Fas ligand or FasL is a type II transmembrane protein belonging to the tumor necrosis factor superfamily (TNFSF). It ishomotrimeric, which means it consists of three identical polypeptides. It has a long cytoplasmic domain, a stalk region, atransmembrane domain (TM), a TNF homology domain (THD) responsible for the homotrimerization. Including a C-terminal region involved in binding to CD95, also known as the fas receptor.[6][7]
FasL binds to fas, leading to the formation of fas:FasL assemble. This interaction initiates the formation of the death-inducing signaling complex, resulting in apoptosis.[6]
FasL is expressed on various cell types, including T cells, natural killer cells, monocytes, neutrophils, and vascular endothelial cells. FasL exists in both membrane-anchored and soluble forms.[5]
FasR: TheFas receptor (FasR), orCD95, is the most intensely studied member of the death receptor family. The gene is situated onchromosome 10 in humans and 19 in mice. Previous reports have identified as many as eight splice variants, which are translated into sevenisoforms of the protein. Many of these isoforms are associated with rarehaplotypes that are usually associated with a state of disease. Apoptosis-inducing Fas receptor is dubbed isoform 1 and is atype 1 transmembrane protein. It consists of threecysteine-rich pseudorepeats, a transmembrane domain, and an intracellular death domain.[8]
DcR3:Decoy receptor 3 (DcR3) is a recently discovered decoy receptor of thetumor necrosis factor superfamily that binds to FasL,LIGHT, andTL1A. DcR3 is a soluble receptor that has nosignal transduction capabilities (hence a "decoy") and functions to prevent FasR-FasL interactions by competitively binding to membrane-bound Fas ligand and rendering them inactive.[9]
Fas signaling pathway involves activatingapoptosis (programmed cell death). This happens through the interaction of Fas receptor and Fas ligand. As mentioned, Fas ligand/FasL is a type II transmembrane protein that can exist in both membrane-anchored and soluble forms. The interaction between FasR on an adjacent cell and membrane anchored FasL leads to the trimerization, forming thedeath-inducing signaling complex (DISC).[10]
Upon ensuingdeath domain (DD) aggregation, the receptor complex is internalized via the cellular endosomal machinery. This allows the adaptor moleculeFas-associated death domain (FADD) to bind the death domain (DD) of Fas through its own death domain (DD). FADD also contains adeath effector domain (DED) near its amino terminus, which facilitates binding to the DED ofFADD-like ICE (FLICE), more commonly referred to ascaspase-8. FLICE can then self-activate through proteolytic cleavage into p10 and p18 subunits, of which two form the active heterotetramer enzyme. Active caspase-8 is then released from the DISC into the cytosol, where it cleaves other effector caspases, eventually leading to DNA degradation, membrane blebbing, and other hallmarks of apoptosis.[11][10]
Signaling pathways of Fas. Dashed grey lines represent multiple steps in JNK signaling.
Some reports have suggested that the extrinsic Fas pathway is sufficient to induce complete apoptosis in certain cell types through death-inducing signaling complex (DISC) assembly and subsequent caspase-8 activation.[10] These cells are dubbed Type 1 cells and are characterized by the inability of anti-apoptotic members of theBcl-2 family (namely Bcl-2 andBcl-xL) to protect from Fas-mediated apoptosis. Characterized Type 1 cells include H9, CH1, SKW6.4, and SW480, all of which are lymphocyte lineages except for SW480, which is of the colon adenocarcinoma lineage.[10]
Moreover, the pathways in the Fas signal cascade exhibit evidence for crosstalk. In most cell types, caspase-8 catalyzes the cleavage of the pro-apoptoticBH3-only proteinBid into its truncated form, tBid. BH-3 only members of the Bcl-2 family engage exclusively anti-apoptotic members of the family (Bcl-2, Bcl-xL), allowing Bak andBax to translocate to the outer mitochondrial membrane, thus permeabilizing it and facilitating release of pro-apoptotic proteins such ascytochrome c andSmac/DIABLO, an antagonist of inhibitors of apoptosis proteins (IAPs).[10]
