UniProt functional annotation for P25445



	UniProt functional annotation for P25445

UniProt code: P25445.

Organism: Homo sapiens (Human).

Taxonomy: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.

Function: Receptor for TNFSF6/FASLG. The adapter molecule FADD recruits caspase-8 to the activated receptor. The resulting death-inducing signaling complex (DISC) performs caspase-8 proteolytic activation which initiates the subsequent cascade of caspases (aspartate-specific cysteine proteases) mediating apoptosis. FAS-mediated apoptosis may have a role in the induction of peripheral tolerance, in the antigen- stimulated suicide of mature T-cells, or both. The secreted isoforms 2 to 6 block apoptosis (in vitro). {ECO:0000269|PubMed:19118384, ECO:0000269|PubMed:7533181}.

Subunit: Binds DAXX. Interacts with HIPK3 (By similarity). Part of a complex containing HIPK3 and FADD (By similarity). Binds RIPK1 and FAIM2 (PubMed:7538908, PubMed:10535980). Interacts with BABAM2 and FEM1B (PubMed:10542291, PubMed:15465831). Interacts with FADD (PubMed:21109225, PubMed:19118384). Interacts directly (via DED domain) with NOL3 (via CARD domain); inhibits death-inducing signaling complex (DISC) assembly by inhibiting the increase in FAS-FADD binding induced by FAS activation (By similarity). Interacts with CALM (PubMed:24914971). In the absence of stimulation, interacts with BIRC2, DDX3X and GSK3B. The interaction with BIRC2 and DDX3X is further enhanced upon receptor stimulation and accompanied by DDX3X and BIRC2 cleavage (PubMed:18846110). {ECO:0000250|UniProtKB:P25446, ECO:0000250|UniProtKB:Q63199, ECO:0000269|PubMed:10535980, ECO:0000269|PubMed:10542291, ECO:0000269|PubMed:15465831, ECO:0000269|PubMed:18846110, ECO:0000269|PubMed:19118384, ECO:0000269|PubMed:21109225, ECO:0000269|PubMed:24914971, ECO:0000269|PubMed:7538908}.

Subcellular location: [Isoform 1]: Cell membrane {ECO:0000269|PubMed:1713127, ECO:0000269|PubMed:25301068}; Single-pass type I membrane protein {ECO:0000305}. Membrane raft {ECO:0000269|PubMed:25301068}.

Subcellular location: [Isoform 2]: Secreted.

Subcellular location: [Isoform 3]: Secreted.

Subcellular location: [Isoform 4]: Secreted.

Subcellular location: [Isoform 5]: Secreted.

Subcellular location: [Isoform 6]: Secreted.

Tissue specificity: Isoform 1 and isoform 6 are expressed at equal levels in resting peripheral blood mononuclear cells. After activation there is an increase in isoform 1 and decrease in the levels of isoform 6. {ECO:0000269|PubMed:7575433}.

Domain: Contains a death domain involved in the binding of FADD, and maybe to other cytosolic adapter proteins.

Ptm: (Microbial infection) Glycosylated at Arg-250 by enteropathogenic E.coli protein NleB1: arginine GlcNAcylation prevents homotypic/heterotypic death domain interactions. {ECO:0000305|PubMed:23955153}.

Ptm: Palmitoylated (PubMed:25301068). Palmitoylation by ZDHHC7 prevents the lysosomal degradation of FAS regulating its expression at the plasma membrane (PubMed:25301068). {ECO:0000269|PubMed:25301068}.

Ptm: N- and O-glycosylated. O-glycosylated with core 1 or possibly core 8 glycans. {ECO:0000269|PubMed:19159218, ECO:0000269|PubMed:22171320}.

Disease: Autoimmune lymphoproliferative syndrome 1A (ALPS1A) [MIM:601859]: A disorder of apoptosis that manifests in early childhood and results in the accumulation of autoreactive lymphocytes. It is characterized by non-malignant lymphadenopathy with hepatosplenomegaly, and autoimmune hemolytic anemia, thrombocytopenia and neutropenia. {ECO:0000269|PubMed:10090885, ECO:0000269|PubMed:10340403, ECO:0000269|PubMed:10515860, ECO:0000269|PubMed:11418480, ECO:0000269|PubMed:17336828, ECO:0000269|PubMed:20935634, ECO:0000269|PubMed:7540117, ECO:0000269|PubMed:8929361, ECO:0000269|PubMed:9028321, ECO:0000269|PubMed:9028957, ECO:0000269|PubMed:9322534, ECO:0000269|PubMed:9821419, ECO:0000269|PubMed:9927496}. Note=The disease is caused by variants affecting the gene represented in this entry.

Miscellaneous: [Isoform 2]: May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay. {ECO:0000305}.

Miscellaneous: [Isoform 3]: May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay. {ECO:0000305}.

Miscellaneous: [Isoform 4]: May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay. {ECO:0000305}.

Miscellaneous: [Isoform 5]: May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay. {ECO:0000305}.

Miscellaneous: [Isoform 7]: Dominant negative isoform, resistant to Fas-mediated apoptosis. {ECO:0000305}.

Annotations taken from UniProtKB at the EBI.


