopped making them long ago, so it is special when you do see one out on the roads. If something breaks or...
15.02.2018 | Event News
13.02.2018 | Event News
12.02.2018 | Event News
16.02.2018 | Information Technology
16.02.2018 | Health and Medicine
16.02.2018 | Physics and Astronomy