The choice between life and death: apoptosis or autophagy?
The cell experiences stress due to partial self-destructionNadezhda Markina, Infox.ru
Biologists have uncovered the mechanisms that lead to a choice between life and death at the level of a single cell.
Now you can try to control the fate of cells in the body to cope with a variety of diseases.
When a cell feels bad, it behaves, at first glance, paradoxically – it devours itself from the inside. But this is just a survival mechanism in a stressful situation. If there is a shortage of vital resources or if biological molecules are damaged, the cell has two ways: it can commit suicide or get rid of damaged parts and survive. The first way is called apoptosis – it is a program for death, the second is called autophagy – and it is a program for survival. During autophagy, proteins or whole organelles degrade in the cell. What is to be destroyed is delivered to intracellular utilizers – lysosomes. They surround proteins and fragments of organelles with a membrane and digest.
Scientists know that various chemical or physical (for example, ultraviolet) harmful factors or cellular starvation lead to autophagy. In the latter case, the cell switches to economy mode, redistributes nutrients to more important parts and gets rid of less important ones. But how exactly the mechanism of this process works, researchers do not yet understand. Therefore, a team from the University of Pittsburgh Cancer Institute took up the search for an answer. They found a key protein for autophagy and recognized the chain of intracellular interactions associated with it.
How Protein saves a cellIt turned out that the role of the trigger for triggering autophagy is played by HMGB1 — a nuclear protein that normally works on the packaging of DNA chromatin.
It is also involved in inflammatory and other pathological processes in the signaling pathways of apoptosis. But HMGB1 takes the most direct part in autophagy. However, to do this, he needs to change his dislocation – move from the nucleus to the cytoplasm.
The scientists observed the protein in cultures of several mouse and human cell lines. They found that cellular starvation, hypoxia, and ultraviolet irradiation lead to the release of HMGB1 from the nucleus into the cytoplasm. This is followed by autophagy, which can be judged by the activation of lysosome enzymes. To finally prove the role of the protein, microbiologists obtained a culture of mouse fibroblasts with the HMGB1 gene switched off (knocked out). After treatment with hydrogen peroxide or after starvation, such cells are unable to autophagy.
Escape from stressUnfavorable factors of different nature lead to the same consequences – oxidative stress.
The increased formation of free radicals that damage biological molecules is a signal for autophagy. Biologists were convinced of this by treating cells with substances that enhance oxidative processes – the HMGB1 protein moved into the cytoplasm, after which the cell began to digest its damaged fragments more actively.
The researchers managed to understand the chain of processes caused by oxidative stress. The HMGB1 protein moves into the cytoplasm in response to the oxidation of the amino acid cysteine at position 106 (C106). In the cytoplasm, the protein interacts with a complex of two others: Bcl-2–Beclin1. HMGB1 binds to the Bcl-2 protein and detaches it from its partner, and this happens due to an intramolecular disulfide bridge between cysteine at positions 23 and 45 (C23 and C45). After that, Bcl-2 blocks apoptosis, and Beclin1 triggers autophagy.
The fate of the cells can be controlledSo scientists discovered a new function in the HMGB1 protein, defining it as the main regulator of cell survival.
Having dealt with the process, you can learn how to manipulate it for your own purposes. If the autophagy mechanism does not work well, it can lead to neurodegenerative or infectious diseases, so it should be strengthened to prevent these diseases. In cancer cells, on the contrary, the HMGB1 protein is hyperactive, autophagy works too well, which causes their increased survivability. In this case, it should be weakened and the cells should be pushed to suicide – apoptosis.
An article on how and why a cell eats itself is published in the Journal of Cell Biology (Daolin Tang et al., Endogenous HMGB1 regulates autophagy).
Portal "Eternal youth" http://vechnayamolodost.ru09.09.2010