A study by Oregon Health & Science University researchers has uncovered a new way proteins can be changed inside cells. This discovery could be important for understanding how the immune system works.
The scientists have discovered a dual modification process they call "MARUbylation," which combines two different molecular tags, ADP-ribosylation and ubiquitylation, on the same protein. This discovery challenges the long-standing belief that each protein modification involves only one type of tag. Instead, the study, published in The EMBO Journal, shows that some proteins can have two tags at once, which can affect how they function in cells.
The discovery came through a collaboration between two researchers who, on the surface, studied different areas. Jonathan Pruneda, Ph.D., associate professor of molecular microbiology and immunology in the OHSU School of Medicine, studies ubiquitylation, where a small molecule called ubiquitin attaches to a protein, marking it for various actions like being broken down or moved — like putting a tag on a protein.
Michael Cohen, Ph.D., professor of chemical physiology and biochemistry in the OHSU School of Medicine, focuses on ADP-ribosylation, where ADP-ribose attaches to a protein, changing how it works.
Meeting leads to 'aha' moment
A meeting between the two scientists to discuss a graduate student's research led to a lightbulb moment.
"We were just chatting about post-translational modifications and realized that the two we were working on could literally fit together," Pruneda said.
The researchers were excited to find that proteins in human cells can be modified with both ADP-ribosylation and ubiquitylation. They named this process "MARUbylation."
"We realized that two completely different fields — like the ones we work in — are actually looking at the same thing," Cohen said. "No one had really connected them before. Our goal is to see if we can team up to develop new treatments, rather than coming at it from different directions."
Pruneda added, "We think it changes the message that the protein receives, which could impact how it functions in the body."
Proteins are often modified by adding small chemical tags, which change how they act in the cell. It was generally believed that each site on a protein could only be modified by one type of tag at a time. But this study shows that some proteins can have two tags at the same time, opening up new ways to understand how proteins work.
The researchers discovered that a protein called PARP10, which helps repair DNA, can be tagged with both ADP-ribose and ubiquitin. This dual modification is important when the immune system responds to signals, especially in fighting off infections.
Using special tools, the scientists confirmed that MARUbylation happens inside cells. They also found that this process can lead to further reactions inside cells, adding more complexity to how signals are managed.
"This discovery expands our understanding of how complex cellular signals are integrated," Pruneda said. "Until now, it was thought that a single modification would control protein behavior, but our work reveals that different modifications can interact and affect a protein's function in unique ways."
Discovery paves way for immune therapies
The discovery could provide new insights into diseases related to the immune system, such as autoimmune disorders, cancer and neurodegenerative diseases, where protein modifications play a key role. Pruneda hopes that understanding MARUbylation could lead to new treatments.
"What's interesting is that drugs targeting these processes are already in use," Pruneda said. "PARP inhibitors, for example, are being used in the clinic, and now we're starting to appreciate the biology behind these drugs."
Cohen sees the potential for their discovery to improve immune therapy, especially cancer treatment.
"Cancer cells have found ways to evade the immune system, and one of the methods they use is by upregulating PARP enzymes, which helps them avoid the immune response," he said. "By inhibiting those enzymes, we can help reverse that and make cancer cells more susceptible to immune attack."
The researchers are excited to keep working together to better understand how this new modification process works and to discover new ways to target it for treatments. Pruneda and Cohen are hopeful their collaboration will lead to new therapies in the future.
"It's about using this collaboration to build tools that are more than just the sum of their parts," Cohen said. "Our different approaches and methodologies made this project a success."
In addition to Pruneda and Cohen, Daniel Bejan, Ph.D., and Rachel Lacoursiere, Ph.D., both of OHSU, co-authored this study.
This study was supported by the National Institutes of Neurological Disorders & Stroke, and the National Institute of General Medical Sciences, and the National Cancer Institute, of the National Institutes of Health, award numbers R01NS088629, R35GM142486, and F31CA284712. Additional support was provided by Achievement Rewards for College Scientists. The content is solely the responsibility of the authors and does not necessarily represent the official views of the funders.
