Mechanism of apoptosis process

The process of apoptosis can be roughly divided into the following stages:

Receiving apoptosis signal → interaction between apoptosis regulating molecules → activation of proteolytic enzyme (Caspase) → entering into continuous reaction process

Start up phase

The initiation of apoptosis is the opening or closing of a series of control switches in the cell after the cell feels the corresponding signal stimulus. Different external factors start apoptosis in different ways, resulting in different signal transduction. Objectively speaking, the understanding of the signal transmission system in the process of cell apoptosis is still incomplete. The more clear pathways are:

1) Membrane receptor pathway of cell apoptosis: various external factors are initiators of cell apoptosis. They can transmit apoptosis signals through different signal transduction systems and cause cell apoptosis. Let's take Fas FasL as an example:

Fas is a transmembrane protein, which belongs to the tumor necrosis factor receptor superfamily. It can start the apoptosis signal transduction and cause cell apoptosis by binding with FasL. Its activation includes a series of steps: first, the ligand induces the trimerization of the receptor, and then forms an apoptosis inducing complex on the cell membrane, which includes the Fas related protein FADD with the death domain. Fas, also known as CD95, is a receptor molecule composed of 325 amino acids. Once Fas binds to the ligand FasL, it can initiate lethal signal transduction through Fas molecules, eventually causing a series of characteristic changes in cells and cell death. As a universally expressed receptor molecule, Fas can appear on the surface of many kinds of cells, but the expression of FasL has its own characteristics. It usually only appears in activated T cells and NK cells. Therefore, activated killer immune cells can most effectively kill target cells through apoptosis. The intracellular segment of Fas molecule has a special death domain (DD). After the combination of the trimeric Fas and FasL, the death domains of the three Fas molecules are clustered, attracting another protein FADD with the same death domain in the cytoplasm. FADD is a connexin in death signal transcription, which consists of two parts: the C terminal (DD domain) and the N terminal (DED). The DD domain is responsible for binding with the DD domain on the intracellular segment of the Fas molecule. The protein then connects another subsequent component with the DED with the DED, which causes the N-segment DED to immediately cross link with the inactive caspase 8 zymogen, polymerizing multiple caspase 8 molecules. The caspase 8 molecule is then converted from a single chain zymogen to an active double chain protein, causing a subsequent cascade reaction, namely caspases, The latter is activated as a zymogen, causing the following cascade reaction. Apoptosis occurs. Therefore, the apoptosis pathway induced by TNF is similar to this

2) Biochemical pathways of cytochrome C release and Caspases activation

Mitochondria are the control center of cell life activities. They are not only the center of cell respiratory chain and oxidative phosphorylation, but also the center of cell apoptosis regulation. The results showed that the release of cytochrome C from mitochondria was the key step of apoptosis. Cytochrome C released into the cytoplasm can combine with apoptosis related factor 1 (Apaf-1) in the presence of dATP to form a polymer, and promote caspase-9 to combine with it to form apoptotic bodies. Caspase-9 is activated, and activated caspase-9 can activate other caspases, such as caspase-3, to induce apoptosis. In addition, mitochondria also release apoptosis inducing factors, such as AIF, which participate in the activation of caspase. It can be seen that the relevant components of apoptotic bodies exist in different parts of normal cells. Apoptosis promoting factors can induce the release of cytochrome C and the formation of apoptotic bodies. Obviously, the regulation of cytochrome C release from mitochondria is a key issue in the study of the molecular mechanism of apoptosis. Most apoptosis stimulating factors activate the apoptosis pathway through mitochondria. It is believed that cytochrome C is also released from mitochondria through receptor mediated apoptosis. For example, in the cells responding to Fas, a type 1 cell (type 1) contains enough caspase 8, which can be activated by the death receptor to cause apoptosis. Overexpression of Bcl-2 in these cells does not inhibit Fas induced apoptosis. In another kind of cells (type2 2), such as hepatocytes, the activation of caspase 8 mediated by Fas receptor cannot reach a very high level. Therefore, the apoptotic signal in such cells needs to be amplified by the apoptotic mitochondrial pathway, and Bid, a Bcl-2 family protein containing only the BH3 domain, is the messenger that transmits the apoptotic signal from cystolysis enzyme 8 to mitochondria.