BNIP3L (BCL2/adenovirus E1B 19kDa interacting protein 3-like)
2012-11-01 Paul Ney , Ji Zhang AffiliationCell & Molecular Biology, New York Blood Center, 310 E 67th St, New York, NY 10065, USA (PN); Cancer Biology & Genetics, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10065, USA (JZ)
DNA/RNA
Organization of the human BNIP3L gene. The boxes represent exons, the line introns (not drawn to scale). Black areas represent coding sequence.
Description
The gene spans 30122 bp and has 6 exons. The cytogenetic location of the gene is 8p21.2. The genomic coordinates are 8: 26240522 - 26270643.
Transcription
The mRNA is 3505 bp, and has a 657 bp open reading frame.
Proteins
Functional domains of BNIP3L protein. LIR: LC3-interaction region (WVEL) (Schwarten et al., 2009; Novak et al., 2010); MER: minimal essential region (DMEKILLDAQHE) (Zhang et al., 2012); BH3-like: BCL2 homology 3-like domain (LKKSADWVSDW) (Yasuda et al., 1999); TM: transmembrane domain.
Description
The protein is 219 amino acids, with a predicted MW of 23,8 kDa. The carboxy-terminal transmembrane domain of BNIP3L has been characterized by nuclear magnetic resonance and shown to form a kinked α-helix (Bocharov et al., 2007). Structural bioinformatics analysis indicates that the rest of the protein is mostly disordered. The LIR and the MER are predicted to form secondary structure (β-strand and α-helix, respectively) (Zhang et al., 2012).
Expression
BNIP3L is ubiquitously expressed. Northern blot hybridization reveals two transcripts of 1,6 kb and 3,9 kb. These are expressed in heart, brain, placenta, lung, liver, skeletal muscle, kidney, and pancreas (Yasuda et al., 1999). In another study, transcripts were identified in heart, brain, placenta, lung (low), liver, skeletal muscle (low), kidney, pancreas, spleen, thymus, prostate, testis, ovary, small intestine, colon, and peripheral blood leukocyte (Farooq et al., 2001). In the same study, there was also expression in cancer cell lines, including promyelocytic HL-60 (low), Hela S3 (low), K562, lymphoblastic leukemia Molt-5, Burkitts lymphoma-Raji, colorectal adenocarcinoma SW480, and lung carcinoma A549 cells. In another study, 1,4 and 4,0 kb BNIP3L transcripts were found in primary hematopoietic cells and in cell lines, including K562, Hela, and Jurkat cells (Aerbajinai et al., 2003). BNIP3L is upregulated during erythroid maturation.
BNIP3L protein can form an SDS-resistant dimer, which migrates at twice its predicted MW in SDS-PAGE gels. BNIP3L dimerization is mediated through its transmembrane domain (Imazu et al., 1999).
BNIP3L protein can form an SDS-resistant dimer, which migrates at twice its predicted MW in SDS-PAGE gels. BNIP3L dimerization is mediated through its transmembrane domain (Imazu et al., 1999).
Localisation
BNIP3L primarily localizes to the mitochondrial outer membrane (Chen et al., 1999; Imazu et al., 1999; Yasuda et al., 1999; Vande Velde et al., 2000). BNIP3L is oriented so that its amino terminus is in the cytoplasm, and its carboxy-terminal tail is in the mitochondrial intermembrane space. It also localizes to nuclear envelope, sarcoplasmic reticulum, and endoplasmic reticulum (Ohi et al., 1999; Diwan et al., 2009).
Function
BNIP3L and BNIP3 can cause cell death by several mechanisms, which are mediated by their BH3-like and transmembrane domains. In cardiomyocytes, mitochondria-targeted BNIP3L causes BAX/BAK-dependent mitochondrial outer membrane permeabilization, whereas ER/SR-targeted BNIP3L causes cyclophilin D-dependent opening of the MPT pore and mitochondrial depolarization (Chen et al., 2010). In tumor cells, BNIP3 expression is associated with opening of the MPT pore and autophagy (Vande Velde et al., 2000). Another property of BNIP3L and BNIP3 is their ability to mediate mitochondrial clearance during erythroid development (Schweers et al., 2007; Sandoval et al., 2008) and in response to hypoxia (Zhang et al., 2008; Liu et al., 2012), respectively. BNIP3L mediates mitochondrial clearance in erythroid cells through its LIR (Schwarten et al., 2009; Novak et al., 2010) and MER (Zhang et al., 2012) domains.
