Bags of tricks to fight diseases
(A) Control: vesicular bags contained in a multivesicular body in the cell, prior to their release
(B) Removal of the RAL protein (total inactivation of the gene): the vesicles are well produced but fewer
(C) Reduction of the RAL protein (partial inactivation of the gene): vesicular bags are normally produced but remain blocked inside the cell (the fusion with the plasma membrane is stopped)
J Cell Biol Oct. 12, 2015
Oct. 10, 2015
In recent years, researchers got very interested in exosomes, vesicular bags produced by the cells and which can transport molecules throughout the body. They indeed offer new therapeutic perspectives especially for the treatment of cancer. Vincent Hyenne, first with the team of Michel Labouesse at IGBMC, then with that of Jacky Goetz at Inserm Unit U 1109, has just highlighted the key role of a protein in the production and expulsion process of these vesicular bags. Their findings are published on October 11th in the Journal of Cell Biology.
Exosomes emerge from the shadows
Exosomes are vesicles formed within the cell by the multivesicular bodies. These vesicles contain cellular components that are either degraded within the cell, or expelled into the extracellular space. Long considered as ordinary by-products of the cellular machinery aiming to rid the cell of harmful or unnecessary molecules, these vesicles finally won their spurs in the last few years. The scientific community has indeed found that they are present in all our body fluids (tears, saliva, urine, semen, milk, blood, sweat) but especially that their content is anything but neutral and was carrying important information... a new way of intercellular communication had been discovered!
Mechanisms of production of exosomes
Can we master the formation of these bags to control their content? Why are some released outside of the cell instead of being degraded? To answer these questions, it was necessary to define which proteins govern the production mechanisms of the bags. The team of Michel Labouesse has tackled this issue for several years by studying a very small animal model, the nematode C. elegans, which also secretes these vesicles. They identified a protein, called RAL-1, responsible for the production of exosomes by multivesicular bodies, but also responsible for their release outside the cell. This well-known protein of the small GTPase family had never been associated with this process. The researchers also demonstrated that mouse RAL proteins (RalA and RalB) similar to that of nematodes had the same function and were also important for the release of these small bags, demonstrating that the mechanism was also active in mammals.
Interesting therapeutic perspectives
Several clinical trials to use exosomes are currently underway in the community to divert intelligently these vesicles to transport therapeutic molecules and fight well against various diseases, including cancer. Better understand how they are formed and secreted is therefore essential to optimize these new treatments. In addition, the RAL protein is frequently abnormal in certain types of cancer, which seems to confirm the importance of the role of exosomes in immune response and evacuation of tumor cells. Thus the new work on RAL-1 adds to our knowledge on how to manipulate and produce those vesicles.