Fas receptor

The Fas receptor (FasR), also known as Fas or as CD95 (Cluster of differentiation 95), belongs to the TNF receptor family, which triggers apoptosis of the cell concerned after binding to its ligand(Fas ligand, FasL). FasR is a so-called type I transmembrane protein with 335 amino acids and a molecular weight of 45 kDa. It consists of three cysteine-rich repeat units (trimers) in the extracellular protein domain. The trimer structure is essential for the function of the receptor and typical for TNF receptors.

The FasR is the most intensively studied member of the death receptor family. The gene is located on chromosome 10 in humans and seven isoforms of the protein are known to date. Many of these isoforms are rare haplotypes that are normally associated with a disease state. The apoptosis-inducing Fas receptor is known as isoform 1.

The physiological ligand of the Fas receptor is the Fas ligand (FasL, CD95L, CD178, TNFSF6). As a type II transmembrane glycoprotein, it belongs to the TNF superfamily of cytokines. Like all members of this family, the Fas ligand has a characteristic TNF homology domain (THD) that enables it to bind to the cysteine-rich domains (CRD) of the Fas receptor.

After binding to its receptor-specific ligand, a cytotoxic signal leading to apoptosis is transmitted into the cell. The signal transmission is made possible by the specific recruitment of the corresponding adaptor proteins TRADD (TNF receptor-associated protein with death domain) and FADD (Fas-associated protein with death domain). Depending on the receptor type, the interaction of TRADD/FADD (for TNF-R1) or only FADD with the binding domain of the death receptor (DD=death domains) causes the recruitment of the initiator caspases 8 and 10 (aspartate-specific cysteine proteases). This leads to the formation of a cell death inducing signaling complex (DISC) and the induction of a proteolytic cascade.

In addition to apoptosis induction, FasR can mediate signals by activating NF-B (nuclear factor-B) and MAPK (mitogen-activated protein kinase), which contribute to the proliferation and differentiation of a cell.

The decision between a pro- or anti-apoptotic signalling pathway is due to a variety of different regulatory mechanisms. In addition to the intrinsic regulation of adaptor proteins and the targeted inhibition of pro-apoptotic proteins, the subcellular localization of the receptor is of great importance. Although the Fas receptor is detectable in almost all tissues of the human body, it is found in particular in kidney, heart, liver, pancreas, brain, thymus and in activated T-lymphocytes. Tumor cells can also express the Fas receptor on their surface in varying densities.

Furthermore, FasR (CD95) can be induced by various endogenous and exogenous factors. These include TNF-alpha (tumor-necrosis-factor-alpha), IFN-gamma, IL-1 (interleukin-1), IL-6, IL-7, infectious agents, nitric oxide (NO), chemotherapy and radiation.

In addition to a membrane-bound form, FasR can occur as a soluble protein through alternative splicing or matrix metalloprotease-mediated shedding. By competitive binding and neutralization of the ligand specific for the receptor, the soluble FasR probably has an anti-apoptotic function.

Furthermore, FasL/FasR interactions play an important role in the regulation of the immune system and the progression of malignant cells. Tumor cells may prove resistant to FasL-mediated apoptosis. This may be due to the downregulation of Fas receptor expression. However, resistance can also occur if a large number of Fas receptors are present on the cell surface. In this case, the apoptotic signal is interrupted at the level of the death-inducing signaling complex (DISC), which prevents the activation of the initiator caspases. Due to these resistances, recombinant FasL does not represent a useful anti-tumour strategy.

1. Alderson MR et al (1993) Fas transduces activation signals in normal human T lymphocytes. The Journal of experimental medicine 178: 2231-2235
2. Cheng J et al (1994) Protection from Fas-mediated apoptosis by a soluble form of the Fas molecule. Science 263: 1759-1762
3. Desbarats J et al (2000) Fas engagement accelerates liver regeneration after partial hepatectomy. Nat Med 6: 920-923
4. Guégan JP et al (2018) Nonapoptotic functions of Fas/CD95 in the immune response. FEBS J 285:809-827
5. Peter ME et al (w015) The role of CD95 and CD95 ligand in cancer. Cell Death And Differentiation 22: 549
6. Rieux-Laucat F et al (2008) The Autoimmune Lymphoproliferative Syndrome with Defective FAS or FAS-Ligand Functions. J Clin Immunol 38:558-568
7. Sharma R X et al (2000) Death the Fas way: regulation and pathophysiology of CD95 and its ligand. In: Pharmacology & therapeutics. Volume 88, Number 3, December 2000, pp. 333-347
8. Sträter J et al (1999) CD95 Ligand (CD95L) in Normal Human Lymphoid Tissues: A Subset of Plasma Cells Are Prominent Producers of CD95L. The American Journal of Pathology 154:193-201
9. Suda T et al (1993) Molecular cloning and expression of the Fas ligand, a novel member of the tumor necrosis factor family. Cell 75: 1169-1178
10. Trauth BC et al (1989) Monoclonal antibody-mediated tumor regression by induction of apoptosis. Science 245: 301-305
11. Volpe E et al (2016) Fas-Fas Ligand: Checkpoint of T Cell Functions in Multiple Sclerosis. Front Immunol 7:382.
12. Waring P et al (1999) Cell death induced by the Fas/Fas ligand pathway and its role in pathology. Immunol Cell Biol 77:312-317. https://pubmed.ncbi.nlm.nih.gov/10457197-cell-death-induced by the Fas/Fas ligand pathway and its role in pathology
13. Wu J et al (1996) Fas ligand mutation in a patient with systemic lupus erythematosus and lymphoproliferative disease. J Clin Invest 98: 1107-1113
14. Zhang X et al (2005) Functional polymorphisms in cell death pathway genes FAS and FASL contribute to the risk of lung cancer. J Med Genet 42: 479-484