FAS (Fas cell surface death receptor)

Alias (NCBI)	ALPS1A
	APO-1
	APT1
	CD95
	FAS1
	FASTM
	TNFRSF6
HGNC (Hugo)	FAS
HGNC Alias symb	CD95
	APO-1
HGNC Alias name	TNF receptor superfamily member 6
HGNC Previous name	FAS1
	APT1
	TNFRSF6
HGNC Previous name	"tumor necrosis factor receptor superfamily, member 6
	Fas (TNF receptor superfamily, member 6)"
LocusID (NCBI)	355
Atlas_Id	207
Location	10q23.31  [Link to chromosome band 10q23]
Location_base_pair	Starts at 88990798 and ends at 89017059 bp from pter ( according to GRCh38/hg38-Dec_2013)  [Mapping FAS.png]
	Gene localisation: CD95 gene spans approximately 25 kb on human chromosome 10.

Note	Gene annotation is APT1.
	According to Ensembl, CD95 gene is composed of 9 exons encoding 3 variants.
Description	CD95 gene is composed of 9 exons.
Transcription	According to Ensembl, the gene has 18 transcripts (splice variants). Among them, three transcripts encode for proteins (represented in the diagram). Variant 1 encodes for the longest protein of 335 aa. Variant 2 encodes for a CD95 protein lacking transmembrane region (exon 6) and thus corresponding to a soluble receptor. Variant 3 contains a distinct and shorter c-terminus compare to variant 1 and encodes for a protein of 220 aa.
Pseudogene	No known pseudogenes.

Note	Type I transmembrane protein.
	CD95 is a 335 amino acids type 1 transmembrane glycoprotein. Signal peptide corresponds to amino acid 1 to 16 (Itoh et al., 1991). The PLAD (pre-ligand assembly domain) and the CRDs (cysteine-rich domain) are encoded by exon 2 to 5. Exon 6 encompasses the transmembrane domain (TM), and the CD95 intracellular region consists in exons 7 to 9. The FAS DD is encoded by exon 9.
Description	CD95 displays two different numberings. While some researchers start to count from the first translated amino acid after methionine (335 aa), others start at the first amino acid after signal peptide (319 aa) (Itoh et al., 1991). CD95 contains three cysteine-rich domains (CRDs). CRD2 and the upper part of CRD3 interact with CD95L (Schneider et al., 1997). CD95 is expressed at the plasma membrane as a pre-associated homotrimer (Siegel et al., 2000) because of homotypic interactions occurring between its pre-ligand assembly domains (PLAD) (amino acids 43 to 66 (Edmond et al., 2014), count starts after signal peptide). The intracellular region of CD95 encompasses an 87-amino-acid-long stretch designated the death domain (DD) whose structure consists of six amphipathic α-helices arranged anti-parallel to one another (Huang et al., 1997). The 15 last amino acids of CD95 exert an inhibitory action on the CD95-mediated apoptotic signal due to the recruitment of the phosphatase FAP1 (Yanagisawa et al., 1997).
	The molecular weight of CD95 varies between 40 to 50 kDa due to different post-translational modifications: glycosylation (Shatnyeva et al., 2011; Keppler et al., 1999), nitrosylation (Leon-Bollotte et al., 2011), S-glutathionylation (Anathy et al., 2009) and palmitoylation (Chakrabandhu et al., 2007; Feig et al., 2007).
Expression	CD95 is ubiquitously expressed in human body.
Localisation	CD95 is mainly found at cell surface. CD95 is retained internalized in cells through a FAP-1-driven mechanism, while its translocation to the cell surface relies on dynamin-2 (Ivanov et al., 2003; Ivanov et al., 2006).
Function	CD95 contributes to immune homeostasis, elimination of transformed and infected cells, and plays a pivotal role in peripheral tolerance. CD95/CD95L pair is also responsible for preventing inflammation in certain tissues designated immune privileged sites, such as eyes and testis. More recently, CD95 has been shown to promote carcinogenesis ((Chen et al., 2010; Hoogwater et al., 2010; Kleber et al., 2010; Malleter et al., 2013; O' Reilly et al., 2009). Upon binding of membrane-bound CD95L to CD95, CD95-DD recruits the adaptor molecule Fas-associated death domain protein (FADD) and caspase-8, leading to caspase activation and apoptosis (Kischkel et al., 1995). The complex CD95/FADD/Caspase-8 is called death-inducing signalling complex (DISC) (Kischkel et al., 1995). DISC formation is regulated by several molecular mechanisms including c-FLIP (FLICE-like-inhibitory-protein) (Irmler et al., 1997), FAP-1 (Fas associated phosphatase 1) (Sato et al., 1995) and PED-PEA15 (Condorelli et al., 1999). Cells can be divided in two groups with regard to the magnitude of DISC formation, and the role played by the mitochondrion in this pathway (Scaffidi et al., 1998). In type I cells, DISC formation occurs rapidly and efficiently, resulting in the release of a large amount of activated caspase-8 in the cytosol. Whereas, type II cells have difficulties forming this complex, and the amount of active caspase-8 is insufficient to directly activate the effector caspase-3 and caspase-7 (Scaffidi et al., 1998). The low level of activated caspase-8 in type II cells is sufficient to cleave BID, a BH3-only protein, which links the death receptor to the apoptotic activity of mitochondria. Indeed, caspase-8-driven BID truncation generates tBID, which translocates to mitochondria, and triggers the release of pro-apoptotic factors (Yin, 2000; Yin et al., 1999). Type II cells are addicted to this latter signal because they contain higher levels of the caspase-3 inhibitor XIAP than type I cells (Jost et al., 2009). To summarize, DISC formation and IAP amount are two cellular markers that allow a clear discrimination between type I and type II cells. CD95 engagement also induces non-apoptotic signalling pathways promoting cell motility, invasiveness (Hoogwater et al., 2010; Kleber et al., 2010; Malleter et al., 2013; Steller et al., 2011; Barnhart et al., 2004), inflammation (O' Reilly et al., 2009; Audo et al., 2014; Letellier et al., 2010; Tauzin et al., 2011) and organ regeneration (Desbarats et al., 2003; Desbarats and Newell, 2000). Indeed, CD95 can implement NFκB (O' Reilly et al., 2009; Barnhart et al., 2004; Wajant et al., 1998), phosphatidylinositol 3-kinase (PI3K) (Kleber et al., 2008;Tauzin et al., 2011) or MAPK signaling pathways (Hoogwater et al., 2010; Desbarats et al., 2003). CD95 has also been reported to play a pivotal role in T cell activation (Akimzhanov et al., 2010; Alderson et al., 1993). Of note, while interaction of transmembrane CD95L with CD95 triggers cell death, its metalloprotease-cleaved counterpart (cl-CD95L) does not form DISC, but induces the formation of an atypical complex designated motility-inducing signalling complex (MISC)5.
Homology	The CD95-mediated apoptotic system is conserved among all mammals. The most primitive invertebrate TNF/TNFR pair has been reported in the fruit fly Drosophila melangastor (Kauppila et al., 2003; Moreno et al., 2002; Collette et al., 2003). However, a more recent study highlighted that TNFSF and TNFRSF members are conserved in more ancient invertebrates such as Cnidaria (Quistad et al., 2014). Moreover, comparison of coral TNFSF/TNFRSF members with proteins from Homo sapiens reveals high genetic and structural conservation.

