Apoptosis Database

Description [+]

Synonyms: BNIP3L, NIX, BNIP3A
Species: Metazoa;Bilateria;Deuterostoma;Chordata;Vertebrata;Mammalia;Primates;Hominidae; Homo sapiens
Short gene description: BCL2/adenovirus E1B 19 kDa protein-interacting protein 3-like (NIP3-like protein X)(NIP3L)(BCL2/adenovirus E1B 19 kDa protein-interacting protein 3A)(Adenovirus E1B19K-binding protein B5) [Source:UniProtKB/Swiss-Prot;Acc:O60238]
Family: Bcl-2 family : BH3-only
Process: cell death (other), apoptosis,
Pathways:
Criteria: manually curated
Curator comment:
Mouse ortholog(s): Bnip3l CT030242.6
WIKI: BNIP3L-H_sapiens

References [+]

Adenovirus E1B-19K/BCL-2 interacting protein BNIP3 contains a BH3 domain and a mitochondrial targeting sequence.
Yasuda M, Theodorakis P, Subramanian T, Chinnadurai G
Adenovirus E1B-19K and BCL-2 anti-apoptosis proteins interact with certain BCL-2 family pro-apoptotic proteins. A conserved domain, BH3, present in these proteins is essential for their pro-apoptotic activity and for heterodimerization with anti-apoptosis proteins. Cellular protein BNIP3 (previously NIP3) interacts with E1B-19K, BCL-2, BCL-xL, and EBV-BHRF1. BNIP3 contains a motif similar to the BH3 domain. Deletion of the BH3-like motif in BNIP3 abrogates its ability to heterodimerize with E1B-19K and BCL-xL. Substitution of the BH3 domain of BNIP3 for the corresponding sequences of BAX functionally restores the pro-apoptotic and protein heterodimerization activities of BAX. BNIP3 exhibits a delayed cell death activity that is partially relieved by deletion of the BH3 domain. BNIP3 suppresses the anti-apoptosis activity of BCL-xL in a BH3-dependent manner. BNIP3 contains a C-terminal trans-membrane (TM) domain similar to other BCL-2 family proteins and BNIP1 (previously NIP1). The TM domains of BNIP3 and BNIP1 can functionally substitute for the TM domain of a BCL-2 family member EBV-BHRF1. The BNIP3 TM domain exclusively targets the heterologous green fluorescent protein (GFP) to mitochondria. These results suggest that BNIP3 is a member of the BH3-contaning BCL-2 family of pro-apoptotic proteins and functions in mitochondria. J Biol Chem. 1998 May 15;273(20):12415-21.

The role of Bcl-2 family member BNIP3 in cell death and disease: NIPping at the heels of cell death.
Burton TR, Gibson SB
Bcl-2 nineteen-kilodalton interacting protein (BNIP3) is a BH-3-only Bcl-2 family member whose expression levels increase during stress such as hypoxia through hypoxia-inducing factor-1-dependent or -independent mechanisms. When BNIP3 expression is induced, it localizes to the mitochondria and triggers a loss of membrane potential, and an increase in the reactive oxygen species production, which often leads to cell death. Cells under normal growth conditions suppress BNIP3 expression through transcriptional repression. There is considerable debate in the literature regarding what type of cell death is induced by BNIP3. It has been observed that BNIP3 could induce necrosis, autophagy and/or apoptosis. In contrast, other studies indicate that BNIP3 could promote cell survival. Besides its cell death regulation, BNIP3 plays a key role in the pathogenicity of many diseases. In cardiac infarction, loss of BNIP3 expression has been shown to reduce the number of damaged cardiomyocytes after ischemia and reperfusion. BNIP3 expression also plays an important role in the deregulation of cell death in many cancers. In this review, we will discuss the different and often contradictory mechanisms of BNIP3 regulation of cell death and the role that BNIP3 may play in diseases. Cell Death Differ. 2009 Apr;16(4):515-23. Epub 2009 Jan 9.

References from Mouse ortholog(s):

The E1B 19K/Bcl-2-binding protein Nip3 is a dimeric mitochondrial protein that activates apoptosis.
Chen G, Ray R, Dubik D, Shi L, Cizeau J, Bleackley RC, Saxena S, Gietz RD, Greenberg AH
Nip3 (nineteen kD interacting protein-3) is an E1B 19K and Bcl-2 binding protein of unknown function. Nip3 is detected as both a 60- and 30-kD protein in vivo and in vitro and exhibits strong homologous interaction in a yeast two-hybrid system indicating that it can homodimerize. Nip3 is expressed in mitochondria and a mutant (Nip3(163)) lacking the putative transmembrane domain and COOH terminus does not dimerize or localize to mitochondria. Transient transfection of epitope-tagged Nip3 in Rat-1 fibroblasts and MCF-7 breast carcinoma induces apoptosis within 12 h while cells transfected with the Nip3(163) mutant have a normal phenotype, suggesting that mitochondrial localization is necessary for induction of cell death. Nip3 overexpression increases the sensitivity to apoptosis induced by granzyme B and topoisomerase I and II inhibitors. After transfection, both Nip3 and Nip3(163) protein levels decrease steadily over 48 h indicating that the protein is rapidly degraded and this occurs in the absence of cell death. Bcl-2 overexpression initially delays the onset of apoptosis induced by Nip3 but the resistance is completely overcome in longer periods of incubation. Nip3 protein levels are much higher and persist longer in Bcl-2 expressing cells. In conclusion, Nip3 is an apoptosis-inducing dimeric mitochondrial protein that can overcome Bcl-2 suppression. J Exp Med. 1997 Dec 15;186(12):1975-83.

