Ubiquitin: small things matter

Protein degradation, cell growth regulation, DNA repair, neural and muscle degeneration and response to stress are some of the functions that ubiquitin, a small protein that is found in most body cells, regulates. Its name comes from the Latin word ubīque, which means “everywhere”.

Proteins are molecules that fulfill fascinating roles within the body cells: they work hard to maintain the balance of proteins just as the body regulates its temperature or maintains the blood pressure within certain limits. This significant role of protein balance is played by the ubiquitin-proteasome system.

The ubiquitin is a small protein found in all the body and it is formed by 76 amino acids. When several ubiquitin molecules label the protein that must be eliminated, the proteasome- a great multiprotein complex responsible for protein degradation- identifies it as “disposable” and sets off a chain reaction that ends with the degradation of the molecule.

“Scientists discovered that ubiquinated protein, that is to say that were labeled with ubiquitin, are marked to be degraded. This is of outmost importance because, for the first time, a well-defined mechanism was established to recycle old proteins and generate new ones. It was an important finding as a quality control system, and investigators that discovered this mechanism were awarded with the Nobel Prize in Chemistry 2004” Gaston Soria, assistant investigator of CONICET, explains.

This system is like a great molecular machine in the shape of a barrel with a top similar to rubbish bins. Furthermore, it has a pedal that validates, introduces and destroys rubbish in its interior. Therefore, ubiquitin labeling is one of the mechanisms the cell uses to eliminate molecules.

“The barrel is a stack of four overlapping rings with a cavity in the middle. It is composed by 28 protein components. Inside it, there are active sites in the interior walls that break polypeptide – molecules smaller than proteins- chains in short segments with seven to nine amino acid units that could be reused by the cell or degraded to individual amino acid to be recycled” says Michael Glickman, professor of chemistry at Technion – Israel Institute of Technology.

The finding of ubiquitin has been important to understand how vital it is for our body to discard cell waste. In fact, when the system does not work appropriately, consequences do not go unnoticed.

Alterations in proteins and organelles degradation have a strong impact on the proliferative capacity of cells, and therefore they are normally associated with the development of a wide range of disorders, including cancer and different neurodegenerative diseases.

“If the ‘bad proteins’ are not eliminated, they are accumulated and they can cause severe disorders such as Alzheimer’s or Parkinson’s diseases. This labelling system is vital to determine what has to be eliminated or not in many other cell functions such as protein quality control systems, DNA repair or the body’s immune response”, Simona Polo, biologist and investigator at the Department of Health Science of Milan, explains.

There are occasions in which the system does not work appropriately and the ubiquitin attaches to proteins that should not be degraded. For instance, cell division is a precise and extremely controlled phenomenon that occurs thanks to that process and, in many cases, when the inhibition or stimulation of these proteins does not work, it could lead to cancer.

On the other hand, this complex system is also in charge of combating different viruses that could attack the body. Simona Polo comments: “Viruses have managed to manipulate the labeling system in order to mislead the cell. They manage to add ‘to be eliminates’ labels in cellular defense proteins important for the immune system. Afterwards, the virus is free to act within the cell, as in the case of the Human Papillomavirus”.

Protein degradation also plays an important role in metabolism regulation. For instance, during malnutrition, proteasome of the muscle cells are very active because when they degrade proteins into their basic constituents- amino acids- they are free to produce glucose for them, which is later used as fuel to produce energy. That is how muscle cells’ protein destruction explains the atrophy and weakness of the muscle mass that occurs in individuals who suffer from malnutrition or an advanced disease such as AIDS or untreated diabetes.

“Destroying to create is the fundamental basis of life; it is important even for the units smaller than living beings: their basic molecules”; Polo concludes.