Apoptosis regulator BAX explained

Apoptosis regulator BAX, also known as bcl-2-like protein 4, is a protein that in humans is encoded by the BAX gene.^[1] 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.^[2]

Structure

The BAX gene was the first identified pro-apoptotic member of the Bcl-2 protein family.^[3] Bcl-2 family members share one or more of the four characteristic domains of homology entitled the Bcl-2 homology (BH) domains (named BH1, BH2, BH3 and BH4), and can form hetero- or homodimers.^[3] These domains are composed of nine α-helices, with a hydrophobic α-helix core surrounded by amphipathic helices and a transmembrane C-terminal α-helix anchored to the mitochondrial outer membrane (MOM). A hydrophobic groove formed along the C-terminal of α2 to the N-terminal of α5, and some residues from α8, binds the BH3 domain of other BAX or BCL-2 proteins in its active form. In the protein's inactive form, the groove binds its transmembrane domain, transitioning it from a membrane-bound to a cytosolic protein. A smaller hydrophobic groove formed by the α1 and α6 helices is located on the opposite side of the protein from the major groove, and may serve as a BAX activation site.^[4]

Orthologs of the BAX gene have been identified in most mammals for which complete genome data are available.^[5]

Function

In healthy mammalian cells, the majority of BAX is found in the cytosol, but upon initiation of apoptotic signaling, Bax undergoes a conformational shift. Upon induction of apoptosis, BAX becomes organelle membrane-associated, and in particular, mitochondrial membrane associated.^{[6] [7] [8] [9] [10]}

BAX is believed to interact with, and induce the opening of the mitochondrial voltage-dependent anion channel, VDAC.^[11] Alternatively, growing evidence also suggests that activated BAX and/or Bak form an oligomeric pore, MAC in the MOM (mitochondrial outer membrane).^{[12] [13]} This results in the release of cytochrome c and other pro-apoptotic factors from the mitochondria, often referred to as mitochondrial outer membrane permeabilization, leading to activation of caspases.^[14] This defines a direct role for BAX in mitochondrial outer membrane permeabilization. BAX activation is stimulated by various abiotic factors, including heat, hydrogen peroxide, low or high pH, and mitochondrial membrane remodeling. In addition, it can become activated by binding BCL-2, as well as non-BCL-2 proteins such as p53 and Bif-1. Conversely, BAX can become inactivated by interacting with VDAC2, Pin1, and IBRDC2.^[4]

Clinical significance

The expression of BAX is upregulated by the tumor suppressor protein p53, and BAX has been shown to be involved in p53-mediated apoptosis. The p53 protein is a transcription factor that, when activated as part of the cell's response to stress, regulates many downstream target genes, including BAX. Wild-type p53 has been demonstrated to upregulate the transcription of a chimeric reporter plasmid utilizing the consensus promoter sequence of BAX approximately 50-fold over mutant p53. Thus it is likely that p53 promotes BAX's apoptotic faculties in vivo as a primary transcription factor. However, p53 also has a transcription-independent role in apoptosis. In particular, p53 interacts with BAX, promoting its activation as well as its insertion into the mitochondrial membrane.^{[15] [16] [17]}

Drugs that activate BAX, such as ABT-737, a BH3 mimetic, hold promise as anticancer treatments by inducing apoptosis in cancer cells.^[4] For instance, binding of HA-BAD to BCL-xL and concomitant disruption of BAX:BCL-xL interaction was found to partly reverse paclitaxel resistance in human ovarian cancer cells.^[18] Meanwhile, excessive apoptosis in such conditions as ischemia reperfusion injury and amyotrophic lateral sclerosis may benefit from drug inhibitors of BAX.^[4]

Interactions

Bcl-2-associated X protein has been shown to interact with:

• Bcl-2,^{[19] [20] [21] [22]}
• BCL2L1,^{[23] [24]}
• BCL2A1^[25]
• SH3GLB1,^[26]
• SLC25A4,^[27]
• VDAC1,
• TCTP,^[28]
• YWHAQ,^[29]
• Bid,
• Bim,
• Puma,
• Noxa,
• Mfn2,^[30]
• cholesterol,^[31] and
• cardiolipin.

See also

• Apoptosis
• Apoptosome
• Bcl-2
• BH3 interacting domain death agonist (BID)
• Caspases
• Cytochrome c
• Noxa
• Mitochondrion
• p53 upregulated modulator of apoptosis (PUMA)

