BNIP3

Last updated
BNIP3
Protein BNIP3 PDB 2j5d.png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases BNIP3 , NIP3, BCL2/adenovirus E1B 19kDa interacting protein 3, BCL2 interacting protein 3, HABON
External IDs OMIM: 603293; MGI: 109326; HomoloGene: 2990; GeneCards: BNIP3; OMA:BNIP3 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

664

12176

Ensembl

ENSG00000176171

ENSMUSG00000078566

UniProt

Q12983

O55003

RefSeq (mRNA)

NM_004052

NM_009760

RefSeq (protein)

NP_004043

NP_033890

Location (UCSC) Chr 10: 131.97 – 131.98 Mb Chr 7: 138.49 – 138.51 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

BCL2/adenovirus E1B 19 kDa protein-interacting protein 3 is a protein found in humans that is encoded by the BNIP3 gene. [5]

Contents

BNIP3 is a member of the apoptotic Bcl-2 protein family. It can induce cell death while also assisting with cell survival. Like many of the Bcl-2 family proteins, BNIP3 modulates the permeability state of the outer mitochondrial membrane by forming homo- and hetero-oligomers inside the membrane. [6] Upregulation results in a decrease in mitochondrial potential, an increase in reactive oxygen species, mitochondrial swelling and fission, and an increase in mitochondrial turnover via autophagy. [7] Sequence similarity with Bcl-2 family members was not detected. Humans and other animals ( Drosophila, Caenorhabditis ), as well as lower eukaryotes ( Dictyostelium, Trypanosoma, Cryptosporidium, Paramecium ) encode several BNIP3 paralogues including the human NIP3L, which induces apoptosis by interacting with viral and cellular anti-apoptosis proteins.

Structure

The right-handed parallel helix-helix structure of the domain with a hydrogen bond-rich His-Ser node in the middle of the membrane, accessibility of the node for water, and continuous hydrophilic track across the membrane suggest that the domain can provide an ion-conducting pathway through the membrane. Incorporation of the BNIP3 transmembrane domain into an artificial lipid bilayer resulted in a pH-dependent conductivity increase. Necrosis-like cell death induced by BNIP3 may be related to this activity. [8]

Function

BNIP3 interacts with the E1B 19 kDa protein which is responsible for the protection of virally induced cell death, as well as E1B 19 kDa-like sequences of BCL2, also an apoptotic protector. This gene contains a BH3 domain and a transmembrane domain, which have been associated with pro-apoptotic function. The dimeric mitochondrial protein encoded by this gene is known to induce apoptosis, even in the presence of BCL2. [9] Change of BNIP3 expression along other members of the Bcl-2 family measured by qPCR captures important characteristics of malignant transformation, and are defined as markers of resistance toward cell death, a key hallmark of cancer. [10]

Transport reaction

The reaction catalyzed by BNIP3 is:

small molecules (out) ⇌ small molecules (in)

Autophagy

Autophagy is important for recycling cellular contents and prolonging cell life. Hanna et al. show that BNIP3 and LC3 interact to remove endoplasmic reticulum and mitochondria. [11] When inactive BNIP3 is activated on the membrane of the mitochondria, they form homodimers where LC3 can bind to the LC3-interacting region (LIR) motif on BNIP3 and facilitates the formation of an autophagosome. [11] [12] Interestingly, when disrupting BNIP3 and LC3 interaction, researchers found that autophagy was reduced but not completely erased. This suggests that BNIP3 is not the only receptor on the mitochondria and ER to promote autophagy. [11]

This relationship between autophagy and BNIP3 is widely supported in many studies. In ceramide- and arsenic trioxide- treated malignant glioma cells, increased BNIP3 expression led to mitochondrial depolarization and autophagy. [13] [14]

Autophagic cell death

Increased expression of BNIP3 has been shown to induce cell death in different ways in multiple cell lines. BNIP3 can induce classical apoptosis through cytochrome c and caspase activation in some cells, while in others, cells have undergone autophagic cell death, occurring in the absence of apaf-1, caspase-1 or caspase 3, and without cytochrome c release. [7] [15]

However, it still remains unclear if cell death is from excess autophagy itself or another mechanism. Cell death through excessive autophagy has only been shown experimentally and not in mammalian in vivo models. Kroemer and Levine believe that this name is a misnomer because cell death usually occurs with autophagy rather than by autophagy. [16]