Homology
BNIP3L is conserved from zebrafish to man.
Mutations
Note
Not yet described.
Implicated in
Entity name
Various cancers
Oncogenesis
BNIP3L and the related protein BNIP3 (56% identical overall) are implicated in cancer progression. BNIP3 deregulation is more often implicated in cancer than BNIP3L, but the two proteins have a similar mechanism of action, so both are potentially relevant. BNIP3 and BNIP3L are reported to function as both tumor suppressors and oncogenes. This dual nature presumably reflects the roles of BNIP3 and BNIP3L in cell death pathways and autophagy; autophagy can promote cell survival. The frequent finding of BNIP3 deregulation in cancer is likely related to its induction by hypoxia, and HIF1α signaling (Bruick, 2000). BNIP3L is also induced during hypoxia, by p53 (Fei et al., 2004). There are several mechanisms of BNIP3 and BNIP3L-induced cell death, which have recently been reviewed (Zhang and Ney, 2011). The role of BNIP3 and BNIP3L in cell death may explain their frequent deletion and silencing in tumors by promoter methylation (see below). By contrast, some advanced cancers express abnormally high levels of BNIP3 and BNIP3L. In these cases, the prosurvival role of these proteins in the induction of autophagy appears to dominate.
Entity name
Prostate cancer
Note
BNIP3 is expressed in 95% of prostate cancer samples and is either nuclear, cytoplasmic, or both. Cytoplasmic BNIP3 expression correlates with Gleason score, but not other clinicopathological parameters. By contrast, nuclear BNIP3 correlates with HIF1α and HIF2α expression (Shaida et al., 2008). BNIP3 promoter hypermethylation is present in 16% of prostate cancers, and BNIP3 expression is decreased in 21% of prostate cancers, but the two do not correlate (Murphy et al., 2011). BNIP3L exhibits homozygous deletion in a prostate cancer cell line and primary prostate tumor (Liu et al., 2008). Another study showed LOH of BNIP3L in 5% of prostate cancers, and a correlation with increasing disease stage (Cheng et al., 2012).
Entity name
Breast cancer
Note
BNIP3 expression in ductal carcinoma in situ is associated with higher grade, necrosis and invasive disease, whereas BNIP3L expression does not correlate with these parameters (Sowter et al., 2003). BNIP3L is not deregulated and infrequently mutated in ovarian and breast cancer (Lai et al., 2003). Loss of BNIP3 expression correlates with lymph node metastases and mitotic index, but not with the hypoxic response (Koop et al., 2009). Proteasome inhibition with Bortezomib blocks autophagy-mediated catabolism of long-lived proteins, and is associated with increased BNIP3 and cell death in breast cancer cell lines (Periyasamy-Thandavan et al., 2010). On the other hand, resistance to the cytotoxic effects of TNFα in a subclone of breast cancer MCF-7 cells is associated with increased BNIP3 and upregulation of the autophagy program (Moussay et al., 2011). Notably, hypoxic induction of BNIP3 and BNIP3L can cause breast cancer cell death and at the same time promote the survival of cancer-associated fibroblasts (Chiavarina et al., 2010). Thus, BNIP3 and BNIP3L may have compartment-specific effects on cell death and survival.
Entity name
Colorectal and gastric cancers
Note
BNIP3 promoter hypermethylation is found in 66% of primary colorectal and 49% of gastric cancers, but not in adjacent normal tissue (Murai et al., 2005b). Promoter hypermethylation but not gene mutation correlates with decreased BNIP3 expression.
Entity name
Pancreatic cancer
Note
BNIP3 is silenced by promoter hypermethylation in 80% of pancreatic adenocarcinoma samples (Okami et al., 2004). BNIP3 expression is diminished in chronic pancreatitis and pancreatic ductal adenocarcinoma, and loss of BNIP3 expression correlates with decreased survival and chemotherapy resistance (Erkan et al., 2005). Similarly, BNIP3L is reduced in liver metastases and the tumor invasion front compared with the primary pancreatic tumor, in an orthotopic SCID mouse model (Niedergethmann et al., 2007).
