The elF2B protein plays an important role in the normal cellular process of protein synthesis and in its regulation. Protein synthesis is the process by which cells make all the components they need, following the instructions provided by the genome (DNA), relayed by a messenger RNA molecule, and using the building blocks called amino acids, that come from our food. The elF2B protein is therefore needed everywhere in the body. Since CACH / VWM only affects certain tissues, it can be concluded that, in general, cells have sufficient amounts of the elF2B protein to function. The brain and myelin are an obvious exception to this rule; these tissues are therefore particularly sensitive to impairment of the function of elF2B. We do not yet know the reasons for this.

Currently, the most widely recognised hypothesis stems from the known role of elF2B in the cellular stress response. Various studies have shown that the regulation of the elF2B protein is essential for cells in response to several stressors.

We know that when stress is prolonged or too intense, cells that cannot resolve stress switch to a process called cell death or apoptosis. In experimental models, this process contributes to causing pathology similar to that associated with elF2B mutations in CACH / VWM.

In our lab, we are studying the function of the elF2B protein using a simple cell model system. We have experimentally demonstrated how elF2 acts as a major activator of protein synthesis. The elF2B protein is a class of proteins called ’guanine nucleotide exchange factor (or GEF)’, which acts as a molecular switch to switch to its partner, another protein called elf2. The elF2 protein binds to GTP (on state) and GDP (off state) and must be activated at the start of each cycle of protein synthesis. GTP is a co-factor that provides energy. When the elF2b protein is active, cells can make proteins, and when it is not, the level of protein synthesis drops. We have shown that part of the elF2B protein (called the epsilon subunit) has GEF function, while other parts of this protein are important in regulating this activity in response to stress.

In recent work, we have discovered that elF2B performs a second related function and that it is needed to move a third translation factor (named elF5) from elF2 before elF2B can perform its GEF function. We have found that some elF2b mutations affect GEF function while others affect elF5 displacement function.

Another unexpected finding is the fact that the elF2B protein is larger than we previously thought. It exists in cells as a complex made up of two subunits. We are currently working to elucidate the structure of elF2b using a technique called electron cryomicroscopy. We hope that this will provide us with important elements for understanding how it works and the effect of mutations on its functioning.

In our studies, we purify elF2 and elF2B protein complexes from cells. We have modified our methods so that we can produce human elF2 in a yeast cell-based expression system. We have demonstrated that the elF2 protein we produce works as well as a protein produced by other more laborious means and that it can be used in a diagnostic test as part of the procedures used to confirm that a patient has CACH / VWM. During studies carried out in collaboration with Pr Odile Boespflug-Tanguy’s team, we used blood cells isolated from patients as a source of elF2B and our human elF2 to show that patients’ cells have elF2b GEF activity lower than that of healthy controls.

We are currently discovering new and interesting insights into the role and biology of elF2B. We have developed a strategy to purify elF2. After some modifications, our biochemical assay can be used with other diagnostic tests used in the hospital to confirm the diagnosis of CACH / VWM.