About FAS Ligand:
Fas ligand (FasL or CD95L) is a type two transmembrane protein that is part of the tumor necrosis factor (TNF) group. When it binds to its receptor, it starts apoptosis. The Fas ligand and receptor interactions play a vital role in the regulation of the immune system and the progression of various cancers.
Structure
FasL is what is called a homotrimeric type two transmembrane protein, which is expressed on cytotoxic T lymphocytes. It creates signals through trimerization of FasR, spamming the membrane of the target cell. This process of trimerization either leads to apoptosis or death of the cell. The process of creating soluble Fas ligand is created by cleaving membrane-bound FasL at a conserved cleavage site via external matrix metalloproteinase, known as MMP-7.
Function
The process of apoptosis, which is triggered by Fas-Fas ligand binding, plays a major role in the regulation of the human immune system. Its functions include the following:
● T-cell homeostasis, which is the activation of T-cells which lead the expression of the Fas ligand. These T-cells start out resistant to Fas-mediated apoptosis but become increasingly more sensitive the longer they are active for, which can often result in the activation-induced death of the cell. This process is used to prevent an excessive immune system response, eliminating autoreactive T-cells. Many people with deleterious mutations of Fas ligand, go onto develop a build-up of T-cells, which can lead to lymphadenopathy, splenomegaly, and lupus.
● Cytotoxic T-cell activity is Fas-induced apoptosis, with the perforin pathway being the two main mechanisms of which cytotoxic T lymphocytes cause cell death in cells that are expressing foreign antigens.
● Immune privilege is when cells in immune privileged areas, like the testes or cornea, express Fas ligand and cause the apoptosis of infiltrating lymphocytes. This is one of many of the body’s mechanisms used to establish and maintain the power of immune privilege.
● Maternal tolerance is when Fas ligand may be able to prevent leukocyte trafficking between a mother and baby, despite the fact that no birth defects have been attributed to a faulty Fas ligand system.
● Tumor counter attack: tumors sometimes over-express Fas ligand and cause the apoptosis of infiltrating lymphocytes, which allows the tumor to escape the effects of an immune response. This up-regulation of Fas ligand can occur after chemotherapy, due to which the tumor cells attain apoptosis resistance.
Mechanism
Fas creates the death-inducing signalling complex known as DISC when ligand binding occurs. Membrane connectected Fas ligand trimer on the surface of an adjacent cell can cause trimerization of Fas receptor. This can also be mimicked by the binding of an agonistic Fas antibody. Although some evidence does suggest that the apoptotic signal created by the antibody is unreliable when it comes to Fas signalling. Because of this, various ways of trimerized an antibody for in vitro research have been put into action. When it enters DD (death domain), the receptor complex is internalized via cellular endosomal machinery. This gives the adaptor molecule FADD to bind the death domain of Fas through its own domain.