Entity name
Liver cancer
Note
Epigenetic silencing of BNIP3 and BNIP3L is associated with poor prognosis in hepatocellular carcinoma (Calvisi et al., 2007). In addition, a cSNP that causes premature termination of BNIP3L was reported in 40% of hepatocellular carcinoma cases (Wang et al., 2005). BNIP3 is a HIF1α target in HepG2 tumor spheroids, and its expression is associated with increased autophagy and attenuation of apoptosis (Menrad et al., 2010).
Entity name
Lung cancer
Note
There is strong cytoplasmic expression of BNIP3 in 38% of non-small cell lung cancer, which was associated with an aggressive phenotype and decreased survival (Giatromanolaki et al., 2004).
Entity name
Malignant glioblastoma
Note
BNIP3 is expressed in hypoxic regions of glioblastoma multiforme (GBM), but is sequestered in the nucleus in ~80% of tumors (Burton et al., 2006). In another study, BNIP3L appeared to act as a tumor suppressor in low-grade astrocytomas, and as an oncogene in high grade GBM. In the latter case, BNIP3L expression correlated with NFκB activation through an unknown mechanism (Lu et al., 2012).
Entity name
Hematopoietic malignancy
Note
BNIP3 promoter hypermethylation is found in 15% of acute lymphocytic leukemia, 17% of acute myelogenous leukemia, and 21% of multiple myeloma. Promoter hypermethylation correlates with decreased BNIP3 expression (Murai et al., 2005a). BNIP3 promoter hypermethylation correlates with decreased survival in multiple myeloma (Heller et al., 2008). Another study found BNIP3 promoter hypermethylation in 13% of newly diagnosed multiple myeloma but no association with prognosis (Braggio et al., 2010).
Entity name
Ischemic and hypertrophic heart disease
Note
Most of the evidence that BNIP3 and BNIP3L have a role in heart disease comes from animal models. BNIP3 is regulated by hypoxia in cardiomyocytes through HIF1α binding sites in its promoter (Bruick, 2000). By contrast, BNIP3L is regulated by Gαq signaling in the setting of cardiac hypertrophy (Gálvez et al., 2006). Enforced expression of BNIP3L causes lethal cardiomyopathy in mice, whereas BNIP3L deficiency protects mice from Gαq-mediated and pressure overload cardiomyopathy (Yussman et al., 2002; Diwan et al., 2008). Further, BNIP3 deficiency protects against post-infarction ventricular remodeling (Diwan et al., 2007). Mice with combined deficiency of BNIP3 and BNIP3L in the heart develop normally, but by 30 weeks exhibit cardiac enlargement and decreased left ventricular ejection fraction (Dorn, 2010). Mitochondria in the hearts of these mice are increased in number and show variation in size and internal structure. Furthermore, young BNIP3/BNIP3L-deficient mice subjected to aortic banding rapidly develop heart failure.
Entity name
Cerebral ischemia
Note
Animal models and in vitro studies also provide evidence that BNIP3 and to a lesser extent BNIP3L are a cause of neuronal cell death after hypoxia or denervation. BNIP3 is expressed in striatal and cortical neurons following transient focal ischemia in rats; prolonged BNIP3 expression in this setting is associated with delayed neuronal cell death (Althaus et al., 2006). BNIP3 knockdown inhibits nuclear translocation of EndoG and protects against hypoxia-induced, caspase-independent, delayed neuronal cell death (Zhang et al., 2007). Hypoxic mimetics cause BAX/BAK- and caspase-dependent neuronal precursor cell death in vitro, but also cause HIF1α and BNIP3 upregulation. BNIP3 knockdown failed to prevent caspase activation, but inhibits nuclear translocation of apoptosis-inducing factor and cell death (Walls et al., 2009). Thus, BNIP3 mediates hypoxia-induced, caspase-independent neuronal cell death. Also, following neonatal nerve axotomy, BNIP3 and to a lesser extent BNIP3L, are induced in facial motoneurons and associated with cell death (Cho et al., 2012).
