Regulation of apoptosis

Apoptosis is strictly regulated. Caspase is in an inactive zymogen state in normal cells. Once the apoptosis process starts, caspase is activated and then cascading reactions of apoptosis proteases occur. Irreversible apoptosis occurs. Examples of cells regulating apoptosis are as follows.

Inhibitor of apoptosis

So far, humans have found a variety of apoptosis inhibitors, including P53, CrmA, IAPs, FLIPs and Bcl-2 family of apoptosis inhibitors.

1) P35 and CrmA are broad-spectrum apoptosis inhibitors. In vitro research results show that P35 forms a stable complex with steric hindrance effect with target molecules in a competitive way and inhibits Caspases activity. At the same time, P53 is located at DMQD! G is specifically cleaved by target caspases, and the cleaved P35 has stronger binding with caspase. CrmA (Cytokine response modfer A) is a serum protease inhibitor, which can directly inhibit the activity of various proteases, but no homologous molecules of P35 and CrmA have been found in mammals.

2) FLIPs (FLICE invasive precursors) can inhibit Fas/TNFR1 mediated apoptosis. It has a variety of variants, but its N-terminal Prodomain is identical, and its C-terminal length is different. FLIPs bind to FADD and Caspase-8, 10 through the DED functional area to antagonize their interaction, thereby inhibiting Caspase-8, 10 from recruiting death receptor complexes and their initiation.

3) Inhibitors of apoptosis proteins (IAPs) are a group of proteins that can inhibit apoptosis. First, they were cloned from the genome of baculovirus and found to inhibit the host cell death response caused by virus infection. Its characteristic is that it has a functional area composed of about 20 amino acids, which is necessary for IAPs to inhibit apoptosis. They mainly inhibit Caspase3, - 7, but do not bind its zymogen. They can bind activated Caspase, and also bind zymogen, thereby inhibiting apoptosis.

Bcl-2 Family

This family has many members, such as Mcl-1, NR-B, A1, Bcl-w, Bcl-x, Bax, Bak, Bad, Bim, etc. They have both anti apoptotic and pro apoptotic effects respectively. There are two structural homologous regions between most members, which play an important role in the dimerization process between members. Dimerization among Bcl-2 members is an important form of functional realization or regulation among members. The physiological function of Bcl-2 is to inhibit cell apoptosis and prolong cell life. In some leukemias, Bcl-2 is overexpressed.

The subcellular localization of Bcl-2 has been clarified. It can be located in mitochondria, endoplasmic reticulum and nuclear membrane in different cell types, and plays an anti apoptotic role by preventing the release of mitochondrial cytochrome C. In addition, Bcl-2 has the function of protecting cells. Overexpression of Bcl-2 can cause the accumulation of glutathione (GSH) in the nucleus, leading to changes in the redox balance in the nucleus, thereby reducing the activity of Caspase. Bax is a member of the Bcl-2 family involved in apoptosis. When apoptosis is induced, it migrates from the cytosol to mitochondria and nuclear membrane. It has been found that when cytotoxic drugs induce apoptosis, the increase of Bax level in nuclear membrane is positively related to the degradation of lamin and PARP nucleoproteins. Cells treated with Bax oligonucleotides can only specifically block the degradation of Lamin, and have no effect on the degradation of PARP. The regulatory mechanism of this effect is still unclear.

In a word, the regulation of apoptosis is very complex, and there are many molecules involved. There are still many unknown mechanisms that need our further exploration