Лиганд Fas (FASL/CD95L): роль в апоптозе и иммунной регуляции.

Protein coding gene in the species Homo sapiens

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.

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. 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.

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). 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. Cytotoxic T cell activity: Fas induced apoptosis and the perforin pathway are the two main mechanisms by which cytotoxic T lymphocytes induce cell death in cells expressing foreign antigens. Immune privilege: Cells in immune privileged areas such as the cornea or testes express Fas ligand and induce the apoptosis of infiltrating lymphocytes. It is one of many mechanisms the body employs in the establishment and maintenance of immune privilege. 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. The up regulation of Fas ligand often occurs following chemotherapy, from which the tumor cells have attained apoptosis resistance.

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. Increases in Fas mediated signaling have been implicated in the pathology of low risk myelodysplastic syndromes (MDS) and glioblastoma. 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.