Organism:		Homo sapiens (Human).
Taxonomy:		Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.



Function:		Receptor for TNFSF6/FASLG. The adapter molecule FADD recruits caspase-8 to the activated receptor. The resulting death-inducing signaling complex (DISC) performs caspase-8 proteolytic activation which initiates the subsequent cascade of caspases (aspartate-specific cysteine proteases) mediating apoptosis. FAS-mediated apoptosis may have a role in the induction of peripheral tolerance, in the antigen- stimulated suicide of mature T-cells, or both. The secreted isoforms 2 to 6 block apoptosis (in vitro). {ECO:0000269\|PubMed:19118384, ECO:0000269\|PubMed:7533181}.


Subunit:		Binds DAXX. Interacts with HIPK3 (By similarity). Part of a complex containing HIPK3 and FADD (By similarity). Binds RIPK1 and FAIM2 (PubMed:7538908, PubMed:10535980). Interacts with BABAM2 and FEM1B (PubMed:10542291, PubMed:15465831). Interacts with FADD (PubMed:21109225, PubMed:19118384). Interacts directly (via DED domain) with NOL3 (via CARD domain); inhibits death-inducing signaling complex (DISC) assembly by inhibiting the increase in FAS-FADD binding induced by FAS activation (By similarity). Interacts with CALM (PubMed:24914971). In the absence of stimulation, interacts with BIRC2, DDX3X and GSK3B. The interaction with BIRC2 and DDX3X is further enhanced upon receptor stimulation and accompanied by DDX3X and BIRC2 cleavage (PubMed:18846110). {ECO:0000250\|UniProtKB:P25446, ECO:0000250\|UniProtKB:Q63199, ECO:0000269\|PubMed:10535980, ECO:0000269\|PubMed:10542291, ECO:0000269\|PubMed:15465831, ECO:0000269\|PubMed:18846110, ECO:0000269\|PubMed:19118384, ECO:0000269\|PubMed:21109225, ECO:0000269\|PubMed:24914971, ECO:0000269\|PubMed:7538908}.
Subcellular location:		[Isoform 1]: Cell membrane {ECO:0000269\|PubMed:1713127, ECO:0000269\|PubMed:25301068}; Single-pass type I membrane protein {ECO:0000305}. Membrane raft {ECO:0000269\|PubMed:25301068}.
Subcellular location:		[Isoform 2]: Secreted.
Subcellular location:		[Isoform 3]: Secreted.
Subcellular location:		[Isoform 4]: Secreted.
Subcellular location:		[Isoform 5]: Secreted.
Subcellular location:		[Isoform 6]: Secreted.
Tissue specificity:		Isoform 1 and isoform 6 are expressed at equal levels in resting peripheral blood mononuclear cells. After activation there is an increase in isoform 1 and decrease in the levels of isoform 6. {ECO:0000269\|PubMed:7575433}.
Domain:		Contains a death domain involved in the binding of FADD, and maybe to other cytosolic adapter proteins.
Ptm:		(Microbial infection) Glycosylated at Arg-250 by enteropathogenic E.coli protein NleB1: arginine GlcNAcylation prevents homotypic/heterotypic death domain interactions. {ECO:0000305\|PubMed:23955153}.
Ptm:		Palmitoylated (PubMed:25301068). Palmitoylation by ZDHHC7 prevents the lysosomal degradation of FAS regulating its expression at the plasma membrane (PubMed:25301068). {ECO:0000269\|PubMed:25301068}.
Ptm:		N- and O-glycosylated. O-glycosylated with core 1 or possibly core 8 glycans. {ECO:0000269\|PubMed:19159218, ECO:0000269\|PubMed:22171320}.
Disease:		Autoimmune lymphoproliferative syndrome 1A (ALPS1A) [MIM:601859]: A disorder of apoptosis that manifests in early childhood and results in the accumulation of autoreactive lymphocytes. It is characterized by non-malignant lymphadenopathy with hepatosplenomegaly, and autoimmune hemolytic anemia, thrombocytopenia and neutropenia. {ECO:0000269\|PubMed:10090885, ECO:0000269\|PubMed:10340403, ECO:0000269\|PubMed:10515860, ECO:0000269\|PubMed:11418480, ECO:0000269\|PubMed:17336828, ECO:0000269\|PubMed:20935634, ECO:0000269\|PubMed:7540117, ECO:0000269\|PubMed:8929361, ECO:0000269\|PubMed:9028321, ECO:0000269\|PubMed:9028957, ECO:0000269\|PubMed:9322534, ECO:0000269\|PubMed:9821419, ECO:0000269\|PubMed:9927496}. Note=The disease is caused by variants affecting the gene represented in this entry.
Miscellaneous:		[Isoform 2]: May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay. {ECO:0000305}.
Miscellaneous:		[Isoform 3]: May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay. {ECO:0000305}.
Miscellaneous:		[Isoform 4]: May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay. {ECO:0000305}.
Miscellaneous:		[Isoform 5]: May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay. {ECO:0000305}.
Miscellaneous:		[Isoform 7]: Dominant negative isoform, resistant to Fas-mediated apoptosis. {ECO:0000305}.