Protein Shows Promise in Reducing Stress and Slowing Aging

Researchers have discovered a novel form of ubiquitin that plays a crucial role in maintaining proteostasis and promoting healthy aging. Termed CxUb (C-terminally extended ubiquitin), this newly identified ubiquitin variant is both necessary and sufficient to help cells withstand stress, marking a significant breakthrough in understanding cellular defense mechanisms (1^✔ ✔Trusted Source
Ubiquitin precursor with C-terminal extension promotes proteostasis and longevity

Go to source). The findings were led by Dr. Mafalda Escobar-Henriques (Institute for Genetics and CECAD Cluster of Excellence on Aging Research, University of Cologne) and Professor Dr. Andreas Reichert (Institute of Biochemistry and Molecular Biology I, Heinrich Heine University Düsseldorf) and published in Molecular Cell.

Ubiquitin is a small protein with many essential biological functions. In particular, it monitors other proteins to detect if they are damaged or not assembled correctly. If that is the case, it earmarks them for destruction.

Why Targeting Ubiquitin is Crucial for Cell Health—and Why Current Drugs Cause Side Effects

This process is essential to restoring and maintaining proteostasis (protein homeostasis) in disease situations and to precisely time cellular division in healthy cells. Currently used drugs targeting either ubiquitin itself or the degradation machinery can be highly effective in cancer treatment, but also come with significant side effects, including gastrointestinal issues, nerve damage, fatigue, cardiovascular problems, etc.

The research teams at the two universities discovered that in response to stress, cells in both baker’s yeast S. cerevisiae and the nematode C. elegans engage a unique ubiquitin precursor form that was observed to be essential for both organisms’ survival. This ubiquitin precursor, CxUb, is universally present in all eucaryotic organisms, yet until now it has been largely overlooked and assumed to be inactive.

To understand CxUb’s unique role, the researchers compared it to standard ubiquitin and found out that only CxUb is capable of amplifying ubiquitin tagging on other abnormal proteins, dramatically increasing their destruction. Under stress, CxUb switches from a precursor to an active molecule that is incorporated into defective proteins, but does not interfere with the housekeeping functions of ubiquitin in healthy cells. This allows it to support the organism’s healthy regeneration.

CxUb Protein: A Simple, Fast Defense Strategy for Healthy Aging Across Organisms

“This very simple and fast defense strategy allows cells to specifically target harmful protein aggregates or damaged mitochondria. By targeting the sources of cellular stress, CxUb arms the studied organisms with tools that ensure healthy aging”, said senior and co-corresponding author Andreas Reichert. As CxUb is common to all complex organisms, the research team believes the function to operate similarly in humans as well.

“This discovery is likely to open up very exciting new opportunities in the fields of aging and age-associated diseases, as specifically targeting CxUb has the potential to significantly improve current therapies against cancer and neurodegenerative diseases by reducing their side effects”, added Principal Investigator Mafalda Escobar-Henriques.

Since CxUb was able to resolve every stress the yeast cells were exposed to in the lab, the research team believes that this might also be the case for age-associated diseases that are linked to proteostasis defects – like cancer and neurodegenerative diseases. Further research is planned to test the importance of CxUb for those targets.

Reference:

1. Ubiquitin precursor with C-terminal extension promotes proteostasis and longevity - (https://www.cell.com/molecular-cell/fulltext/S1097-2765(25)00737-3)

Source-Eurekalert