KU Medical Center scientists work to uncover biology behind cellular system that destroys damaged proteins and prevents disease

Our bodies are composed of trillions of cells, each of which contains thousands of proteins that carry out countless tiny processes that keep our organs and tissues working properly. With so much activity happening, our cells also generate a lot of trash — misfolded proteins and proteins that have become nonfunctional. If too many of these waste products build up, they can lead to disease and even death.

Luckily, cells in the human body are equipped with their own garbage disposals.

One such disposing machine is the ubiquitin-proteasome system. Ubiquitin, a small protein that earned its name by being ubiquitous, functions as a kind of “on” switch for this system by tagging proteins that need to be degraded. The proteasome, a large cylindrical protein complex that forms when 66 separate subunits come together, then sucks in those tagged proteins, chops them up and recycles them. 

A number of these complexes form within the cell. And when they do not function properly, they can lead to diseases.

“In many neurodegenerative diseases, you have proteins that are not properly folded that start accumulating and forming toxic aggregates or amyloid,” said Jeroen Roelofs, Ph.D., professor of biochemistry and molecular biology at the University of Kansas Medical Center. “If the proteasome complex doesn't work well, you get more accumulation of proteins and more chance of them becoming aggregates or amyloids. So we think the proteasome is an important component in many of these diseases.”

Roelofs and his colleagues conduct basic science to gain a better understanding of how proteasome complexes form and function. In a study published earlier this year in the Proceedings of the National Academy of Sciences, they identified what forces bring and keep these proteasome complexes together when they move from the nucleus to the cell cytosol under stress conditions.

Typically, 70% of proteasome complexes are located in the cell nucleus, while 30% are spread around in the cytosol, the fluid in the cytoplasm that surrounds the nucleus, Roelofs said. But under stress, such as when cells are deprived of glucose, that can change. Instead of doing their usual job of degrading proteins, many of the proteasomes in the nucleus move to the cytosol and form tight little granules without even a membrane to hold them together. Research has shown that this relocalization also happens in human cells under certain conditions.  

Roelofs and his colleagues had observed that the same thing happened — proteasomes moved to the cytosol and formed granules — when they stressed yeast cells by treating them with a mitochondrial inhibitor. (Roelofs’ lab uses baker’s yeast to study proteasome processes because its components are very similar to those of human cells, and yeast is easier to manipulate.)

But not much is understood about the mechanics of how these granules form, or what purpose they serve. In their study, Roelofs and his colleagues tried to answer the first question. They found that these granules form by interactions between three components: proteasomes, proteins that have long ubiquitin chains and two “shuttle factors,” which can bind the proteasomes and ubiquitinated proteins.

Now that they better understand the interactions that drive the formation of the granules, the researchers can try to learn why it is beneficial for cells to form these structures. “We think they help cells that are in stress conditions or low on energy, potentially to protect the proteasomes and ubiquitinated proteins and store them for conditions when nutrients become abundant again,” Roelofs said.

Answering these basic science questions can lay the groundwork for the development of drugs that target these processes to treat disease.

“Our research is important for understanding what underlies some diseases,” Roelofs said. “By understanding the basic cell biology, we might be able to identify new ways of manipulating this system.”