CD178 FASLG (Fas ligand [TNF superfamily, member 6]), CD95L
Molecule TypeAntigen ExpressionMolecular Weight
Min / Max
Non-lineage Restricted Molecule
Type 2 glycoprotein
T Lymphocyte
NK Cell
Neutrophil
T Cell
Tumor Cell
Dendritic Cell
Epithelial Cell
Astrocyte
Monocyte
Erythroblast
Thymocyte
40 / 40

Expression
CD178 is expressed on CD4+ and CD8+ T lymphocytes.  It is induced following T cell activation.  Expression is on non-activated NK cells, upregulated by CD16 ligation, IL-2 and IL-12.  Expression is found on parenchymal cells of the retina and cornea, retinal pigment epithelial cells, neutrophils, autoimmune thymocytes.  CD178 is expressed weakly on keratinocytes which are upregulated by UV-B light.  On astrocytes expression is upregulated by IL-1, IL6, TNF-a and IFN-g, and on microglia it is downregulated by IFN-g.  It is present on mature erythroblasts, breast epithelial cells, vascular endothelial cells, on the placenta and is highly expressed by various tumors.  CD95, FasL, expression can be induced in a variety of cell types by heat shock, genotoxic insult such as chemotherapeutic agents and radiation, growth factor withdrawal and viral infection.  Expression is also located on the plasma membrane, intracellular in monocyte cells and in secretory lysosomes present in CD4+ and CD8+ T cells and NK cells.  CD178 can be found on immature dendritic cells.  CD178 is widely expressed outside the immune system including sites of "immune privilege", where it provides protection from excessive immune pathology in viral infection.  Expressed on some tumors does provide a degree of protection from immune attack.  Expresssion is induced on many cell types by activation or stress in the skin by UV radiation.

Structure
MOLECULAR FAMILY NAME:  Belongs to the tumor necrosis factor superfamily.

CD178 is a single-pass type-2 281 aa glycoprotein.  It contains an 103-281 aa extracellular domain which contains a C-terminal domain which is homologous to TNF and is responsible for the trimeric quaternary organization of TNF ligands which can be found in soluble form and is necessary and sufficient for receptor binding and contains 3 N-glycosylation sites, a transmembrane domain and an 1-80 aa cytoplasmic domain which is proline-rich and contains a consensus SH3 binding motif.  CD178 is expressed in the membrane (and as a soluble cleavage product) as a trimer suggesting that CD178 has the potential to trimerize.  Other members of the TNF superfamily are clustered on chromosome 1 in humans. 

MOLECULAR MASS
Cell Type Unreduced Reduced Comment
Recombinant FasL in COS cells 40 kDa, 80 kDa, 120 Kda 40 kDa Unreduced molecular weights correspond to monomeric, dimeric and trimeric forms of FasL
Neutrophils, monocytes 37 kDa, 30 kDa The 30 kDa form corresponds to soluble FasL (sFasL)
Keratinocytes 27 kDa, 32 kDa, 40 kDa
NK cells 40 kDa
Autoimmune thyrocytes 40 kDa
Melanoma cells 70 kDa 40 kDa, 27 kDa The 70 kDa unreduced form is a sFasL oligomer.  The 27 kDa form corresponds to sFasL
T cells (Jurkat) 42 kDa, 26 kDa The 26 kDa form corresponds to sFasL
Placental cells 29 kDa, 46 kDa, 50 kDa
Recombinant soluble FasL 26 kDa

POST-TRANSCRIPTIONAL MODIFICATION

Alternative splicing yields 2 different isoforms.  The splicing of murine CD178 generates a soluble form that may protect cells from FasL-induced apoptosis.

POST-TRANSLATIONAL MODIFICATION

CD178 is N-glycosylated.  In human cells, CD178 is cleaved between residues S126 and L127 to generate a soluble form.  In mouse cell transfected with human CD178 cleavage occurs between Lys 129 and Gln 130 and is possibly due to different specificity of murine metalloprotinase.


Ligands
The extracellular region of CD178 binds to CD95, a member of the TNFR superfamily.  The protein encoded by FASLG is the ligand for FAS.  Both are transmembrane proteins.