NK cell memory formation

The innate immune system is generally not known to exhibit memory traits, but emerging research has proven otherwise. In 2017, O’Sullivan et al. found that BNIP3 and BNIP3L play a necessary role in promoting NK cell memory formation. [17] Expression of BNIP3 in NK cells is lowered upon viral infection as NK cell proliferation occurs but returns to its basal amounts by day 14 and through the contraction phase. [17] By using BNIP3-knockout mice, they found a significant decrease in surviving NK cells suggesting they are important to maintain survival of NK memory cells. [17] Additionally, by tracking mitochondria amounts and quality, they found that BNIP3 is necessary for clearing dysfunctional mitochondria with low membrane potential and reducing the build up of ROS to promote cell survival. [17] BNIP3L was also tested and was found to play a nonredundant role in cell survival. [17]

Activities in the mitochondrial membrane

Integration

Various stimuli like decreased intracellular pH, increased cytosolic calcium concentrations, and other toxic stimuli can induce BNIP3 integration into the outer mitochondrial membrane (OMM). [18] When integrated, its N-terminus remains in the cytoplasm while it stays anchored to the OMM via its C-terminal transmembrane domain (TMD). [19] The TMD is essential for targeting BNIP3 to the mitochondria, homodimerization, and pro-apoptotic function. [20] [21] [22] Its deletion results in the inability to induce autophagy. [11] Once integrated in the OMM, BNIP3 exists as an inactive monomer until activated.

Activation

Upon activation, BNIP3 can form heterodimers with BCL2 and BCL-XL and bind to itself. [15] Various conditions have been shown to induce activation and upregulation. Hypoxia has been shown to induce transcriptional upregulation of BNIP3 through an HIF1-dependent pathway in a p53-independent manner in HeLa cells, human skeletal muscle cells, and adult rat cardiomyocytes. [23]

Using BNIP3 phosphomimetics in HEK 293 cells, researchers found that phosphorylation of BNIP3's C-terminus is necessary to prevent mitochondrial damage and promote cell survival by allowing a significant amount of autophagy to occur without the induction of cell death. [7] Factors like cAMP and cGMP levels, calcium availability and growth factors like IGF and EGF can affect this kinase activity. [7]

Interactions

BNIP3 has been shown to interact with CD47, [24] BCL2-like 1 [20] and Bcl-2. [5] [20]

Related Research Articles

Programmed cell death is the death of a cell as a result of events inside of a cell, such as apoptosis or autophagy. PCD is carried out in a biological process, which usually confers advantage during an organism's lifecycle. For example, the differentiation of fingers and toes in a developing human embryo occurs because cells between the fingers apoptose; the result is that the digits are separate. PCD serves fundamental functions during both plant and animal tissue development.

<span class="mw-page-title-main">Bcl-2</span> Protein found in humans

Bcl-2, encoded in humans by the BCL2 gene, is the founding member of the Bcl-2 family of regulator proteins. BCL2 blocks programmed cell death (apoptosis) while other BCL2 family members can either inhibit or induce it. It was the first apoptosis regulator identified in any organism.

<span class="mw-page-title-main">Autophagy</span> Process of cells digesting parts of themselves

Autophagy is the natural, conserved degradation of the cell that removes unnecessary or dysfunctional components through a lysosome-dependent regulated mechanism. It allows the orderly degradation and recycling of cellular components. Although initially characterized as a primordial degradation pathway induced to protect against starvation, it has become increasingly clear that autophagy also plays a major role in the homeostasis of non-starved cells. Defects in autophagy have been linked to various human diseases, including neurodegeneration and cancer, and interest in modulating autophagy as a potential treatment for these diseases has grown rapidly.

<span class="mw-page-title-main">Bafilomycin</span> Chemical compound

The bafilomycins are a family of macrolide antibiotics produced from a variety of Streptomycetes. Their chemical structure is defined by a 16-membered lactone ring scaffold. Bafilomycins exhibit a wide range of biological activity, including anti-tumor, anti-parasitic, immunosuppressant and anti-fungal activity. The most used bafilomycin is bafilomycin A1, a potent inhibitor of cellular autophagy. Bafilomycins have also been found to act as ionophores, transporting potassium K+ across biological membranes and leading to mitochondrial damage and cell death.

<span class="mw-page-title-main">Apoptosis regulator BAX</span> Mammalian protein found in Homo sapiens

Apoptosis regulator BAX, also known as bcl-2-like protein 4, is a protein that in humans is encoded by the BAX gene. BAX is a member of the Bcl-2 gene family. BCL2 family members form hetero- or homodimers and act as anti- or pro-apoptotic regulators that are involved in a wide variety of cellular activities. This protein forms a heterodimer with BCL2, and functions as an apoptotic activator. This protein is reported to interact with, and increase the opening of, the mitochondrial voltage-dependent anion channel (VDAC), which leads to the loss in membrane potential and the release of cytochrome c. The expression of this gene is regulated by the tumor suppressor P53 and has been shown to be involved in P53-mediated apoptosis.

