麻豆淫院

Researchers from the University of Cologne and Heinrich Heine University D眉sseldorf have identified a new ubiquitin form dedicated to proteostasis and healthy aging. They show that CxUb (C-terminally extended ubiquitin), is necessary and sufficient to overcome stress, a discovery that opens up new routes for the treatment of cancer and aging-related diseases.

The study, "Ubiquitin precursor with C-terminal extension promotes proteostasis and longevity," is in Molecular Cell and was 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 D眉sseldorf).

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

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 eukaryotic 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.

"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 Dr. 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 Escobar-Henriques.

Since CxUb was able to resolve every stress to which the yeast cells were exposed 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.

The authors used a combination of state-of-the-art proteomics, microscopy, and biochemistry techniques, mainly thanks to facilities at the CECAD Cluster of Excellence on Aging Research. This novel discovery of how cells deal with stress was possible thanks to a very fruitful collaborative effort from various labs at the Universities of Cologne and D眉sseldorf.