LIGANDS AND MOLECULES ASSOCIATED WITH CD178
Molecule Comment
Decoy receptor 3 (DcR3) Binds CD178 and inhibits CD178-induced apoptosis.  The gene for DcR3 is amplified in 50% of primary lung and colon tumors



Function
CD178 (FasL) induces apoptosis in cells expressing CD95 (Fas).  It is involved in regulation of the immune response as well as many other situations in which Fas-mediated apoptosis is part of homeostasis or pathology.  This is a key mechanism in elimination of virus-infected or transformed cells.  Fas-positive activated T cells can undergo apoptosis as a result of interaction with Fas ligand expressed on other lymphocytes and on other cells such as in immune privileged sites where CD178 expression protects the tissue from T cell mediated damage or on the same cell (lymphocyte suicide).  CD178 induces activation, not cell death, in Fas-positive dendritic cells.  Apart from its activity in killing Fas-bearing cells, engagement of CD178 transmits signals to the cell, inhibiting proliferation or, in some in vitro situations acting as a costimulator.  The shed soluble domain can induce apoptosis but it is less active than membrane-bound CD178 and may inhibit cell-mediated apoptosis by competing for Fas sites.  A cytokine that binds to CD178/CD95 is a receptor that transduces the apoptotic signal into cells and maybe involved in cytotoxic T cell mediated apoptosis and T cell development.  CD178/CD95-mediated a role in the induction of peripheral tolerance, in the antigen-stimulated suicide of mature T cells or both but does not appear critical in development.  CD178 on cytotoxic T cells can induce cytolysis of CD95-expressing target cells.  CD178 is a key effector of cytotoxicity and is involved in Fas/FasL interaction, apoptosis and regulation of immune responses.  CD178 has been proposed to transduce a costimulatory signal into CD8+ and naive CD4+ T cells within 24 hours of TCR crosslinking.  In CD4+ T cells, CD178 stimulation leads to cell cycle arrest.  CD178 upregulates the expression of pro-inflammatory cytokines in vascular smooth muscle cells and inducing macrophage recruitment in vivo. 

BIOCHEMICAL ACTIVITY

CD178 is the ligand for the apoptosis-inducing receptor CD95 (Fas/APO-1).

DISEASE RELEVANCE AND FUNCTION OF CD178 IN INTACT ANIMAL

Knockout mice and humans with CD95L mutation show severe autoimmune disease.  Defects in CD178 are a cause of autoimmune lymphoproliferative syndrome (ALPS), a childhood sydrome involving hemolytic anemia and thrombocytopenia with massive lymphadenopathy and splenomegaly.  There may be an association of  defects in CD178 with the occurrence systemic lupus erythematosus (SLE).  CD178 is expressed by immune privileged tissues where it may inhibit inflammation and confer protection against transplantation.  CD178 alone is not sufficient to prevent allograft rejection and other factors seem to be involved such as the expression of TGF-b.  Fas-FasL interaction may be involved in target distribution during organ specific autoimmune diseases, such as Hashimoto's thyroiditis, insulin-dependent diabetes mellitus and multiple scherosis.  CD178 expression has been found in many tumors, where it has been proposed to counterattack tumor infiltrating CTL and to be correlated with disease prognosis.  Expression is upregulated by HIV proteins possible leading to loss of virus-specific CTL.  CD178 has been reported to mediate neuronal death during ischemia and has been shown to mediate keratinocyte apoptosis and may contribute to the pathology of toxic epidermal necrolysis, TEN.

Comments
MOLECULAR INTERACTIONS -
PROTEINS AND DNA ELEMENTS WHICH REGULATE TRANSCRIPTION OF CD178: No information.

SUBSTRATES: No information.

ENZYMES WHICH MODIFY CD178
Enzyme Comment
Metalloproteinase of the ADAM family Cleaves human membrane-bound CD178 to yield the soluble form
Matrilysin Converts murine CD178 to soluble form



Database accession numbers
AnimalPIRSWISSPROTEMGBL/GENBANK
 
HumanEntrezgene 356P48023
MouseP41047S76752
RatP36940U03470
Antibodies

Revised June 25, 2008


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