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PMID: 19229244 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Review

Role of BNIP3 and NIX in cell death, autophagy, and mitophagy.

Cell death and differentiation ·Vol. 16 ·No. 7 ·2009-07-00 ·Pages 939-46

Zhang J, Ney PA

Abstract

BNIP3 and NIX are proteins related to the BH3-only family, which induce both cell death and autophagy. Consistent with their ability to induce cell death, BNIP3 and NIX are implicated in the pathogenesis of cancer and heart disease. In tumor cells, BNIP3 and NIX are regulated by hypoxia, and the deregulation of BNIP3 or NIX expression is associated with tumor growth. In heart muscle, BNIP3 and NIX are regulated by hypoxia and Galphaq-dependent signaling, respectively, and their expression is associated with decreased myocardial function. Apart from their role in cell death, BNIP3 and NIX are also implicated in the induction of autophagy. In erythroid cells, NIX is required for a specialized type of autophagy that targets mitochondria for elimination (mitophagy). Similarly, BNIP3 regulates mitophagy in response to hypoxia. In this review, we will discuss possible mechanisms by which BNIP3 and NIX induce cell death and mitophagy. We will also consider the potential relationship between cell death pathways and autophagy in development and homeostasis.

MeSH Terms
Animals Autophagy/physiology Cell Death/physiology Cell Hypoxia/physiology Heart Diseases/metabolism Humans Membrane Proteins/genetics,metabolism Mice Mitochondria/physiology Mitochondrial Proteins/genetics,metabolism Neoplasms/metabolism Protein Structure, Tertiary Proto-Oncogene Proteins/genetics,metabolism Rats Tumor Suppressor Proteins/genetics,metabolism
Chemicals
BNIP3 protein, human BNIP3L protein, human BNip3 protein, mouse Membrane Proteins Mitochondrial Proteins Nix protein, mouse Proto-Oncogene Proteins Tumor Suppressor Proteins
Authors & Affiliations
2 authors, click to expand affiliations / ORCID
Zhang J
Department of Biochemistry, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38117-3678, USA.
Ney P A
References (82)
82 references, click to expand
  1. Unrestrained erythroblast development in Nix-/- mice reveals a mechanism for apoptotic modulation of erythropoiesis.
    Proc Natl Acad Sci U S A. 2007 Apr 17;104(16):6794-9 PMID: 17420462
  2. Protection against fatal Sindbis virus encephalitis by beclin, a novel Bcl-2-interacting protein.
    J Virol. 1998 Nov;72(11):8586-96 PMID: 9765397
  3. Fission and selective fusion govern mitochondrial segregation and elimination by autophagy.
    EMBO J. 2008 Jan 23;27(2):433-46 PMID: 18200046
  4. The role of Bcl-2 family member BNIP3 in cell death and disease: NIPping at the heels of cell death.
    Cell Death Differ. 2009 Apr;16(4):515-23 PMID: 19136941
  5. NIX induces mitochondrial autophagy in reticulocytes.
    Autophagy. 2008 Apr;4(3):354-6 PMID: 18623629
  6. Analysis of the candidate 8p21 tumour suppressor, BNIP3L, in breast and ovarian cancer.
    Br J Cancer. 2003 Jan 27;88(2):270-6 PMID: 12610513
  7. The adenovirus E1A proteins induce apoptosis, which is inhibited by the E1B 19-kDa and Bcl-2 proteins.
    Proc Natl Acad Sci U S A. 1992 Aug 15;89(16):7742-6 PMID: 1457005
  8. The role of autophagy in mammalian development: cell makeover rather than cell death.
    Dev Cell. 2008 Sep;15(3):344-357 PMID: 18804433
  9. The carboxy terminal C-tail of BNip3 is crucial in induction of mitochondrial permeability transition in isolated mitochondria.
    Arch Biochem Biophys. 2002 Feb 15;398(2):147-52 PMID: 11831844
  10. Phylogenomics of life-or-death switches in multicellular animals: Bcl-2, BH3-Only, and BNip families of apoptotic regulators.
    Mol Biol Evol. 2005 Dec;22(12):2395-416 PMID: 16093567
  11. Adenovirus E1B 19 kDa and Bcl-2 proteins interact with a common set of cellular proteins.
    Cell. 1994 Oct 21;79(2):341-51 PMID: 7954800
  12. HIF-1-dependent regulation of hypoxic induction of the cell death factors BNIP3 and NIX in human tumors.
    Cancer Res. 2001 Sep 15;61(18):6669-73 PMID: 11559532
  13. The BH3 mimetic ABT-737 targets selective Bcl-2 proteins and efficiently induces apoptosis via Bak/Bax if Mcl-1 is neutralized.
