UniProt functional annotation for P10415



	UniProt functional annotation for P10415

UniProt code: P10415.

Organism: Homo sapiens (Human).

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

Function: Suppresses apoptosis in a variety of cell systems including factor-dependent lymphohematopoietic and neural cells. Regulates cell death by controlling the mitochondrial membrane permeability. Appears to function in a feedback loop system with caspases. Inhibits caspase activity either by preventing the release of cytochrome c from the mitochondria and/or by binding to the apoptosis-activating factor (APAF-1). May attenuate inflammation by impairing NLRP1-inflammasome activation, hence CASP1 activation and IL1B release (PubMed:17418785). {ECO:0000269|PubMed:17418785, ECO:0000269|PubMed:18570871}.

Subunit: Forms homodimers, and heterodimers with BAX, BAD, BAK and Bcl- X(L). Heterodimerization with BAX requires intact BH1 and BH2 motifs, and is necessary for anti-apoptotic activity (PubMed:8183370, PubMed:25609812). Interacts with EI24 (By similarity). Also interacts with APAF1, BBC3, BCL2L1, BNIPL, MRPL41 and TP53BP2. Binding to FKBP8 seems to target BCL2 to the mitochondria and probably interferes with the binding of BCL2 to its targets. Interacts with BAG1 in an ATP- dependent manner. Interacts with RAF1 (the 'Ser-338' and 'Ser-339' phosphorylated form). Interacts (via the BH4 domain) with EGLN3; the interaction prevents the formation of the BAX-BCL2 complex and inhibits the anti-apoptotic activity of BCL2. Interacts with G0S2; this interaction also prevents the formation of the anti-apoptotic BAX-BCL2 complex. Interacts with RTL10/BOP. Interacts with the SCF(FBXO10) complex. Interacts (via the loop between motifs BH4 and BH3) with NLRP1 (via LRR repeats), but not with NLRP2, NLRP3, NLRP4, PYCARD, nor MEFV (PubMed:17418785). Interacts with GIMAP3/IAN4, GIMAP4/IAN1 and GIMAP5/IAN5 (By similarity). Interacts with BCAP31 (PubMed:31206022). Interacts with IRF3; the interaction is inhibited by Sendai virus infection (PubMed:25609812). {ECO:0000250|UniProtKB:P10417, ECO:0000269|PubMed:11463391, ECO:0000269|PubMed:12901880, ECO:0000269|PubMed:15547950, ECO:0000269|PubMed:15733859, ECO:0000269|PubMed:15849194, ECO:0000269|PubMed:17090549, ECO:0000269|PubMed:17418785, ECO:0000269|PubMed:19228691, ECO:0000269|PubMed:19706769, ECO:0000269|PubMed:20849813, ECO:0000269|PubMed:23055042, ECO:0000269|PubMed:23431138, ECO:0000269|PubMed:25609812, ECO:0000269|PubMed:31206022, ECO:0000269|PubMed:8183370, ECO:0000269|PubMed:8668206, ECO:0000269|PubMed:9305631}.

Subcellular location: Mitochondrion outer membrane {ECO:0000269|PubMed:2250705}; Single-pass membrane protein {ECO:0000269|PubMed:2250705}. Nucleus membrane {ECO:0000269|PubMed:2250705}; Single-pass membrane protein {ECO:0000269|PubMed:2250705}. Endoplasmic reticulum membrane {ECO:0000269|PubMed:2250705}; Single-pass membrane protein {ECO:0000269|PubMed:2250705}.

Tissue specificity: Expressed in a variety of tissues.

Domain: BH1 and BH2 domains are required for the interaction with BAX and for anti-apoptotic activity. {ECO:0000269|PubMed:8183370}.

Domain: The BH4 motif is required for anti-apoptotic activity and for interaction with RAF1 and EGLN3.

Domain: The loop between motifs BH4 and BH3 is required for the interaction with NLRP1. {ECO:0000269|PubMed:17418785}.

Ptm: Phosphorylation/dephosphorylation on Ser-70 regulates anti- apoptotic activity. Growth factor-stimulated phosphorylation on Ser-70 by PKC is required for the anti-apoptosis activity and occurs during the G2/M phase of the cell cycle. In the absence of growth factors, BCL2 appears to be phosphorylated by other protein kinases such as ERKs and stress-activated kinases. Phosphorylated by MAPK8/JNK1 at Thr-69, Ser-70 and Ser-87, wich stimulates starvation-induced autophagy. Dephosphorylated by protein phosphatase 2A (PP2A) (By similarity). {ECO:0000250}.

Ptm: Proteolytically cleaved by caspases during apoptosis. The cleaved protein, lacking the BH4 motif, has pro-apoptotic activity, causes the release of cytochrome c into the cytosol promoting further caspase activity. {ECO:0000269|PubMed:9395403}.

Ptm: Monoubiquitinated by PRKN, leading to increase its stability. Ubiquitinated by SCF(FBXO10), leading to its degradation by the proteasome. {ECO:0000269|PubMed:20889974, ECO:0000269|PubMed:23431138}.

Disease: Note=A chromosomal aberration involving BCL2 has been found in chronic lymphatic leukemia. Translocation t(14;18)(q32;q21) with immunoglobulin gene regions. BCL2 mutations found in non-Hodgkin lymphomas carrying the chromosomal translocation could be attributed to the Ig somatic hypermutation mechanism resulting in nucleotide transitions. {ECO:0000269|PubMed:2875799, ECO:0000269|PubMed:3285301}.

