Study shows how UCH37 enzyme regulates a cell’s waste management system

Eric Strieter from the University of Massachusetts Amherst and his chemistry laboratory group have reported the discovery of a new enzyme, called UCH37, that controls the waste management system of a cell. According to Strieter, the senior author of the study, the results are “incredibly surprising.”

Study shows how UCH37 enzyme regulates a cell’s waste management system
Eric Strieter. Image Credit: University of Massachusetts Amherst.

It took us eight years to figure it out, and I’m very proud of this work. We had to develop a lot of new methods and tools to understand what this enzyme is doing.”

Eric Strieter, Study Senior Author, University of Massachusetts Amherst

Strieter explained that an extremely large protease known as a proteasome accounts for breaking down the huge majority of proteins in a cell; it may be composed of up to 40 proteins. Scientists have known for over two decades that UCH37 is one of the regulatory enzymes that bind with the proteasome, “But no one understood what it was doing,” he added.

He further added that the crux of the entire process is how complex modifications in a small protein, known as ubiquitin, can be.

In addition to modifying other proteins, ubiquitin modifies itself resulting in a wide array of chains. Some of these chains can have extensive branching. We found that UCH37 removes branchpoints from chains, allowing degradation to proceed.”

Eric Strieter, Study Senior Author, University of Massachusetts Amherst

Writing recently in the Molecular Cell journal, Strieter and the study’s first author and PhD candidate Kirandeep Deol, who headed and performed the experiments, along with co-authors Sean Crowe, Jiale Du, Heather Bisbee, and Robert Guenette, discussed how they answered the query. The study was funded by the National Institute of General Medical Sciences of NIH.

According to Strieter, this development could ultimately result in new cancer treatment, because tumor cells require the proteasome to grow and spread.

Strieter pointed out that, “Many cancer cells are essentially addicted to proteasome function. Its cells produce proteins at such a fast rate that mistakes are made, and if these are not cleared out, cells can’t function. Since UCH37 aids in clearing out proteins, it could be a useful therapeutic target to add to the proteasome inhibitors that have already been successful in the clinic.”

To initiate their years-long process, “we had to come up with a way to generate a wide variety of ubiquitin chains that would represent the potential diversity in a cell. Using that new library of ubiquitin chains allowed us to interrogate the activity of UCH37 in a controlled setting. That series of experiments gave us the first clue that this enzyme was doing something unique,” added Strieter.

They developed another new technique that utilizes mass spectrometry to define the architecture of ubiquitin chains in complex mixtures.

Strieter added that “This allowed us to see that the activity we discovered with our library of substrates was also present in a more heterogeneous mixture.”

The chemists finally employed the CRISPR gene-editing tool to eliminate the UCH37 enzyme from cells to quantify the latter’s effect on proteasome-mediated degradation in cells and in vitro.

This method resulted in one more surprise.

Instead of acting as expected and opposing the degradation process, it turned out that UCH37 was removing branchpoints from ubiquitin chains to help degrade proteins. You would think that by removing the signal for degradation that degradation would be impaired, but it didn’t work that way.”

Eric Strieter, Study Senior Author, University of Massachusetts Amherst

In upcoming experiments, Strieter and collaborators hope to additionally study the degradation process and learn more thoroughly how the UCH37 enzyme manages to control the function of cells.

Journal reference:

Deol, K. K., et al. (2020) Proteasome-Bound UCH37/UCHL5 Debranches Ubiquitin Chains to Promote Degradation. Molecular Cell.


The opinions expressed here are the views of the writer and do not necessarily reflect the views and opinions of AZoLifeSciences.
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