Note
Entity	Hodgkin's lymphoma
Note	Hodgkin's lymphoma is a cancer of the immune system characterised by the presence of mononucleated Hodgkin's cells and multinucleated Reed-Sternberg cell. This disease can be caused by somatic mutation of CD95 (Tables 1 and 2). The symptoms are enlargement of lymph nodes, spleen or other immune tissue. Also non hodgkin's lymphoma (NHL) show somatic mutations of CD95 (Tables 1 and 2): thyroid lymphoma, mucosa associated lymphoid tissue-type lymphomas, follicle center lymphomas, mycosis fungoide (cutaneous T cell lymphoma), nasal NK/T cell lymphoma, anaplastic large lymphoma, B-chronic lymphocytic lymphoma, and diffuse large B cells lymphomas. 8% of patients with NHL exhibits autoimmune phenomena (Grønbaek et al., 1995).
	Table1. Germinal mutations in the APT1 gene.
Oncogenesis	Table 2. Somatic mutations in the APT1 gene. * Amino acid numbers have been modified according to the regular amino acid annotation. ** Threonine 256 depicted in this study corresponded in fact to amino acid 254.
Entity	Various cancers
Note	Somatic mutations of CD95 have been also identified in various cancers (Table 2): multiple myelomas, T cell leukemia, cutaneous malignant melanoma, squamous cell carcinoma, bladder carcinoma, prostatic cancer, gastric cancer, testicular germ cell tumor, and non small cell lung cancer.
Entity	Autoimmune lymphoproliferative syndrome type Ia
Note	ALPS is characterised by chronic lymphadenopathy and splenomegaly, expanded populations of double-negative α/β T lymphocytes (CD3+, CD4-, CD8-). ALPS patients often develop autoimmunity. These patients exhibit germinal mutations in CD95 gene with no or rare "loss of heterozygosity" (Table 1). The ALPS patients show an increased risk to develop Hodgkin and non-Hodgkin lymphomas (Straus et al., 2001).
Entity	Systemic lupus erythematous
Note	Systemic lupus erythematous is a prototypic systemic autoimmune disorder characterized by autoantibody production, immune complex formation and cell-mediated reactivity against self. CD95/CD95L have been implicated in this disease.

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