Apoptosis: Significance, Mechanism and Regulation

Cell can induce self-destruction, when it is damaged, useless or potentially dangerous to other cells. The phenomena of programmed cell death is known as apoptosis. ‘Apoptosis’ is a Greek term which refers to “falling off” or “dropping off”. It was coined by John F. Kerr, Andrew H. Wyllie and A.R. Curie in 1972. Cell death is as essential to the body as cell growth through healthy mitosis. It occurs universally in cells of plants, animals and even bacteria.

1.1. Biological Significance of Apoptosis:

Apoptosis is a normal process involved in cell aging and development. It keeps the cell population in check. It helps to eliminate the cells that threaten the integrity of the organism. Cell death is responsible for keeping our hands from being webbed, discontinuing presence of embryonic tail, and preventing our immune system from responding to our own proteins. It also prevents our brain from being filled with useless electrical connection.¹

Apoptosis has a dual role. It either acts as a protecter by removing and balancing harmful cells or as a potential contributor when dysregulated. Dysregulation in apoptosis pathway may cause many diseases such as AIDS, Cancer, Neurodegenerative disease (Alzheimer’s, Parkinson’s, Huntington’s disease), Autoimmune condition like Lupus, Rheumatoid arthritis etc.

Figure 1: Cell undergoing Apoptosis (Source: https://healthjade.com/apoptosis/)

1.2. Events in Apoptosis:

Apoptosis occurs as a response to specific suicide signals or lack of survival signals emanating within the cell. The synchronized events during apoptosis includes condensation of chromatin, chromatin migration to the nuclear membrane, shrinkage of the cytoplasm and change in the shape of plasma membrane. The internal organelles though still functioning are engulfed by neighbours. Blebbing of plasma membrane and nuclear membrane are also observed. Blebbing is a process where a bulge is formed in plasma membrane which eventually separates from the cell.²

1.3. Caspase:

They are family of proteases that contains Cysteine at their active site and cleave their target proteins at specific aspartic acids. It plays a central role in the transduction of ER apoptotic signals. Caspases are primarily inactive, but can be activated by proenzymes by proteolytic processing. Once, it is activated, caspases cleave and activate other procaspases resulting in an amplifying proteolytic cascade.

1.4. Mechanism of Apoptosis:

According to popular beliefs, there are two major apoptotic pathways:

Extrinsic or death receptor pathway
Intrinsic or mitochondrial pathway

Figure 2: Extrinsic and Intrinsic Mechanism of Apoptosis (Source: https://animalia-life.club/qa/pictures/extrinsic-pathway-apoptosis)

Extrinsic or death receptor pathway:

It is initiated by binding of extracellular ligands to the cell surface receptors such as TNF receptor (p55), Fas (CD95/APO-1), DR4(TRAIL-4) etc. Activation of death receptor is followed by formation of death inducing signalling pathway complex (DISC), made up of adaptor molecule FADD (Fas-associated death domain) and Caspase-8.

Incoming Fas-ligand binds with the Fas-receptor domain. DISC is synthesized. Procaspase-8 is activated by death domain receptor signalling and becomes Caspase-8. Caspase-8 in turn activates Caspase-3. Caspase-3 degrades the inhibitor of nuclease enzyme. Permeability of nucleus increases. Hence, it penetrates the nucleus and degrades the nucleic acid causing the cell to die.

Intrinsic or mitochondrial pathway:

In this pathway, the source of death signal is inside the cell. When the cell receives signal indicating DNA damage, proteins like ATM, CHK senses it and activates p53 protein. P53 starts recruiting other proteins like Bax. Bax is responsible for creating pore in the mitochondria, which allows release of cytochrome-c from mitochondria to cytosol. Cytochrome-c acts as a death signal pairing with Apap-1 protein. It activates procaspase-9 into caspase-9. Caspase-9 further activates procaspase-3 to caspase-3. Caspase-3 activates nuclease enzyme by degrading its inhibitor. Once nuclease enzyme is active, it enters inside nucleus and degrades chromosome and DNA. This eventually halts cell cycle and prompts cell death.

Linkage between Extrinsic and Intrinsic Pathways:

Caspase-8( from extrinsic pathway) activates bid protein to Tbid. Tbid activates Bax/Bak. They are responsible for creating pore in the mitochondrial membrane which eventually leads to triggering of intrinsic pathway.

1.5. Regulation of Apoptosis:

Regulation of Apoptosis takes place at three levels:

Membrane level
Nucleus level
Cytoplasmic level

Membrane level: Cell membranes contain many death receptors. These recognize and bind with secreted death ligands. These receptors are provided with cysteine rich extracellular domain and an intracellular domain called death domain. Death domain is responsible for sending apoptotic signal to the inside of the cell. These receptors can induce apoptosis within hours of ligand-binding. They initiate cascade reaction and transfer the signal downstream.

Nucleus level: p53 is a tumour suppressor gene. it is unstable and acts as a DNA binding transcription factor but gets stabilized when the DNA is damaged. If the damage is extensive and cannot be repaired it initiates cell death by stimulating Fas-receptor complex and Bax on mitochondrial membrane. This eventually activates caspase-3. Cells lacking functional p53 gene fail to induce apoptosis.

Cytoplasmic level: Process of apoptosis requires a number of cytoplasmic proteins. For instance, Bcl-2 family can inhibit or induce apoptosis. Products of Bcl-2 gene and Bcl-x gene inhibit it while Bax and Bak promote it. Inhibitors prevents the release of cytochrome-c from mitochondria by blocking the formation of pores. The activators enhance the release of cytochrome-c. This leads to enhanced mitochondrial permeability and ionic imbalance as a result of which cell death occurs. Cytochrome-c activates caspase-9 which in turn activates caspase-3.²

1.6. Apoptosis and Diseases:

Dysregulation of apoptosis (either excessive activation or failure to activate appropriately) can result into development and progression of wide range of diseases. For instance, Human Papilloma Viruses (HPV) which causes cervical cancer, produces a protein, E6 that binds and inactivates apoptosis promoter p53. Some B-cell Leukaemia and Lymphomas express high level of Bcl-2 which blocks apoptotic signals. In the case of HIV/AIDS, rapid apoptosis has a direct role in depletion of CD4+ T-helper cells, which leads to the progression of HIV infection into AIDS. Dysregulated apoptosis is also responsible for diseases like Alzheimer, Parkinson and damage from stroke.

REFERENCES

1. Lodish, Berk, Matsudaira, et al. Molecular Cell Biology. Fifth edition. W. H. Freeman; 2008.
2. S.C. Rastogi. Cell and Molecular Biology. Third edition. New Age International Publishers; 2010