Fas ligand
Fas ligand (FASL or
Structural features
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]
Receptors
- FasR: The
- DcR3: TL1A. DcR3 is a soluble receptor that has no signal transduction capabilities (hence a "decoy") and functions to prevent FasR-FasL interactions by competitively binding to membrane-bound Fas ligand and rendering them inactive.[8]
Cell signaling and mechanism
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). [9]
Upon ensuing
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. [9] 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.[9]
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
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.[9]
Function of apoptosis in the immune system
Apoptosis triggered by FasR-Fas ligand binding plays a fundamental role in the regulation of the immune system. Its functions include:
- T-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 in activation-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 to lymphadenopathy, splenomegaly, and lupus erythematosus. [11]
- cytotoxic T lymphocytes induce cell death in cells expressing foreign antigens.[12]
- lymphocytes. It is one of many mechanisms the body employs in the establishment and maintenance of immune privilege.[13]
- 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.[13]
- Tumor counterattack: Tumors may over-express Fas ligand and induce the lymphocytes, allowing the tumor to escape the effects of an immune response.[14] The up-regulation of Fas ligand often occurs following chemotherapy, from which the tumor cells have attained apoptosis resistance.[15]
Role in disease
Defective Fas-mediated apoptosis may lead to
Increases in Fas-mediated signaling have been implicated in the pathology of low-risk
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
Interactions
Fas ligand has been shown to
See also
References
- ^ a b c GRCh38: Ensembl release 89: ENSG00000117560 - Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000000817 - Ensembl, May 2017
- ^ "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.
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- ^ S2CID 17145731.
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- ^ S2CID 26765451.
- ^ S2CID 33084576.
- S2CID 24130275.
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- PMID 11994433.
- S2CID 4427455.
Further reading
- Choi C, Benveniste EN (January 2004). "Fas ligand/Fas system in the brain: regulator of immune and apoptotic responses". Brain Res. Brain Res. Rev. 44 (1): 65–81. S2CID 46587211.
- Tolstrup M, Ostergaard L, Laursen AL, Pedersen SF, Duch M (2004). "HIV/SIV escape from immune surveillance: focus on Nef". Curr. HIV Res. 2 (2): 141–51. PMID 15078178.
External links
- GeneReviews/NCBI/NIH/UW entry on Autoimmune Lymphoproliferative Syndrome
- Online Mendelian Inheritance in Man (OMIM): 601859
- Fas+Ligand+Protein at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
- Overview of all the structural information available in the PDB for UniProt: P48023 (Tumor necrosis factor ligand superfamily member 6) at the PDBe-KB.