    Cancer Cell. 2006 Nov;10(5):389-99 PMID: 17097561
  14. Promotion of tumorigenesis by heterozygous disruption of the beclin 1 autophagy gene.
    J Clin Invest. 2003 Dec;112(12):1809-20 PMID: 14638851
  15. Unique dimeric structure of BNip3 transmembrane domain suggests membrane permeabilization as a cell death trigger.
    J Biol Chem. 2007 Jun 1;282(22):16256-66 PMID: 17412696
  16. Sequence-specific dimerization of the transmembrane domain of the "BH3-only" protein BNIP3 in membranes and detergent.
    J Biol Chem. 2003 Dec 19;278(51):51950-6 PMID: 14532263
  17. Arsenic trioxide induces autophagic cell death in malignant glioma cells by upregulation of mitochondrial cell death protein BNIP3.
    Oncogene. 2005 Feb 3;24(6):980-91 PMID: 15592527
  18. FoxO3a regulates erythroid differentiation and induces BTG1, an activator of protein arginine methyl transferase 1.
    J Cell Biol. 2004 Jan 19;164(2):175-84 PMID: 14734530
  19. The C. elegans orthologue ceBNIP3 interacts with CED-9 and CED-3 but kills through a BH3- and caspase-independent mechanism.
    Oncogene. 2000 Nov 16;19(48):5453-63 PMID: 11114722
  20. Cytoplasmic components in hepatic cell lysosomes.
    J Cell Biol. 1962 Jan;12:198-202 PMID: 13862833
  21. Mitochondrial autophagy is an HIF-1-dependent adaptive metabolic response to hypoxia.
    J Biol Chem. 2008 Apr 18;283(16):10892-903 PMID: 18281291
  22. Ulk1 plays a critical role in the autophagic clearance of mitochondria and ribosomes during reticulocyte maturation.
    Blood. 2008 Aug 15;112(4):1493-502 PMID: 18539900
  23. Inhibition of ischemic cardiomyocyte apoptosis through targeted ablation of Bnip3 restrains postinfarction remodeling in mice.
    J Clin Invest. 2007 Oct;117(10):2825-33 PMID: 17909626
  24. Cellular differentiation in the kidneys of newborn mice studies with the electron microscope.
    J Biophys Biochem Cytol. 1957 May 25;3(3):349-62 PMID: 13438920
  25. Bcl-2 decreases the free Ca2+ concentration within the endoplasmic reticulum.
    Proc Natl Acad Sci U S A. 2000 May 23;97(11):5723-8 PMID: 10823933
  26. Isolation, mapping, and functional analysis of a novel human cDNA (BNIP3L) encoding a protein homologous to human NIP3.
    Genes Chromosomes Cancer. 1998 Mar;21(3):230-5 PMID: 9523198
  27. Maturation of the reticulocyte in vitro.
    J Cell Sci. 1984 Oct;71:177-97 PMID: 6097593
  28. Proapoptotic BH3-only Bcl-2 family members induce cytochrome c release, but not mitochondrial membrane potential loss, and do not directly modulate voltage-dependent anion channel activity.
    Proc Natl Acad Sci U S A. 2000 Jan 18;97(2):577-82 PMID: 10639121
  29. Bax and Bak promote apoptosis by modulating endoplasmic reticular and mitochondrial Ca2+ stores.
    J Biol Chem. 2002 Mar 15;277(11):9219-25 PMID: 11741880
  30. Inducible expression of BNIP3 provokes mitochondrial defects and hypoxia-mediated cell death of ventricular myocytes.
    Circ Res. 2002 Aug 9;91(3):226-31 PMID: 12169648
  31. Adenovirus E1B-19K/BCL-2 interacting protein BNIP3 contains a BH3 domain and a mitochondrial targeting sequence.
    J Biol Chem. 1998 May 15;273(20):12415-21 PMID: 9575197
  32. Loss of cyclophilin D reveals a critical role for mitochondrial permeability transition in cell death.
    Nature. 2005 Mar 31;434(7033):658-62 PMID: 15800627
  33. Autophagy: molecular machinery for self-eating.
    Cell Death Differ. 2005 Nov;12 Suppl 2:1542-52 PMID: 16247502
  34. Bnip3L is induced by p53 under hypoxia, and its knockdown promotes tumor growth.
    Cancer Cell. 2004 Dec;6(6):597-609 PMID: 15607964
  35. Functional and physical interaction between Bcl-X(L) and a BH3-like domain in Beclin-1.
    EMBO J. 2007 May 16;26(10):2527-39 PMID: 17446862
  36. Regulation of apoptosis by a Caenorhabditis elegans BNIP3 homolog.
    Oncogene. 1998 Nov 12;17(19):2525-30 PMID: 9824163
  37. Molecular basis of Bcl-xL's target recognition versatility revealed by the structure of Bcl-xL in complex with the BH3 domain of Beclin-1.
