Novel Protein Analysis Technique Offers Fresh Insights into Immune System Disorders

A study by researchers at Oregon Health & Science University has uncovered a previously unknown way that proteins can be modified inside cells—an insight that could have wide-ranging implications for how we understand immune system behavior.

The team identified a dual-modification process they've named MARUbylation, which combines two distinct molecular tags—ADP-ribosylation and ubiquitylation—on a single protein. This discovery challenges the longstanding assumption that each protein site is modified by only one type of tag at a time.

Published in The EMBO Journal, the research shows that some proteins can carry both tags simultaneously, potentially influencing how they function in the cell.

A Chance Meeting Sparks a New Insight

The breakthrough resulted from a conversation between two researchers from different scientific backgrounds. Jonathan Pruneda, Ph.D., an associate professor of molecular microbiology and immunology at the OHSU School of Medicine, studies ubiquitylation—a process in which a small molecule called ubiquitin attaches to a protein, directing it for actions like degradation or relocation.

Michael Cohen, Ph.D., a professor of chemical physiology and biochemistry at the same institution, focuses on ADP-ribosylation, where the attachment of ADP-ribose modifies a protein’s behavior.

Their collaboration began when they discussed a graduate student’s project.

“We were just chatting about post-translational modifications and realized that the two we were working on could literally fit together,” said Pruneda.

That conversation led to the realization that proteins in human cells can be modified by both ADP-ribose and ubiquitin at the same time—a finding that prompted them to coin the term MARUbylation.

“We realized that two completely different fields like the ones we work in are actually looking at the same thing. No one had really connected them before,” Cohen said. “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.”

Challenging Assumptions About Protein Behavior

Proteins are often modified by small chemical tags that change how they behave in cells. Until now, the prevailing view was that each site on a protein could only host one type of modification. But this study shows that some proteins—such as PARP10, which is involved in DNA repair—can receive both ADP-ribose and ubiquitin tags at once.

This dual tagging appears to play a critical role in how the immune system responds to signals, especially during infections. Using specialized tools, the researchers confirmed that MARUbylation occurs inside cells and can spark further cellular responses, adding a new layer to our understanding of intracellular communication.

“This discovery expands our understanding of how complex cellular signals are integrated,” said Pruneda. “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.”

Opening New Doors for Immune Therapies

This finding could have important implications for treating immune-related conditions—such as cancer, autoimmune disorders, and neurodegenerative diseases—where protein modifications play a central role.

“What’s interesting is that drugs targeting these processes are already in use,” Pruneda noted. “PARP inhibitors, for example, are being used in the clinic, and now we’re starting to appreciate the biology behind these drugs.”

Cohen sees particular promise for cancer therapy.

“Cancer cells have found ways to evade the immune system, and one method is by increasing the activity of PARP enzymes,” he explained. “By inhibiting those enzymes, we can help reverse that and make cancer cells more susceptible to immune attack.”

Looking ahead, Pruneda and Cohen plan to deepen their collaborative research, hoping to further unravel the details of MARUbylation and its therapeutic potential.

“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.”