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Protein-coding gene in the species Homo sapiens From Wikipedia, the free encyclopedia
Fas ligand (FASL or CD95L) is a type-II transmembrane protein expressed on various types of cells, including cytotoxic T lymphocytes, monocytes, neutrophils, breast epithelial cells, vascular endothelial cells and natural killer (NK) cells. It binds with its receptor, called FAS receptor (also called CD95) and plays a crucial role in the regulation of the immune system and in induction of apoptosis, a programmed cell death.[5]
Fas ligand or FasL is a type II transmembrane protein belonging to the tumor necrosis factor superfamily (TNFSF). It is homotrimeric, which means it consists of three identical polypeptides. It has a long cytoplasmic domain, a stalk region, a transmembrane 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]
Fas signaling pathway involves activating apoptosis (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 the death-inducing signaling complex (DISC). [10]
Upon ensuing death domain (DD) aggregation, the receptor complex is internalized via the cellular endosomal machinery. This allows the adaptor molecule Fas-associated death domain (FADD) to bind the death domain (DD) of Fas through its own death domain (DD). FADD also contains a death effector domain (DED) near its amino terminus, which facilitates binding to the DED of FADD-like ICE (FLICE), more commonly referred to as caspase-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]
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 the Bcl-2 family (namely Bcl-2 and Bcl-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-apoptotic BH3-only protein Bid 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 and Bax to translocate to the outer mitochondrial membrane, thus permeabilizing it and facilitating release of pro-apoptotic proteins such as cytochrome c and Smac/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]
Apoptosis triggered by FasR-Fas ligand binding plays a fundamental role in the regulation of the immune system. Its functions include:
Defective Fas-mediated apoptosis may lead to oncogenesis as well as drug resistance in existing tumors. Germline mutation of Fas is associated with autoimmune lymphoproliferative syndrome (ALPS), a childhood disorder of apoptosis.[17]
Increases in Fas-mediated signaling have been implicated in the pathology of low-risk myelodysplastic syndromes (MDS)[18] and glioblastoma.[19]
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 as PD-1 and CTLA-4.[20][21][22]
Fas ligand has been shown to interact with:
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