Notes and References

1. Web site: UniProt . www.uniprot.org . 30 April 2023.
2. Web site: Entrez Gene: BCL2-associated X protein .
3. Oltvai ZN, Milliman CL, Korsmeyer SJ . Bcl-2 heterodimerizes in vivo with a conserved homolog, Bax, that accelerates programmed cell death . Cell . 74 . 4 . 609–19 . August 1993. 8358790 . 10.1016/0092-8674(93)90509-O . 31151334 .
4. Westphal. D. Kluck. RM. Dewson. G. Building blocks of the apoptotic pore: how Bax and Bak are activated and oligomerize during apoptosis.. Cell Death & Differentiation. February 2014. 21. 2. 196–205. 24162660. 10.1038/cdd.2013.139. 3890949.
5. Web site: OrthoMaM phylogenetic marker: BAX coding sequence . 20 December 2009 . https://web.archive.org/web/20150924061906/http://www.orthomam.univ-montp2.fr/orthomam/data/cds/detailMarkers/ENSG00000087088_BAX.xml . 24 September 2015 . dead .
6. Gross A, Jockel J, Wei MC, Korsmeyer SJ . Enforced dimerization of BAX results in its translocation, mitochondrial dysfunction and apoptosis . EMBO J. . 17 . 14 . 3878–85 . July 1998. 9670005 . 1170723 . 10.1093/emboj/17.14.3878 .
7. Hsu YT, Wolter KG, Youle RJ . Cytosol-to-membrane redistribution of Bax and Bcl-X(L) during apoptosis . Proc. Natl. Acad. Sci. U.S.A. . 94 . 8 . 3668–72 . April 1997. 9108035 . 20498 . 10.1073/pnas.94.8.3668 . 1997PNAS...94.3668H . free .
8. Nechushtan A, Smith CL, Hsu YT, Youle RJ . Conformation of the Bax C-terminus regulates subcellular location and cell death . EMBO J. . 18 . 9 . 2330–41 . May 1999. 10228148 . 1171316 . 10.1093/emboj/18.9.2330 .
9. Pierrat B, Simonen M, Cueto M, Mestan J, Ferrigno P, Heim J . SH3GLB, a new endophilin-related protein family featuring an SH3 domain . Genomics . 71 . 2 . 222–34 . January 2001. 11161816 . 10.1006/geno.2000.6378 .
10. Wolter KG, Hsu YT, Smith CL, Nechushtan A, Xi XG, Youle RJ . Movement of Bax from the cytosol to mitochondria during apoptosis . J. Cell Biol. . 139 . 5 . 1281–92 . December 1997. 9382873 . 2140220 . 10.1083/jcb.139.5.1281 .
11. Shi Y, Chen J, Weng C, Chen R, Zheng Y, Chen Q, Tang H . Identification of the protein–protein contact site and interaction mode of human VDAC1 with Bcl-2 family proteins . Biochem. Biophys. Res. Commun. . 305 . 4 . 989–96 . June 2003. 12767928 . 10.1016/S0006-291X(03)00871-4 .
12. Buytaert E, Callewaert G, Vandenheede JR, Agostinis P . Deficiency in apoptotic effectors Bax and Bak reveals an autophagic cell death pathway initiated by photodamage to the endoplasmic reticulum . Autophagy . 2 . 3 . 238–40 . 2006 . 16874066 . 10.4161/auto.2730 . free .
13. McArthur. Kate. Whitehead. Lachlan W.. Heddleston. John M.. Li. Lucy. Padman. Benjamin S.. Oorschot. Viola. Geoghegan. Niall D.. Chappaz. Stephane. Davidson. Sophia. San Chin. Hui. Lane. Rachael M.. Dramicanin. Marija. Saunders. Tahnee L.. Sugiana. Canny. Lessene. Romina. Osellame. Laura D.. Chew. Teng-Leong. Dewson. Grant. Lazarou. Michael. Ramm. Georg. Lessene. Guillaume. Ryan. Michael T.. Rogers. Kelly L.. van Delft. Mark F.. Kile. Benjamin T.. BAK/BAX macropores facilitate mitochondrial herniation and mtDNA efflux during apoptosis. Science. 22 February 2018. 359. 6378. eaao6047. 10.1126/science.aao6047. 29472455. free.
14. Weng C, Li Y, Xu D, Shi Y, Tang H . Specific cleavage of Mcl-1 by caspase-3 in tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis in Jurkat leukemia T cells . J. Biol. Chem. . 280 . 11 . 10491–500 . March 2005. 15637055 . 10.1074/jbc.M412819200 . free .
15. Miyashita T, Krajewski S, Krajewska M, Wang HG, Lin HK, Liebermann DA, Hoffman B, Reed JC . Tumor suppressor p53 is a regulator of bcl-2 and bax gene expression in vitro and in vivo . Oncogene . 9 . 6 . 1799–805 . June 1994. 8183579 .
16. Selvakumaran M, Lin HK, Miyashita T, Wang HG, Krajewski S, Reed JC, Hoffman B, Liebermann D . Immediate early up-regulation of bax expression by p53 but not TGF beta 1: a paradigm for distinct apoptotic pathways . Oncogene . 9 . 6 . 1791–8 . June 1994. 8183578 .
