Intracellular stress is necessary for hemoglobin synthesis

Anna Stavina, XX2 century, based on ScienceDaily: How stress controls hemoglobin levels in blood

The ability to breathe oxygen is critical to our survival. This process is provided by the protein hemoglobin, which carries oxygen in the blood. Since mountain air contains significantly less oxygen than the air on the plain, the body is faced with the urgent need to develop an additional volume of hemoglobin – this is stress. But what role does stress at the cellular level play in the synthesis of oxygen-carrying protein?

In an article published in the journal Cell Research (Ilan et al., PKR activation and eIF2a phosphorylation mediate human globin mRNA splicing at spliceosome assembly), a group of researchers from the Hebrew University of Jerusalem reports the discovery of a new mechanism that determines the expression of hemoglobin genes. It turns out that stress is necessary for cells to produce hemoglobin.

In the process of hemoglobin synthesis, the corresponding section of DNA is first transcribed into a long RNA molecule containing segments that must subsequently be removed. This process is known as "splicing". Only after its completion, the RNA turns into a matrix for hemoglobin synthesis. A group of researchers led by Professor Raymond Kaempfer from the Hebrew University reports that the splicing of RNA transcribed from hemoglobin genes is strictly controlled by intracellular stress signals. This statement applies both to the prenatal period of human development and to the rest of life.

Intracellular stress signals are transmitted using the PKR (Protein kinase RNA-activated) protein present in every cell of the human body. It remains inactive until it is activated by a specific fragment of RNA. It was believed that such RNA is present only in viruses. However, Professor Kempfer and his colleagues found that an immature RNA transcribed from hemoglobin genes contains a fragment capable of activating the PKR protein. Until this protein is activated in this way, splicing (and hence the process of hemoglobin synthesis) will not begin.

"Unexpectedly, we discovered a completely new mechanism that controls the expression of hemoglobin genes through stress. The intracellular signal used to cope with stress is absolutely essential for hemoglobin synthesis. This signal is activated by the gene itself, associated with the production of hemoglobin. We have long known that the stress signal suppresses protein synthesis in general, but in the case of hemoglobin, the situation is completely different. At first, this signal stimulates the production of hemoglobin, and then it is completely turned off to start the massive process of synthesizing large volumes of hemoglobin necessary for respiration," says Professor Kempfer, who is engaged in the problems of molecular biology and oncological research at the Hebrew University.

Once activated, PKR places a phosphate residue on the initiation factor eIF2-alpha. The latter is necessary for the synthesis of all proteins. The attachment of a phosphate residue or phosphorylation leads to the inactivation of eIF2-alpha and the cessation of protein production. This is necessary for the cell to cope with stress.

The most unexpected result of the study was the fact that activated PKR should phosphorylate eIF2-alpha and that the phosphorylated form of this factor plays a key role in the formation of structures necessary for hemoglobin synthesis. During maturation, the RNA loses a segment associated with PKR activation. Due to this, the cell begins to produce hemoglobin in quantities necessary for respiration. In other words, the ability of RNA to activate PKR is temporary, it is necessary only to enable the splicing process.

A group of researchers managed to demonstrate the positive effect of PKR activation and eIF2-alpha phosphorylation on the splicing of RNA necessary for hemoglobin synthesis. Previously, it was believed that intracellular stress affects the process of protein synthesis in an exclusively negative way. Understanding that this stress is not just important, but necessary, can change our understanding of the processes of hemoglobin synthesis. "Even at the cellular level, stress and the ability to overcome it are critically important for our survival. The link between stress and survival has been known for a long time, but now we know that it is important even for small oxygen–carrying molecules in the blood," says Professor Kempfer.

Portal "Eternal youth" http://vechnayamolodost.ru  07.04.2017