Additionally, the c-FLIP protein, structurally resembling caspase-8 but lacking enzymatic activity, plays a dual role in Fas-induced apoptosis. At low concentrations, c-FLIP is believed to promote caspase-8 activation. There is a possibility it is because caspase-8 binds to c-FLIP with higher affinity than to itself (caspase-8 homo-dimerization). However, at high concentrations, c-FLIP reduces the proteolytic activity of caspase-8, potentially by competing for binding to FADD. This dual role underscores the complexity of Fas signaling and its regulation by c-FLIP at different concentrations.[10]
Overview of signal transduction pathways involved inapoptosis
Apoptosis triggered by FasR-Fas ligand binding plays a fundamental role in the regulation of theimmune system. Its functions include:
T-cellhomeostasis: the activation ofT-cells leads to their expression of the Fas ligand. T cells are initially resistant to Fas-mediated apoptosis during clonal expansion, but become progressively more sensitive the longer they are activated, ultimately resulting inactivation-induced cell death (AICD). This process is needed to prevent an excessive immune response and eliminate autoreactive T-cells. Humans and mice with deleterious mutations of Fas or Fas ligand develop an accumulation of aberrant T-cells, leading tolymphadenopathy,splenomegaly, andlupus erythematosus.[12]
Immune privilege: Cells in immune privileged areas such as thecornea ortestes express Fas ligand and induce the apoptosis of infiltratinglymphocytes. It is one of many mechanisms the body employs in the establishment and maintenance of immune privilege.[14]
Maternal tolerance: Fas ligand may be instrumental in the prevention of leukocyte trafficking between the mother and the fetus, although no pregnancy defects have yet been attributed to a faulty Fas-Fas ligand system.[14]
Tumor counterattack: Tumors may over-express Fas ligand and induce theapoptosis of infiltratinglymphocytes, allowing the tumor to escape the effects of animmune response.[15] The up-regulation of Fas ligand often occurs followingchemotherapy, from which the tumor cells have attainedapoptosis resistance.[16]
More recently, FasL-mediated apoptosis of T cells has also been suggested as an immune-evasive mechanism by which tumors can suppress T cell infiltration similar to inhibitory immune checkpoints such asPD-1 andCTLA-4.[20][21][22]
^"Human PubMed Reference:".National Center for Biotechnology Information, U.S. National Library of Medicine.
^"Mouse PubMed Reference:".National Center for Biotechnology Information, U.S. National Library of Medicine.
^abKrippner-Heidenreich A, Scheurich P (2006). "FasL and Fas. Typical Members of the TNF Ligand and Receptor Family".Fas Signaling. Medical Intelligence Unit. Boston, MA: Springer.doi:10.1007/0-387-34573-6_1.ISBN0-387-34573-6.
^Orlinick JR, Vaishnaw AK, Elkon KB (1999). "Structure and function of Fas/Fas ligand".International Reviews of Immunology.18 (4):293–308.doi:10.3109/08830189909088485.PMID10626245.
^abJerzak M, Bischof P (January 2002). "Apoptosis in the first trimester human placenta: the role in maintaining immune privilege at the maternal-foetal interface and in the trophoblast remodelling".European Journal of Obstetrics, Gynecology, and Reproductive Biology.100 (2):138–142.doi:10.1016/S0301-2115(01)00431-6.PMID11750952.
^Tachibana O, Nakazawa H, Lampe J, Watanabe K, Kleihues P, Ohgaki H (December 1995). "Expression of Fas/APO-1 during the progression of astrocytomas".Cancer Research.55 (23):5528–5530.PMID7585627.
^abcGhadimi MP, Sanzenbacher R, Thiede B, Wenzel J, Jing Q, Plomann M, et al. (May 2002). "Identification of interaction partners of the cytosolic polyproline region of CD95 ligand (CD178)".FEBS Letters.519 (1–3):50–58.doi:10.1016/s0014-5793(02)02709-6.PMID12023017.S2CID26765451.
^abWenzel J, Sanzenbacher R, Ghadimi M, Lewitzky M, Zhou Q, Kaplan DR, et al. (December 2001). "Multiple interactions of the cytosolic polyproline region of the CD95 ligand: hints for the reverse signal transduction capacity of a death factor".FEBS Letters.509 (2):255–262.doi:10.1016/s0014-5793(01)03174-x.PMID11741599.S2CID33084576.
^Pitti RM, Marsters SA, Lawrence DA, Roy M, Kischkel FC, Dowd P, et al. (December 1998). "Genomic amplification of a decoy receptor for Fas ligand in lung and colon cancer".Nature.396 (6712):699–703.Bibcode:1998Natur.396..699P.doi:10.1038/25387.PMID9872321.S2CID4427455.
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