17. Miyashita T, Reed JC . Tumor suppressor p53 is a direct transcriptional activator of the human bax gene . Cell . 80 . 2 . 293–9 . January 1995. 7834749 . 10.1016/0092-8674(95)90412-3 . 14495370 . free .
18. Strobel T, Tai YT, Korsmeyer S, Cannistra SA . BAD partly reverses paclitaxel resistance in human ovarian cancer cells . Oncogene . 17 . 19 . 2419–27 . November 1998. 9824152 . 10.1038/sj.onc.1202180 . 44240363 .
19. Sedlak TW, Oltvai ZN, Yang E, Wang K, Boise LH, Thompson CB, Korsmeyer SJ . Multiple Bcl-2 family members demonstrate selective dimerizations with Bax . Proc. Natl. Acad. Sci. U.S.A. . 92 . 17 . 7834–8 . August 1995 . 7644501 . 41240 . 10.1073/pnas.92.17.7834 . 1995PNAS...92.7834S . free .
20. Hoetelmans RW . Nuclear partners of Bcl-2: Bax and PML . DNA Cell Biol. . 23 . 6 . 351–4 . 2004 . 15231068 . 10.1089/104454904323145236 .
21. Lin B, Kolluri SK, Lin F, Liu W, Han YH, Cao X, Dawson MI, Reed JC, Zhang XK . Conversion of Bcl-2 from protector to killer by interaction with nuclear orphan receptor Nur77/TR3 . Cell . 116 . 4 . 527–40 . 2004 . 14980220 . 10.1016/S0092-8674(04)00162-X . 17808479 . free .
22. Komatsu K, Miyashita T, Hang H, Hopkins KM, Zheng W, Cuddeback S, Yamada M, Lieberman HB, Wang HG . Human homologue of S. pombe Rad9 interacts with BCL-2/BCL-xL and promotes apoptosis . Nat. Cell Biol. . 2 . 1 . 1–6 . 2000 . 10620799 . 10.1038/71316 . 52847351 .
23. Zhang H, Nimmer P, Rosenberg SH, Ng SC, Joseph M . Development of a high-throughput fluorescence polarization assay for Bcl-x(L) . Anal. Biochem. . 307 . 1 . 70–5 . 2002 . 12137781 . 10.1016/S0003-2697(02)00028-3 .
24. Gillissen B, Essmann F, Graupner V, Stärck L, Radetzki S, Dörken B, Schulze-Osthoff K, Daniel PT . Induction of cell death by the BH3-only Bcl-2 homolog Nbk/Bik is mediated by an entirely Bax-dependent mitochondrial pathway . EMBO J. . 22 . 14 . 3580–90 . 2003 . 12853473 . 165613 . 10.1093/emboj/cdg343 .
25. Zhang H, Cowan-Jacob SW, Simonen M, Greenhalf W, Heim J, Meyhack B . Structural basis of BFL-1 for its interaction with BAX and its anti-apoptotic action in mammalian and yeast cells . J. Biol. Chem. . 275 . 15 . 11092–9 . 2000 . 10753914 . 10.1074/jbc.275.15.11092 . free .
26. Cuddeback SM, Yamaguchi H, Komatsu K, Miyashita T, Yamada M, Wu C, Singh S, Wang HG . Molecular cloning and characterization of Bif-1. A novel Src homology 3 domain-containing protein that associates with Bax . J. Biol. Chem. . 276 . 23 . 20559–65 . 2001 . 11259440 . 10.1074/jbc.M101527200 . free .
27. Marzo I, Brenner C, Zamzami N, Jürgensmeier JM, Susin SA, Vieira HL, Prévost MC, Xie Z, Matsuyama S, Reed JC, Kroemer G . Bax and adenine nucleotide translocator cooperate in the mitochondrial control of apoptosis . Science . 281 . 5385 . 2027–31 . 1998 . 9748162 . 10.1126/science.281.5385.2027 . 1998Sci...281.2027M .
28. Susini L . TCTP protects from apoptotic cell death by antagonizing bax function . Cell Death Differ . 15. 8 . 1211–20 . August 2008 . 18274553 . 10.1038/cdd.2008.18 . etal. free .
29. Nomura M, Shimizu S, Sugiyama T, Narita M, Ito T, Matsuda H, Tsujimoto Y . 14-3-3 Interacts directly with and negatively regulates pro-apoptotic Bax . J. Biol. Chem. . 278 . 3 . 2058–65 . 2003 . 12426317 . 10.1074/jbc.M207880200 . free .
30. Hoppins . Suzanne . Edlich . Frank . Cleland . Megan M. . Banerjee . Soojay . McCaffery . J. Michael . Youle . Richard J. . Nunnari . Jodi . The Soluble Form of Bax Regulates Mitochondrial Fusion via MFN2 Homotypic Complexes . Molecular Cell . 41 . 2 . 150–160 . 10.1016/j.molcel.2010.11.030 . 3072068 . 21255726. 2011 .
31. Mignard . V . Lalier . L . Paris . F . Vallette . FM . Bioactive lipids and the control of Bax pro-apoptotic activity. . Cell Death & Disease . 29 May 2014 . 5 . 5 . e1266 . 24874738 . 10.1038/cddis.2014.226 . 4047880.