Fruit Fly Study Reveals New Mechanism for Protein Production

Scientists from the University of California, Merced, used fruit flies to discover a biological mechanism shared by numerous creatures. This mechanism could significantly influence our understanding of cancer and aging.

Professor Fred Wolf of the Department of Molecular and Cell Biology, Sammy Villa, a graduate student at the time, and Vishva Dixit, Vice President and Senior Fellow in Physiological Chemistry and Research Biology at Genentech, uncovered a mechanism that cells employ to regulate the amount of protein they produce during the translation of RNA into protein.

Professor Fred Wolf from the University of California said, “This mechanism may be responsible for changes in protein translation in stress, cancer, and aging.”

Their study was published in the journal Nature Communications.

Since Wolf was an undergraduate and a technician in Dixit's research lab at the University of Michigan, the two have collaborated on projects together. Following Wolf's graduation from Berkeley Graduate School and Dixit's employment at Genentech, a Roche Group member and pioneer in the biotech business, they continued to correspond.

Wolf said, “Vishva knew I was an expert in Drosophila (fruit fly) genetics, a resource that was not available at Genentech.”

Normally, Wolf's group works on deciphering the genetics and brain circuits that govern animal behavior, especially about the effects of alcohol on the brain and how motivation is reflected in it.

He and his colleagues work with Drosophila, a widely used model organism in research, because of its low cost of living, rapid and plentiful reproduction, and ease of genetic modification for hypothesis testing. According to Wolf, research on fruit flies has produced a wide range of advanced technologies.

Dixit, however, was interested in learning how the protein OTUD6 worked.

He asked us to use the awesome power of the fly model to discover its function, and we took up the challenge. Vishva granted me seed funding to start generating flies with mutations in OTUD6 and testing the mutant flies for any problems they might have. The project really got going when the paper’s first author, Sammy Villa, joined my lab in 2018. Sammy took on the project and his skills in molecular biology and biochemistry were instrumental to the success of the project.”

Fred Wolf, Professor, Department of Molecular and Cell Biology, University of California

The researchers were not sure what they were searching for at first. When the OTUD6 mutant flies were first created, the researchers anticipated seeing something visible, such as changes in the number or form of wings or defects in the reproductive system. Rather, the flies seemed to be normal.

We stressed the flies in as many ways as we could conceive of and found they were susceptible to chemical stress, for example, oxidative stress. This allowed us to search for how OTUD6 contributed to resilience to stress.”

Fred Wolf, Professor, Department of Molecular and Cell Biology, University of California

To understand what OTUD6 does, the researchers searched for all proteins that interacted with it. They discovered that it cuts the amount of protein produced by ribosomes in half, increasing the amount of protein that cells make.

We were quite surprised by the huge impact OTUD6 had on how much protein was made in cells: Making flies mutant for OTUD6 cut protein production in half. That is a big difference, The amount of protein produced in cells is known to affect how long animals live, with less protein being made correlating with longer lifespan. Our OTUD6 mutants lived twice as long. We think this is because there is less protein being made.”

Fred Wolf, Professor, Department of Molecular and Cell Biology, University of California

Certain malignancies can be greatly impacted by the quantity of protein produced.

Many human malignancies have elevated levels of some OTUD6 variants, and many of these tumors also produce more proteins. The researchers emphasized that although they lack concrete proof of a connection, elevated OTUD6 may aid in the development and spread of cancer cells.

To alter the amount of protein produced, cells can modify their OTUD6 levels.

“It has been known for years that there are two other ways for cells to actively tune how much protein is made, and we think we discovered a third way,” Wolf said.

The research goal is to determine how cells modify the quantity of OTUD6 present in them. By doing so, the team hopes to gain insight into the mechanism underlying the initiation of this novel pathway and develop novel approaches for influencing protein creation that may improve longevity and potentially even cancer outcomes.