Tumor necrosis factor ligand superfamily member 6 (FASL)
Type: Family

Like all apoptotic cell death, T cell receptor (TCR)-mediated death can be divided into two phases: an inductive phase and an effector phase. The effector phase includes a sequence of steps that are common to apoptosis in many cell types, which, if not interrupted, will lead to cell death. The induction phase, which often requires the expression of new genes, consists of a set of signals that activate the effector phase. Outside the thymus, most, if not all, of the TCR-mediated apoptosis of mature T cells (sometimes referred to as activation-induced cell death (AICD)) is induced through the surface antigen Fas pathway: activation through the TCR induces expression of the Fas (CD95) ligand (FasL); the expression of FasL on either a neighbouring cell, or on the Fas-bearing cell, induces trimerisation of Fas, which then initiates a signal-transduction cascade, leading to apoptosis of the Fas-bearing cell. This commitment stage requires the activation of key death-inducing enzymes, termed caspases, which act by cleaving proteins that are essential for cell survival and proliferation . However what happens to FasL itself remains unknown. It is possible that it is cleaved from the effector cells and internalised into the target cells; it may be downregulated in the effector cells; or it may be phagocytosed by the target cells.

Fas is also known to be essential in the death of hyperactivated peripheral CD4 cells: in the absence of Fas, mature peripheral T cells do not die, but the activated cells continue to proliferate, producing cytokines that lead to grossly enlarged lymph nodes and spleen. Defects in the Fas-FasL system are associated with various disease syndromes. Mice with non-functional Fas or FasL display characteristics of lymphoproliferative disorder, such as lymphadenopathy, splenomegaly, and elevated secretion of IgM and IgG. These mice also secrete anti-DNA autoantibodies and rheumatoid factor .

FasL (also known as tumor necrosis factor ligand superfamily member 6) is a 40kDa type II membrane protein belonging to the tumour necrosis factor (TNF) family. Its binding to the cognate Fas receptor triggers the apoptosis that plays a pivotal role in the maintenance of immune system homeostasis. It is expressed on activated lymphocytes, NK cells, platelets, certain immune-privileged cells and some tumour cells . The cell death-inducing property of FasL has been associated with its extracellular domain, which can be cleaved off by metalloprotease activity to produce soluble FasL . Human and mouse FasL induce apoptosis in cells expressing either mouse or human Fas with the same specificity. Although the amino acid sequence of FasL is highly conserved between human and mouse, the similarity between human and murine Fas is much less pronounced. Greater conservation of the ligand than the receptor is also observed in other members of the TNF family. By comparison with other TNF family members, FasL has a long N-terminal intracellular region rich in proline residues, which is known to bind to the SH3 domain. SH3 domains play important roles in mediating specific protein-protein interactions, specifically in the cytoskeleton.