<span class="mw-page-title-main">BH3 interacting-domain death agonist</span> Protein-coding gene in the species Homo sapiens

The BH3 interacting-domain death agonist, or BID, gene is a pro-apoptotic member of the Bcl-2 protein family. Bcl-2 family members share one or more of the four characteristic domains of homology entitled the Bcl-2 homology (BH) domains, and can form hetero- or homodimers. Bcl-2 proteins act as anti- or pro-apoptotic regulators that are involved in a wide variety of cellular activities.

<span class="mw-page-title-main">Bcl-2 homologous antagonist killer</span> Protein-coding gene in the species Homo sapiens

Bcl-2 homologous antagonist/killer is a protein which in humans is encoded by the BAK1 gene on chromosome 6. It belongs to the BCL2 protein family. BCL2 family members form oligomers or heterodimers and act as anti- or pro-apoptotic regulators that are involved in a wide variety of cellular activities. This protein localizes to mitochondria, and functions to induce apoptosis. It interacts with and accelerates the opening of the mitochondrial voltage-dependent anion channel, which leads to a loss in membrane potential and the release of cytochrome c. This protein also interacts with the tumor suppressor P53 after exposure to cell stress.

<span class="mw-page-title-main">Bcl-2-like protein 1</span> Protein-coding gene in the species Homo sapiens

Bcl-2-like protein 1 is a protein encoded in humans by the BCL2L1 gene. Through alternative splicing, the gene encodes both of the human proteins Bcl-xL and Bcl-xS.

<span class="mw-page-title-main">Bcl-2-interacting killer</span> Protein-coding gene in the species Homo sapiens

Bcl-2-interacting killer is a protein that in humans is encoded by the BIK gene.

<span class="mw-page-title-main">BECN1</span> Protein-coding gene in the species Homo sapiens

Beclin-1 is a protein that in humans is encoded by the BECN1 gene. Beclin-1 is a mammalian ortholog of the yeast autophagy-related gene 6 (Atg6) and BEC-1 in the C. elegans nematode. This protein interacts with either BCL-2 or PI3k class III, playing a critical role in the regulation of both autophagy and cell death.

<span class="mw-page-title-main">Autophagy protein 5</span> Protein-coding gene in the species Homo sapiens

Autophagy protein 5 (ATG5) is a protein that, in humans, is encoded by the ATG5 gene located on chromosome 6. It is an E3 ubi autophagic cell death. ATG5 is a key protein involved in the extension of the phagophoric membrane in autophagic vesicles. It is activated by ATG7 and forms a complex with ATG12 and ATG16L1. This complex is necessary for LC3-I conjugation to PE (phosphatidylethanolamine) to form LC3-II. ATG5 can also act as a pro-apoptotic molecule targeted to the mitochondria. Under low levels of DNA damage, ATG5 can translocate to the nucleus and interact with survivin.

<span class="mw-page-title-main">BNIP3L</span> Protein-coding gene in the species Homo sapiens

BCL2/adenovirus E1B 19 kDa protein-interacting protein 3-like is a protein that in humans is encoded by the BNIP3L gene.

<span class="mw-page-title-main">HRK (gene)</span>

Activator of apoptosis harakiri is a protein that in humans is encoded by the HRK gene.

<span class="mw-page-title-main">BNIP2</span> Protein-coding gene in the species Homo sapiens

BCL2/adenovirus E1B 19 kDa protein-interacting protein 2 is a protein that in humans is encoded by the BNIP2 gene.

<span class="mw-page-title-main">VDAC1</span> Protein-coding gene in the species Homo sapiens

Voltage-dependent anion-selective channel 1 (VDAC-1) is a beta barrel protein that in humans is encoded by the VDAC1 gene located on chromosome 5. It forms an ion channel in the outer mitochondrial membrane (OMM) and also the outer cell membrane. In the OMM, it allows ATP to diffuse out of the mitochondria into the cytoplasm. In the cell membrane, it is involved in volume regulation. Within all eukaryotic cells, mitochondria are responsible for synthesis of ATP among other metabolite needed for cell survival. VDAC1 therefore allows for communication between the mitochondrion and the cell mediating the balance between cell metabolism and cell death. Besides metabolic permeation, VDAC1 also acts as a scaffold for proteins such as hexokinase that can in turn regulate metabolism.

<span class="mw-page-title-main">ATG12</span> Protein-coding gene in the species Homo sapiens

Autophagy related 12 is a protein that in humans is encoded by the ATG12 gene.