Article Bibliography
| Pubmed ID | Last Year | Title | Authors |
|---|---|---|---|
| 12663450 | 2003 | The proapoptotic factor Nix is coexpressed with Bcl-xL during terminal erythroid differentiation. | Aerbajinai W et al |
| 16464515 | 2006 | Expression of the gene encoding the pro-apoptotic BNIP3 protein and stimulation of hypoxia-inducible factor-1alpha (HIF-1alpha) protein following focal cerebral ischemia in rats. | Althaus J et al |
| 17412696 | 2007 | Unique dimeric structure of BNip3 transmembrane domain suggests membrane permeabilization as a cell death trigger. | Bocharov EV et al |
| 7954800 | 1994 | Adenovirus E1B 19 kDa and Bcl-2 proteins interact with a common set of cellular proteins. | Boyd JM et al |
| 20037750 | 2010 | Methylation status of nine tumor suppressor genes in multiple myeloma. | Braggio E et al |
| 10922063 | 2000 | Expression of the gene encoding the proapoptotic Nip3 protein is induced by hypoxia. | Bruick RK et al |
| 16217754 | 2006 | The pro-cell death Bcl-2 family member, BNIP3, is localized to the nucleus of human glial cells: Implications for glioblastoma multiforme tumor cell survival under hypoxia. | Burton TR et al |
| 17717605 | 2007 | Mechanistic and prognostic significance of aberrant methylation in the molecular pathogenesis of human hepatocellular carcinoma. | Calvisi DF et al |
| 9867803 | 1999 | Nix and Nip3 form a subfamily of pro-apoptotic mitochondrial proteins. | Chen G et al |
| 20418503 | 2010 | Dual autonomous mitochondrial cell death pathways are activated by Nix/BNip3L and induce cardiomyopathy. | Chen Y et al |
| 21965145 | 2012 | Copy number alterations in prostate tumors and disease aggressiveness. | Cheng I et al |
| 20864819 | 2010 | HIF1-alpha functions as a tumor promoter in cancer associated fibroblasts, and as a tumor suppressor in breast cancer cells: Autophagy drives compartment-specific oncogenesis. | Chiavarina B et al |
| 22639046 | 2012 | Differential expression of BNIP family members of BH3-only proteins during the development and after axotomy in the rat. | Cho B et al |
| 17909626 | 2007 | Inhibition of ischemic cardiomyocyte apoptosis through targeted ablation of Bnip3 restrains postinfarction remodeling in mice. | Diwan A et al |
| 19065046 | 2009 | Endoplasmic reticulum-mitochondria crosstalk in NIX-mediated murine cell death. | Diwan A et al |
| 18178777 | 2008 | Nix-mediated apoptosis links myocardial fibrosis, cardiac remodeling, and hypertrophy decompensation. | Diwan A et al |
| 20559783 | 2010 | Mitochondrial pruning by Nix and BNip3: an essential function for cardiac-expressed death factors. | Dorn GW 2nd et al |
| 15856026 | 2005 | Loss of BNIP3 expression is a late event in pancreatic cancer contributing to chemoresistance and worsened prognosis. | Erkan M et al |
| 11642554 | 2001 | Cloning of BNIP3h, a member of proapoptotic BNIP3 family genes. | Farooq M et al |
| 15607964 | 2004 | Bnip3L is induced by p53 under hypoxia, and its knockdown promotes tumor growth. | Fei P et al |
| 16291751 | 2006 | Distinct pathways regulate proapoptotic Nix and BNip3 in cardiac stress. | Gálvez AS et al |
| 15328198 | 2004 | BNIP3 expression is linked with hypoxia-regulated protein expression and with poor prognosis in non-small cell lung cancer. | Giatromanolaki A et al |
| 18172295 | 2008 | Genome-wide transcriptional response to 5-aza-2'-deoxycytidine and trichostatin a in multiple myeloma cells. | Heller G et al |
