Human organs and tissues are made up of millions of microscopic living units called cells. During their useful life, these cells accumulate waste products that include unwanted, poorly folded, and excess protein.
Waste management within these cells is a complex and critically important process that is essential for the proper functioning of organs within any given system.
Malfunctioning of cellular waste management machinery can lead to cancer and neurodegenerative diseases. As researchers in immunology and oncology at the Université de Montréal, we want to explain how this process allows cells to adapt to adverse situations.
Proteins are essential
Each cell, tissue or organ contains thousands of different genes. Like a barcode, the genetic information in our DNA is read and translated, allowing the production of thousands of different proteins. Each protein has a precise 3D structure, a specific location, and a role within a cell type.
Proteins are functional units, similar to small machines, that carry out many processes within cells. These processes include the absorption of nutrients to ensure cell survival, cell respiration using oxygen to promote energy production, cell proliferation to replace dead cells and promote organ growth, and cell migration within tissues to place them in the right place at the right time. In short, proteins are responsible for the proper functioning of all cellular processes and allow cells to coexist in harmony within an organism.
Each of our cells has exactly the same set of genes, but each cell type has a unique protein profile. For example, one type of protein may be present and active in brain cells, but absent in kidney or muscle cells. A protein may be essential for one organ but not for another, and its presence or absence within the cell is governed by a dynamic balance, orchestrated by mechanisms that regulate protein production and elimination.
How cells decide which proteins to discard
Over the past few decades, researchers have learned a lot about how proteins are produced from genes by translating messenger RNA. This process involves a structure called the ribosome, the factory for the production of proteins.
Once produced, some proteins must be removed, either because they are poorly folded or because they have become redundant. Protein degradation is a highly coordinated and complex cellular process.
Balance between protein synthesis by the ribosome and degradation by the proteasome. (The Bachir Affar, created at BioRender.com), Contributed Author
Our laboratory, among others, is interested in understanding how cells make the initial decision to remove proteins and then proceed to destroy them. To ensure their elimination, cells establish a complex process of quality control and decision-making that results in the ubiquitination of proteins. Ubiquitination is an essential process that involves binding a small protein, called ubiquitin, to various unwanted protein targets. It occurs in all cells of the body.
The ubiquitination seal allows the proteasome to recognize unwanted proteins and classify them to remove them. The proteasome is a small cylindrical chamber made up of many specialized proteins, which act as molecular scissors to grind proteins. As an essential protein complex, there are multiple copies of the proteasome in all living cells.
The proteasome is responsible for the rapid and highly specific degradation of unwanted, misfolded, or excess proteins. This process is extremely important for the proliferation and proper functioning of cells.
Aberrant or reduced degradation of cellular proteins can lead to a variety of diseases, such as cancer and brain disease. However, the exact mechanisms underlying normal functions and pathological alterations associated with the proteasome are still poorly understood.
Cells react to a lack of nutrients
We have recently discovered that when the body is deprived of nutrients, proteosomes cluster in the nucleus of cells to form large structures called “bodies” or “fires”. This aggregation of proteasomes can be observed in various cell types and is a general cellular response to nutrient deprivation.
Specifically, this phenomenon only occurs when cells are deprived of amino acids, the necessary components of proteins. Consequently, there is a tightly controlled balance between the supply of amino acids for protein synthesis and their degradation by the proteasome.
Proteasome focus formation amplifies this degradation process during periods of nutrient deprivation. Interestingly, our study also found that these foci promote cell death during severe nutrient stress, where the cell triggers molecular mechanisms that lead to its destruction, a form of cell suicide. Although this cell death is detrimental to individual cells, the result could be beneficial to the overall cell population that forms tissues and organs.
In fact, the death of some cells in an organ, in response to nutrient deficiency, could initially decrease competition between cells for limited resources. The release of cellular components, particularly nutrients, during cell death could help survive nearby cells. In addition, dying cells could send signals to summon specialized rescue cells to repair tissues.
We also found that some cells present in tumors have a reduced ability to form proteasome foci after nutrient deprivation, suggesting that these cells have acquired stress resistance. The formation of these foci, in normal cells, could be a defense mechanism that favors the death of cells that have undergone drastic changes caused by the absence of nutrients.
In this regard, inducing cell suicide by forming proteasome foci in cells that have undergone changes that promote the development of cancer could be an interesting new approach to cancer prevention.
Proteasome foci and their involvement in cell death. (The Bachir Affar, created at BioRender.com), Contributed Author
Now that researchers have a better understanding of what affects proteasome function, they could focus on personalized cancer treatment, which requires knowledge of all the molecular disruptors of cancer cells.
It is possible that cells that escaped death as a result of nutritional stress have accumulated changes in their functioning that may make them vulnerable. We are currently working on this hypothesis.
Malik Affar co-authored this article and helped produce the graphics.