<span class="mw-page-title-main">BCL2L10</span> Protein-coding gene in the species Homo sapiens

Bcl-2-like protein 10 is a protein that in humans is encoded by the BCL2L10 gene.

<span class="mw-page-title-main">BNIPL</span> Protein-coding gene in the species Homo sapiens

Bcl-2/adenovirus E1B 19 kDa-interacting protein 2-like protein is a protein that in humans is encoded by the BNIPL gene.

Mitophagy is the selective degradation of mitochondria by autophagy. It often occurs to defective mitochondria following damage or stress. The process of mitophagy was first described in 1915 by Margaret Reed Lewis and Warren Harmon Lewis. Ashford and Porter used electron microscopy to observe mitochondrial fragments in liver lysosomes by 1962, and a 1977 report suggested that "mitochondria develop functional alterations which would activate autophagy." The term "mitophagy" was in use by 1998.

<span class="mw-page-title-main">AMBRA1</span> Protein-coding gene

AMBRA1 is a protein that is able to regulate cancer cells through autophagy. AMBRA1 is described as a mechanism cells use to divide and there is new evidence demonstrating the role and impact of AMBRA1 as a candidate for the treatment of several disorders and diseases, including anticancer therapy. It is known to suppress tumors and plays a role in mitophagy and apoptosis. AMBRA1 can be found in the cytoskeleton and mitochondria and during the process of autophagy, it is localized at the endoplasmic reticulum. In normal conditions, AMBRA1 is dormant and will bind to BCL2 in the outer membrane. This relocation enables autophagosome nucleation. AMBRA1 protein is involved in several cellular processes and is involved in the regulation of the immune system and nervous system.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000176171 – Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000078566 – Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. 1 2 Boyd JM, Malstrom S, Subramanian T, Venkatesh LK, Schaeper U, Elangovan B, et al. (October 1994). "Adenovirus E1B 19 kDa and Bcl-2 proteins interact with a common set of cellular proteins". Cell. 79 (2): 341–51. doi:10.1016/0092-8674(94)90202-X. PMID   7954800. S2CID   38609845.
  6. ↑ Sassone J, Colciago C, Marchi P, Ascardi C, Alberti L, Di Pardo A, et al. (January 2010). "Mutant Huntingtin induces activation of the Bcl-2/adenovirus E1B 19-kDa interacting protein (BNip3)". Cell Death & Disease. 1 (1): e7. doi:10.1038/cddis.2009.6. PMC   3032515 . PMID   21364626.
  7. 1 2 3 4 Liu KE, Frazier WA (2015-06-23). "Phosphorylation of the BNIP3 C-Terminus Inhibits Mitochondrial Damage and Cell Death without Blocking Autophagy". PLOS ONE. 10 (6): e0129667. Bibcode:2015PLoSO..1029667L. doi: 10.1371/journal.pone.0129667 . PMC   4477977 . PMID   26102349.
  8. ↑ Bocharov EV, Pustovalova YE, Pavlov KV, Volynsky PE, Goncharuk MV, Ermolyuk YS, et al. (June 2007). "Unique dimeric structure of BNip3 transmembrane domain suggests membrane permeabilization as a cell death trigger". The Journal of Biological Chemistry. 282 (22): 16256–66. doi: 10.1074/jbc.M701745200 . PMID   17412696.
  9. ↑ "Entrez Gene: BNIP3 BCL2/adenovirus E1B 19kDa interacting protein 3".
  10. ↑ Menyhárt O, Harami-Papp H, Sukumar S, Schäfer R, Magnani L, de Barrios O, Győrffy B (December 2016). "Guidelines for the selection of functional assays to evaluate the hallmarks of cancer". Biochimica et Biophysica Acta (BBA) - Reviews on Cancer. 1866 (2): 300–319. doi: 10.1016/j.bbcan.2016.10.002 . hdl: 10044/1/42912 . PMID   27742530.
  11. 1 2 3 4 Hanna RA, Quinsay MN, Orogo AM, Giang K, Rikka S, Gustafsson ÅB (June 2012). "Microtubule-associated protein 1 light chain 3 (LC3) interacts with Bnip3 protein to selectively remove endoplasmic reticulum and mitochondria via autophagy". The Journal of Biological Chemistry. 287 (23): 19094–104. doi: 10.1074/jbc.M111.322933 . PMC   3365942 . PMID   22505714.