| 10467396 | 1999 | Bcl-2/E1B 19 kDa-interacting protein 3-like protein (Bnip3L) interacts with bcl-2/Bcl-xL and induces apoptosis by altering mitochondrial membrane permeability. | Imazu T et al |
| 19505343 | 2009 | Expression of BNIP3 in invasive breast cancer: correlations with the hypoxic response and clinicopathological features. | Koop EA et al |
| 12610513 | 2003 | Analysis of the candidate 8p21 tumour suppressor, BNIP3L, in breast and ovarian cancer. | Lai J et al |
| 22267086 | 2012 | Mitochondrial outer-membrane protein FUNDC1 mediates hypoxia-induced mitophagy in mammalian cells. | Liu L et al |
| 18670647 | 2008 | Homozygous deletions and recurrent amplifications implicate new genes involved in prostate cancer. | Liu W et al |
| 22984526 | 2012 | Nix protein positively regulates NF-κB activation in gliomas. | Lu Y et al |
| 9523198 | 1998 | Isolation, mapping, and functional analysis of a novel human cDNA (BNIP3L) encoding a protein homologous to human NIP3. | Matsushima M et al |
| 20513003 | 2010 | Roles of hypoxia-inducible factor-1alpha (HIF-1alpha) versus HIF-2alpha in the survival of hepatocellular tumor spheroids. | Menrad H et al |
| 21490427 | 2011 | The acquisition of resistance to TNFα in breast cancer cells is associated with constitutive activation of autophagy as revealed by a transcriptome analysis using a custom microarray. | Moussay E et al |
| 15709167 | 2005 | Aberrant methylation and silencing of the BNIP3 gene in colorectal and gastric cancer. | Murai M et al |
| 20564325 | 2011 | In silico analysis and DHPLC screening strategy identifies novel apoptotic gene targets of aberrant promoter hypermethylation in prostate cancer. | Murphy TM et al |
| 17940512 | 2007 | Gene expression profiling of liver metastases and tumour invasion in pancreatic cancer using an orthotopic SCID mouse model. | Niedergethmann M et al |
| 20010802 | 2010 | Nix is a selective autophagy receptor for mitochondrial clearance. | Novak I et al |
| 10381623 | 1999 | A novel adenovirus E1B19K-binding protein B5 inhibits apoptosis induced by Nip3 by forming a heterodimer through the C-terminal hydrophobic region. | Ohi N et al |
| 15289340 | 2004 | Silencing of the hypoxia-inducible cell death protein BNIP3 in pancreatic cancer. | Okami J et al |
| 20110775 | 2010 | Bortezomib blocks the catabolic process of autophagy via a cathepsin-dependent mechanism, affects endoplasmic reticulum stress and induces caspase-dependent cell death in antiestrogen-sensitive and resistant ER+ breast cancer cells. | Periyasamy-Thandavan S et al |
| 18454133 | 2008 | Essential role for Nix in autophagic maturation of erythroid cells. | Sandoval H et al |
| 19363302 | 2009 | Nix directly binds to GABARAP: a possible crosstalk between apoptosis and autophagy. | Schwarten M et al |
| 18048346 | 2007 | NIX is required for programmed mitochondrial clearance during reticulocyte maturation. | Schweers RL et al |
| 18163427 | 2008 | Expression of BNIP3 correlates with hypoxia-inducible factor (HIF)-1alpha, HIF-2alpha and the androgen receptor in prostate cancer and is regulated directly by hypoxia but not androgens in cell lines. | Shaida N et al |
| 14648660 | 2003 | Expression of the cell death genes BNip3 and NIX in ductal carcinoma in situ of the breast; correlation of BNip3 levels with necrosis and grade. | Sowter HM et al |
| 10891486 | 2000 | BNIP3 and genetic control of necrosis-like cell death through the mitochondrial permeability transition pore. | Vande Velde C et al |
| 19915483 | 2009 | bcl-2/Adenovirus E1B 19-kd interacting protein 3 (BNIP3) regulates hypoxia-induced neural precursor cell death. | Walls KC et al |
