Fas ligand

Source: Wikipedia, the free encyclopedia.
FASLG
Available structures
Gene ontology
Molecular function
Cellular component
Biological process
Sources:Amigo / QuickGO
Ensembl
UniProt
RefSeq (mRNA)

NM_001302746
NM_000639

NM_001205243
NM_010177

RefSeq (protein)

NP_000630
NP_001289675

NP_001192172
NP_034307

Location (UCSC)Chr 1: 172.66 – 172.67 MbChr 1: 161.61 – 161.62 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Fas ligand (FASL or

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]

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
    type 1 transmembrane protein. It consists of three cysteine-rich pseudorepeats, a transmembrane domain, and an intracellular death domain.[5]
  • 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

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.[10][9]

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. [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

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). [9]

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

Overview of signal transduction pathways involved in apoptosis

Apoptosis triggered by FasR-Fas ligand binding plays a fundamental role in the regulation of the immune system. Its functions include:

Role in disease

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.[16]

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

interact
with:

See also

References

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000117560 - Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000000817 - Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
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Further reading

External links