    J Mol Biol. 2007 Sep 7;372(1):223-35 PMID: 17659302
  38. 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.
    Oncogene. 1999 Aug 12;18(32):4523-9 PMID: 10467396
  39. The E1B 19K/Bcl-2-binding protein Nip3 is a dimeric mitochondrial protein that activates apoptosis.
    J Exp Med. 1997 Dec 15;186(12):1975-83 PMID: 9396766
  40. Bnip3 functions as a mitochondrial sensor of oxidative stress during myocardial ischemia and reperfusion.
    Am J Physiol Heart Circ Physiol. 2008 Nov;295(5):H2025-31 PMID: 18790835
  41. Crystal structure of the Bcl-XL-Beclin 1 peptide complex: Beclin 1 is a novel BH3-only protein.
    J Biol Chem. 2007 Apr 27;282(17):13123-32 PMID: 17337444
  42. Hierarchical regulation of mitochondrion-dependent apoptosis by BCL-2 subfamilies.
    Nat Cell Biol. 2006 Dec;8(12):1348-58 PMID: 17115033
  43. The mitochondrial permeability transition initiates autophagy in rat hepatocytes.
    FASEB J. 2001 Oct;15(12):2286-7 PMID: 11511528
  44. Response to myocardial ischemia/reperfusion injury involves Bnip3 and autophagy.
    Cell Death Differ. 2007 Jan;14(1):146-57 PMID: 16645637
  45. BNIP3 is an RB/E2F target gene required for hypoxia-induced autophagy.
    Mol Cell Biol. 2007 Sep;27(17):6229-42 PMID: 17576813
  46. Bcl-2 antiapoptotic proteins inhibit Beclin 1-dependent autophagy.
    Cell. 2005 Sep 23;122(6):927-39 PMID: 16179260
  47. Hypoxia and acidosis activate cardiac myocyte death through the Bcl-2 family protein BNIP3.
    Proc Natl Acad Sci U S A. 2002 Oct 1;99(20):12825-30 PMID: 12226479
  48. Selective degradation of mitochondria by mitophagy.
    Arch Biochem Biophys. 2007 Jun 15;462(2):245-53 PMID: 17475204
  49. NIX is required for programmed mitochondrial clearance during reticulocyte maturation.
    Proc Natl Acad Sci U S A. 2007 Dec 4;104(49):19500-5 PMID: 18048346
  50. FoxO3 controls autophagy in skeletal muscle in vivo.
    Cell Metab. 2007 Dec;6(6):458-71 PMID: 18054315
  51. Sequence dependence of BNIP3 transmembrane domain dimerization implicates side-chain hydrogen bonding and a tandem GxxxG motif in specific helix-helix interactions.
    J Mol Biol. 2006 Dec 15;364(5):974-90 PMID: 17049556
  52. Hypoxia induces the expression of the pro-apoptotic gene BNIP3.
    Cell Death Differ. 2001 Apr;8(4):367-76 PMID: 11550088
  53. Transmembrane glycine zippers: physiological and pathological roles in membrane proteins.
    Proc Natl Acad Sci U S A. 2005 Oct 4;102(40):14278-83 PMID: 16179394
  54. cyt gene of adenoviruses 2 and 5 is an oncogene for transforming function in early region E1B and encodes the E1B 19,000-molecular-weight polypeptide.