| 16109524 | 2005 | Preparation and analysis of cSNP chip on hepatocellular carcinoma-related genes. | Wang J et al |
| 9973195 | 1999 | BNIP3alpha: a human homolog of mitochondrial proapoptotic protein BNIP3. | Yasuda M et al |
| 12053174 | 2002 | Mitochondrial death protein Nix is induced in cardiac hypertrophy and triggers apoptotic cardiomyopathy. | Yussman MG et al |
| 18281291 | 2008 | Mitochondrial autophagy is an HIF-1-dependent adaptive metabolic response to hypoxia. | Zhang H et al |
| 22906961 | 2012 | A short linear motif in BNIP3L (NIX) mediates mitochondrial clearance in reticulocytes. | Zhang J et al |
| 21126215 | 2011 | Mechanisms and biology of B-cell leukemia/lymphoma 2/adenovirus E1B interacting protein 3 and Nip-like protein X. | Zhang J et al |
| 17379825 | 2007 | BNIP3 upregulation and EndoG translocation in delayed neuronal death in stroke and in hypoxia. | Zhang Z et al |
Other Information
Locus ID:
NCBI: 665
MIM: 605368
HGNC: 1085
Ensembl: ENSG00000104765
Variants:
dbSNP: 665
ClinVar: 665
TCGA: ENSG00000104765
COSMIC: BNIP3L
RNA/Proteins
Expression (GTEx)
Pathways
Protein levels (Protein atlas)
References
| Pubmed ID | Year | Title | Citations |
|---|---|---|---|
| 37876279 | 2024 | Excessive BNIP3- and BNIP3L-dependent mitophagy underlies the pathogenesis of FBXL4-mutated mitochondrial DNA depletion syndrome. | 0 |
| 38519771 | 2024 | Mitophagy mediated by BNIP3 and NIX protects against ferroptosis by downregulating mitochondrial reactive oxygen species. | 1 |
| 38810696 | 2024 | CTCF and BORIS-mediated autophagy regulation via alternative splicing of BNIP3L in breast cancer. | 0 |
| 38934722 | 2024 | Association between BCL2 interacting protein 3 like (BNIP3L) genetic polymorphisms and the risk of multiple myeloma in China. | 0 |
| 37876279 | 2024 | Excessive BNIP3- and BNIP3L-dependent mitophagy underlies the pathogenesis of FBXL4-mutated mitochondrial DNA depletion syndrome. | 0 |
| 38519771 | 2024 | Mitophagy mediated by BNIP3 and NIX protects against ferroptosis by downregulating mitochondrial reactive oxygen species. | 1 |
| 38810696 | 2024 | CTCF and BORIS-mediated autophagy regulation via alternative splicing of BNIP3L in breast cancer. | 0 |
| 38934722 | 2024 | Association between BCL2 interacting protein 3 like (BNIP3L) genetic polymorphisms and the risk of multiple myeloma in China. | 0 |
| 36766737 | 2023 | Mitophagy Effects of Protodioscin on Human Osteosarcoma Cells by Inhibition of p38MAPK Targeting NIX/LC3 Axis. | 2 |
| 36795401 | 2023 | The outer mitochondrial membrane protein TMEM11 demarcates spatially restricted BNIP3/BNIP3L-mediated mitophagy. | 10 |
| 37102372 | 2023 | FBXL4 ubiquitin ligase deficiency promotes mitophagy by elevating NIX levels. | 9 |
| 37419035 | 2023 | Uncovering interactions of mitochondrial proteins BNIP3 and BNIP3L with necroptosis-associated kinase RIPK3: Insights into kinase activation. | 1 |
| 36766737 | 2023 | Mitophagy Effects of Protodioscin on Human Osteosarcoma Cells by Inhibition of p38MAPK Targeting NIX/LC3 Axis. | 2 |
| 36795401 | 2023 | The outer mitochondrial membrane protein TMEM11 demarcates spatially restricted BNIP3/BNIP3L-mediated mitophagy. | 10 |
| 37102372 | 2023 | FBXL4 ubiquitin ligase deficiency promotes mitophagy by elevating NIX levels. | 9 |
Citation
Paul Ney ; Ji Zhang
BNIP3L (BCL2/adenovirus E1B 19kDa interacting protein 3-like)
Atlas Genet Cytogenet Oncol Haematol. 2012-11-01
Online version: http://atlasgeneticsoncology.org/gene/823/bnip3l