  12. ↑ Birgisdottir ÅB, Lamark T, Johansen T (August 2013). "The LIR motif - crucial for selective autophagy". Journal of Cell Science. 126 (Pt 15): 3237–47. doi: 10.1242/jcs.126128 . PMID   23908376.
  13. ↑ Kanzawa T, Zhang L, Xiao L, Germano IM, Kondo Y, Kondo S (February 2005). "Arsenic trioxide induces autophagic cell death in malignant glioma cells by upregulation of mitochondrial cell death protein BNIP3". Oncogene. 24 (6): 980–91. doi: 10.1038/sj.onc.1208095 . PMID   15592527.
  14. ↑ Daido S, Kanzawa T, Yamamoto A, Takeuchi H, Kondo Y, Kondo S (June 2004). "Pivotal role of the cell death factor BNIP3 in ceramide-induced autophagic cell death in malignant glioma cells". Cancer Research. 64 (12): 4286–93. doi: 10.1158/0008-5472.CAN-03-3084 . PMID   15205343.
  15. 1 2 Zhang J, Ney PA (July 2009). "Role of BNIP3 and NIX in cell death, autophagy, and mitophagy". Cell Death and Differentiation. 16 (7): 939–46. doi:10.1038/cdd.2009.16. PMC   2768230 . PMID   19229244.
  16. ↑ Kroemer G, Levine B (December 2008). "Autophagic cell death: the story of a misnomer". Nature Reviews. Molecular Cell Biology. 9 (12): 1004–10. doi:10.1038/nrm2529. PMC   2727358 . PMID   18971948.
  17. 1 2 3 4 5 O'Sullivan TE, Johnson LR, Kang HH, Sun JC (August 2015). "BNIP3- and BNIP3L-Mediated Mitophagy Promotes the Generation of Natural Killer Cell Memory". Immunity. 43 (2): 331–42. doi:10.1016/j.immuni.2015.07.012. PMC   5737626 . PMID   26253785.
  18. ↑ Graham RM, Thompson JW, Wei J, Bishopric NH, Webster KA (September 2007). "Regulation of Bnip3 death pathways by calcium, phosphorylation, and hypoxia-reoxygenation". Antioxidants & Redox Signaling. 9 (9): 1309–15. doi:10.1089/ars.2007.1726. PMID   17638546.
  19. ↑ Vande Velde C, Cizeau J, Dubik D, Alimonti J, Brown T, Israels S, et al. (August 2000). "BNIP3 and genetic control of necrosis-like cell death through the mitochondrial permeability transition pore". Molecular and Cellular Biology. 20 (15): 5454–68. doi:10.1128/mcb.20.15.5454-5468.2000. PMC   85997 . PMID   10891486.
  20. 1 2 3 Ray R, Chen G, Vande Velde C, Cizeau J, Park JH, Reed JC, et al. (January 2000). "BNIP3 heterodimerizes with Bcl-2/Bcl-X(L) and induces cell death independent of a Bcl-2 homology 3 (BH3) domain at both mitochondrial and nonmitochondrial sites". The Journal of Biological Chemistry. 275 (2): 1439–48. doi: 10.1074/jbc.275.2.1439 . PMID   10625696.
  21. ↑ Chen G, Ray R, Dubik D, Shi L, Cizeau J, Bleackley RC, et al. (December 1997). "The E1B 19K/Bcl-2-binding protein Nip3 is a dimeric mitochondrial protein that activates apoptosis". The Journal of Experimental Medicine. 186 (12): 1975–83. doi:10.1084/jem.186.12.1975. PMC   2199165 . PMID   9396766.
  22. ↑ Kubli DA, Quinsay MN, Huang C, Lee Y, Gustafsson AB (November 2008). "Bnip3 functions as a mitochondrial sensor of oxidative stress during myocardial ischemia and reperfusion". American Journal of Physiology. Heart and Circulatory Physiology. 295 (5): H2025-31. doi:10.1152/ajpheart.00552.2008. PMC   2614576 . PMID   18790835.
  23. ↑ Azad MB, Chen Y, Henson ES, Cizeau J, McMillan-Ward E, Israels SJ, Gibson SB (February 2008). "Hypoxia induces autophagic cell death in apoptosis-competent cells through a mechanism involving BNIP3". Autophagy. 4 (2): 195–204. doi:10.4161/auto.5278. PMC   3164855 . PMID   18059169.
  24. ↑ Lamy L, Ticchioni M, Rouquette-Jazdanian AK, Samson M, Deckert M, Greenberg AH, Bernard A (June 2003). "CD47 and the 19 kDa interacting protein-3 (BNIP3) in T cell apoptosis". The Journal of Biological Chemistry. 278 (26): 23915–21. doi: 10.1074/jbc.M301869200 . PMID   12690108.

Further reading

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