    J Virol. 1984 Dec;52(3):793-805 PMID: 6492262
  55. Pivotal role of the cell death factor BNIP3 in ceramide-induced autophagic cell death in malignant glioma cells.
    Cancer Res. 2004 Jun 15;64(12):4286-93 PMID: 15205343
  56. Beclin 1, an autophagy gene essential for early embryonic development, is a haploinsufficient tumor suppressor.
    Proc Natl Acad Sci U S A. 2003 Dec 9;100(25):15077-82 PMID: 14657337
  57. Endoplasmic reticulum-mitochondria crosstalk in NIX-mediated murine cell death.
    J Clin Invest. 2009 Jan;119(1):203-12 PMID: 19065046
  58. Surface area and volume changes during maturation of reticulocytes in the circulation of the baboon.
    J Lab Clin Med. 1997 May;129(5):527-35 PMID: 9142049
  59. Acidosis regulates the stability, hydrophobicity, and activity of the BH3-only protein Bnip3.
    Antioxid Redox Signal. 2006 Sep-Oct;8(9-10):1625-34 PMID: 16987017
  60. Bcl-2-family proteins: the role of the BH3 domain in apoptosis.
    Trends Cell Biol. 1998 Aug;8(8):324-30 PMID: 9704409
  61. Nix-mediated apoptosis links myocardial fibrosis, cardiac remodeling, and hypertrophy decompensation.
    Circulation. 2008 Jan 22;117(3):396-404 PMID: 18178777
  62. BAX and BAK regulation of endoplasmic reticulum Ca2+: a control point for apoptosis.
    Science. 2003 Apr 4;300(5616):135-9 PMID: 12624178
  63. Macroautophagy is required for multicellular development of the social amoeba Dictyostelium discoideum.
    J Biol Chem. 2003 May 16;278(20):17636-45 PMID: 12626495
  64. Bnip3 mediates mitochondrial dysfunction and cell death through Bax and Bak.
    Biochem J. 2007 Aug 1;405(3):407-15 PMID: 17447897
  65. Genetic studies with tumorigenic adenoviruses. I. Isolation of cytocidal (cyt) mutants of adenovirus type 12.
    Virology. 1968 Dec;36(4):575-86 PMID: 5723670
  66. Membrane assembly and remodeling during reticulocyte maturation.
    Blood. 1989 Aug 15;74(3):1112-20 PMID: 2752157
  67. Distinct pathways regulate proapoptotic Nix and BNip3 in cardiac stress.
    J Biol Chem. 2006 Jan 20;281(3):1442-8 PMID: 16291751
  68. BNIP3 and genetic control of necrosis-like cell death through the mitochondrial permeability transition pore.
    Mol Cell Biol. 2000 Aug;20(15):5454-68 PMID: 10891486
  69. Bax and adenine nucleotide translocator cooperate in the mitochondrial control of apoptosis.
    Science. 1998 Sep 25;281(5385):2027-31 PMID: 9748162
  70. 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.
    J Biol Chem. 2000 Jan 14;275(2):1439-48 PMID: 10625696
  71. A novel adenovirus E1B19K-binding protein B5 inhibits apoptosis induced by Nip3 by forming a heterodimer through the C-terminal hydrophobic region.
    Cell Death Differ. 1999 Apr;6(4):314-25 PMID: 10381623
  72. Functional substitution identifies a cell survival promoting domain common to adenovirus E1B 19 kDa and Bcl-2 proteins.
    Oncogene. 1995 Dec 7;11(11):2403-9 PMID: 8570192
  73. In vitro maturation of nascent reticulocytes to erythrocytes.
    Blood. 2005 Mar 1;105(5):2168-74 PMID: 15528310
  74. Foxo3 is required for the regulation of oxidative stress in erythropoiesis.
    J Clin Invest. 2007 Aug;117(8):2133-44 PMID: 17671650
  75. Expression of the gene encoding the proapoptotic Nip3 protein is induced by hypoxia.
    Proc Natl Acad Sci U S A. 2000 Aug 1;97(16):9082-7 PMID: 10922063
  76. Autophagy of mitochondria in rat bone marrow erythroid cells. Relation to nuclear extrusion.
    Cell Tissue Res. 1985;239(1):235-9 PMID: 3967280
  77. The proapoptotic factor Nix is coexpressed with Bcl-xL during terminal erythroid differentiation.
    Blood. 2003 Jul 15;102(2):712-7 PMID: 12663450
  78. Silencing of the hypoxia-inducible cell death protein BNIP3 in pancreatic cancer.
    Cancer Res. 2004 Aug 1;64(15):5338-46 PMID: 15289340
  79. Essential role for Nix in autophagic maturation of erythroid cells.
    Nature. 2008 Jul 10;454(7201):232-5 PMID: 18454133
  80. Nix and Nip3 form a subfamily of pro-apoptotic mitochondrial proteins.
    J Biol Chem. 1999 Jan 1;274(1):7-10 PMID: 9867803
  81. Mitochondrial death protein Nix is induced in cardiac hypertrophy and triggers apoptotic cardiomyopathy.
    Nat Med. 2002 Jul;8(7):725-30 PMID: 12053174
  82. Control of autophagy by oncogenes and tumor suppressor genes.
    Cell Death Differ. 2009 Jan;16(1):87-93 PMID: 18806760
Article Info
Journal
Cell death and differentiation
Abbr.
Cell Death Differ
ISSN
1476-5403
DOI
10.1038/cdd.2009.16
Published
2009-07-00
Epub
2009-00-20
Pages
939-46
Language
English
Region
England
NLM ID
9437445
PMCID
PMC2768230
Subset
IM
Grants
NIDDK NIH HHS · R21 DK074519 · United States
NIDDK NIH HHS · R21 DK074519-01 · United States
NIDDK NIH HHS · R21 DK074519-02 · United States
External Links
PubMed source DOI: 10.1038/cdd.2009.16 PMC Full Text View journal details
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