Similarity: Belongs to the Bcl-2 family. {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:		Suppresses apoptosis in a variety of cell systems including factor-dependent lymphohematopoietic and neural cells. Regulates cell death by controlling the mitochondrial membrane permeability. Appears to function in a feedback loop system with caspases. Inhibits caspase activity either by preventing the release of cytochrome c from the mitochondria and/or by binding to the apoptosis-activating factor (APAF-1). May attenuate inflammation by impairing NLRP1-inflammasome activation, hence CASP1 activation and IL1B release (PubMed:17418785). {ECO:0000269\|PubMed:17418785, ECO:0000269\|PubMed:18570871}.


Subunit:		Forms homodimers, and heterodimers with BAX, BAD, BAK and Bcl- X(L). Heterodimerization with BAX requires intact BH1 and BH2 motifs, and is necessary for anti-apoptotic activity (PubMed:8183370, PubMed:25609812). Interacts with EI24 (By similarity). Also interacts with APAF1, BBC3, BCL2L1, BNIPL, MRPL41 and TP53BP2. Binding to FKBP8 seems to target BCL2 to the mitochondria and probably interferes with the binding of BCL2 to its targets. Interacts with BAG1 in an ATP- dependent manner. Interacts with RAF1 (the 'Ser-338' and 'Ser-339' phosphorylated form). Interacts (via the BH4 domain) with EGLN3; the interaction prevents the formation of the BAX-BCL2 complex and inhibits the anti-apoptotic activity of BCL2. Interacts with G0S2; this interaction also prevents the formation of the anti-apoptotic BAX-BCL2 complex. Interacts with RTL10/BOP. Interacts with the SCF(FBXO10) complex. Interacts (via the loop between motifs BH4 and BH3) with NLRP1 (via LRR repeats), but not with NLRP2, NLRP3, NLRP4, PYCARD, nor MEFV (PubMed:17418785). Interacts with GIMAP3/IAN4, GIMAP4/IAN1 and GIMAP5/IAN5 (By similarity). Interacts with BCAP31 (PubMed:31206022). Interacts with IRF3; the interaction is inhibited by Sendai virus infection (PubMed:25609812). {ECO:0000250\|UniProtKB:P10417, ECO:0000269\|PubMed:11463391, ECO:0000269\|PubMed:12901880, ECO:0000269\|PubMed:15547950, ECO:0000269\|PubMed:15733859, ECO:0000269\|PubMed:15849194, ECO:0000269\|PubMed:17090549, ECO:0000269\|PubMed:17418785, ECO:0000269\|PubMed:19228691, ECO:0000269\|PubMed:19706769, ECO:0000269\|PubMed:20849813, ECO:0000269\|PubMed:23055042, ECO:0000269\|PubMed:23431138, ECO:0000269\|PubMed:25609812, ECO:0000269\|PubMed:31206022, ECO:0000269\|PubMed:8183370, ECO:0000269\|PubMed:8668206, ECO:0000269\|PubMed:9305631}.
Subcellular location:		Mitochondrion outer membrane {ECO:0000269\|PubMed:2250705}; Single-pass membrane protein {ECO:0000269\|PubMed:2250705}. Nucleus membrane {ECO:0000269\|PubMed:2250705}; Single-pass membrane protein {ECO:0000269\|PubMed:2250705}. Endoplasmic reticulum membrane {ECO:0000269\|PubMed:2250705}; Single-pass membrane protein {ECO:0000269\|PubMed:2250705}.
Tissue specificity:		Expressed in a variety of tissues.
Domain:		BH1 and BH2 domains are required for the interaction with BAX and for anti-apoptotic activity. {ECO:0000269\|PubMed:8183370}.
Domain:		The BH4 motif is required for anti-apoptotic activity and for interaction with RAF1 and EGLN3.
Domain:		The loop between motifs BH4 and BH3 is required for the interaction with NLRP1. {ECO:0000269\|PubMed:17418785}.
Ptm:		Phosphorylation/dephosphorylation on Ser-70 regulates anti- apoptotic activity. Growth factor-stimulated phosphorylation on Ser-70 by PKC is required for the anti-apoptosis activity and occurs during the G2/M phase of the cell cycle. In the absence of growth factors, BCL2 appears to be phosphorylated by other protein kinases such as ERKs and stress-activated kinases. Phosphorylated by MAPK8/JNK1 at Thr-69, Ser-70 and Ser-87, wich stimulates starvation-induced autophagy. Dephosphorylated by protein phosphatase 2A (PP2A) (By similarity). {ECO:0000250}.
Ptm:		Proteolytically cleaved by caspases during apoptosis. The cleaved protein, lacking the BH4 motif, has pro-apoptotic activity, causes the release of cytochrome c into the cytosol promoting further caspase activity. {ECO:0000269\|PubMed:9395403}.
Ptm:		Monoubiquitinated by PRKN, leading to increase its stability. Ubiquitinated by SCF(FBXO10), leading to its degradation by the proteasome. {ECO:0000269\|PubMed:20889974, ECO:0000269\|PubMed:23431138}.
Disease:		Note=A chromosomal aberration involving BCL2 has been found in chronic lymphatic leukemia. Translocation t(14;18)(q32;q21) with immunoglobulin gene regions. BCL2 mutations found in non-Hodgkin lymphomas carrying the chromosomal translocation could be attributed to the Ig somatic hypermutation mechanism resulting in nucleotide transitions. {ECO:0000269\|PubMed:2875799, ECO:0000269\|PubMed:3285301}.
Similarity:		Belongs to the Bcl-2 family. {ECO:0000305}.