Structure & Sequence [+]

Source	Domain Name	Start	End
PFAM A	BNIP3	2	219

Evolution [+]

Name	Relationship	Species
A_aegypti_AAEL006711-PA	orthology	Aedes
A_gambiae_AGAP001411-PA	orthology	Anopheles
NP_001026056.1	orthology	Chicken
BNIP3L	orthology	Chimpanzee
BNI3L_BOVIN	orthology	Cow
BNIP3L	orthology	Dog
BNIP3L (2 of 2)	orthology	Fugu
BNIP3L (1 of 2)	orthology	Fugu
BNIP3L (1 of 2)	orthology	Gasterosteus
BNIP3L (2 of 2)	orthology	Gasterosteus
BNIP3L	orthology	Gorilla
BNIP3L	orthology	Horse
BNIP3L	orthology	Lyzard
NP_001032361.1	orthology	Macaca
BNIP3L (2 of 2)	orthology	Medaka
BNIP3L (1 of 2)	orthology	Medaka
BNIP3L	orthology	Monodelphis
CT030242.6	orthology	Mouse
Bnip3l	orthology	Mouse
BNIP3L	orthology	Orangutan
BNIP3L	orthology	Ornithorhynchus
BNIP3L	orthology	Rabbit
Bnip3l	orthology	Rat
BNIP3L	orthology	Tetraodon
BNIP3L	orthology	Xenopus
BNIP3L	orthology	Zebra finch
bnip3l	orthology	Zebrafish
bnip3l2	orthology	Zebrafish
BNIP3	paralogy	Chicken
BNIP3	paralogy	Chimpanzee
BNIP3_BOVIN	paralogy	Cow
Q005W6_CANFA	paralogy	Dog
BNIP3	paralogy	Fugu
T_rubripes_ENSTRUP00000046089	paralogy	Fugu
G_aculeatus_ENSGACP00000021335	paralogy	Gasterosteus
BNIP3	paralogy	Gasterosteus
BNIP3	paralogy	Gorilla
BNIP3	paralogy	Horse
BNIP3	paralogy	Human
BNIP3	paralogy	Lyzard
BNIP3	paralogy	Macaca
O_latipes_ENSORLP00000006124	paralogy	Medaka
BNIP3	paralogy	Medaka
BNIP3	paralogy	Monodelphis
Bnip3	paralogy	Mouse
BNIP3	paralogy	Orangutan
BNIP3	paralogy	Rabbit
R_norvegicus_ENSRNOP00000055295	paralogy	Rat
Bnip3	paralogy	Rat
R_norvegicus_ENSRNOP00000016874	paralogy	Rat
R_norvegicus_ENSRNOP00000049965	paralogy	Rat
R_norvegicus_ENSRNOP00000041876	paralogy	Rat
T_nigroviridis_ENSTNIP00000017287	paralogy	Tetraodon
BNIP3	paralogy	Tetraodon
Q5EAM0_XENTR	paralogy	Xenopus
BNIP3	paralogy	Zebra finch
zgc:123120	paralogy	Zebrafish
zgc:73226	paralogy	Zebrafish
wu:fj49c01	paralogy	Zebrafish

Gene Ontology [+]

GO id	Name	Ontology type	Evidence
GO:0043065	positive regulation of apoptosis	biological_proccess	IEA
GO:0044419	interspecies interaction between organisms	biological_proccess	IEA
GO:0043066	negative regulation of apoptosis	biological_proccess	IDA
GO:0006917	induction of apoptosis	biological_proccess	IDA
GO:0051607	defense response to virus	biological_proccess	IDA
GO:0008634	negative regulation of survival gene product expression	biological_proccess	IDA
GO:0042803	protein homodimerization activity	mollecular_function	IDA
GO:0046982	protein heterodimerization activity	mollecular_function	IDA
GO:0005521	lamin binding	mollecular_function	IDA
GO:0005740	mitochondrial envelope	cell_component	IEA
GO:0016021	integral to membrane	cell_component	IEA
GO:0005634	nucleus	cell_component	IEA
GO:0016020	membrane	cell_component	IEA
GO:0005635	nuclear envelope	cell_component	IDA
GO:0005783	endoplasmic reticulum	cell_component	IDA
GO:0005739	mitochondrion	cell_component	IDA

Check GO Evidence Codes here

Curated Isoforms [+]

Transcript	Translation
OTTHUMT00000216895 *	OTTHUMP00000125280 *

Information from other databases [+]

Gene related links:

Gene info from HGNC [?] :1085
Gene related info from GeneCards [?] : BNIP3L
Ensembl genome browser [?] : ENSG00000104765
Expression info from Arrayexpress [?] : ENSG00000104765
Protein expression from Protein Atlas: [?] ENSG00000104765
Community gene edition from Wikigenes: [?] 665

Protein related links:

Uniprot protein info: O60238
PIR protein info: O60238
Protein interactions from IntAct: O60238

Gene and disease information from OMIM: (For a full disease description table, click here.)

OMIM gene information: 605368
OMIM disease information:

Other links

entrezgene: 665
refseq_dna: NM_004331
refseq_peptide: NP_004322

Click on [?] for more information.

BNIP3L (Homo sapiens)