title: Bcl-X(L) specifically activates Bak to induce swelling and restructuring of the endoplasmic reticulum.
abstract: Bcl-2 family members Bak and Bax constitute a mitochondrial gateway for multiple death pathways. Both proteins are also present in the endoplasmic reticulum where they control apoptosis through the regulation of calcium levels. We show here that reticular Bak has the additional capacity of modulating the structure of this organelle. Coexpression of Bak and Bcl-X(L) provokes extensive swelling and vacuolization of reticular cisternae. A Bak version lacking the BH3 domain suffices to induce this phenotype, and reticular targeting of this mutant retains the activity. Expression of upstream BH3-only activators in similar conditions recapitulates ER swelling and vacuolization if ryanodine receptor calcium channel activity is inhibited. Experiments with Bak and Bax-deficient mouse embryonic fibroblasts show that endogenous Bak mediates the effect, whereas Bax is mainly irrelevant. These results reveal a previously unidentified role of Bak in regulating reticular conformation. Because this activity is absent in Bax, it constitutes one of the first examples of functional divergence between the two multidomain homologues.
authors.affiliation: Centro de Investigación del Cáncer, Universidad de Salamanca-CSIC, Salamanca, 37007 Spain.
authors.forename: Martina
authors.initials: M
authors.lastname: Klee
authors.forename: Felipe X
authors.initials: FX
authors.lastname: Pimentel-Muiños
mesh_terms: D000818:Animals; D051023:BH3 Interacting Domain Death Agonist Protein; D019556:COS Cells; D002352:Carrier Proteins / Q000378:metabolism; D002522:Chlorocebus aethiops; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D017930:Genes, Reporter; D006367:HeLa Cells; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism; D014617:Vacuoles / Q000378:metabolism; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051020:bcl-X Protein
chemical_list: C494772:BAK1 protein, human; C494811:BCL2L1 protein, human; D051023:BH3 Interacting Domain Death Agonist Protein; C494814:BID protein, human; D002352:Carrier Proteins; D008565:Membrane Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D019837:Ryanodine Receptor Calcium Release Channel; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051020:bcl-X Protein
references.citation: EMBO J. 2003 Jul 15;22(14):3580-90
references.pmid: 12853473
references.citation: J Cell Biol. 2003 Jul 7;162(1):59-69
references.pmid: 12847083
references.citation: Oncogene. 2003 Nov 24;22(53):8608-18
references.pmid: 14634622
references.citation: Oncogene. 2003 Nov 24;22(53):8619-27
references.pmid: 14634623
references.citation: Cell. 2004 Jan 23;116(2):205-19
references.pmid: 14744432
references.citation: Biochem Biophys Res Commun. 2004 Mar 26;316(1):18-23
references.pmid: 15003505
references.citation: J Biol Chem. 2004 Jul 9;279(28):29247-54
references.pmid: 15075335
references.citation: Cell. 1987 Mar 13;48(5):899-907
references.pmid: 3545499
references.citation: Int J Biochem. 1991;23(1):93-9
references.pmid: 2022300
references.citation: J Cell Sci. 1993 Sep;106 ( Pt 1):249-59
references.pmid: 8270629
references.citation: Nature. 1995 Apr 20;374(6524):733-6
references.pmid: 7715730
references.citation: Science. 1995 Oct 6;270(5233):96-9
references.pmid: 7569956
references.citation: EMBO J. 1995 Nov 15;14(22):5589-96
references.pmid: 8521816
references.citation: EMBO J. 1996 Aug 15;15(16):4130-41
references.pmid: 8861942
references.citation: Proc Natl Acad Sci U S A. 1996 Dec 10;93(25):14559-63
references.pmid: 8962091
references.citation: Science. 1997 Feb 14;275(5302):983-6
references.pmid: 9020082
references.citation: Proc Natl Acad Sci U S A. 1997 Apr 15;94(8):3668-72
references.pmid: 9108035
references.citation: J Biol Chem. 1997 May 23;272(21):13829-34
references.pmid: 9153240
references.citation: Cell. 1997 Jun 13;89(6):963-71
references.pmid: 9200614
references.citation: Nature. 1997 Aug 28;388(6645):882-7
references.pmid: 9278050
references.citation: Oncogene. 1997 Oct 9;15(15):1871-5
references.pmid: 9362454
references.citation: Eur J Biochem. 1997 Oct 1;249(1):85-91
references.pmid: 9363757
references.citation: Science. 1998 Aug 28;281(5381):1309-12
references.pmid: 9721092
references.citation: Cell. 1998 Aug 21;94(4):491-501
references.pmid: 9727492
references.citation: Science. 1998 Aug 28;281(5381):1322-6
references.pmid: 9735050
references.citation: Oncogene. 1998 Dec 24;17(25):3225-36
references.pmid: 9916985
references.citation: J Cell Biol. 1999 Mar 8;144(5):891-901
references.pmid: 10085289
references.citation: J Cell Biol. 1999 Mar 8;144(5):903-14
references.pmid: 10085290
references.citation: Oncogene. 1999 Oct 7;18(41):5703-13
references.pmid: 10523849
references.citation: Science. 2003 Apr 4;300(5616):135-9
references.pmid: 12624178
references.citation: Immunity. 1999 Dec;11(6):783-93
references.pmid: 10626900
references.citation: Mol Cell Biol. 2000 Feb;20(3):929-35
references.pmid: 10629050
references.citation: Genes Dev. 2000 Aug 15;14(16):2060-71
references.pmid: 10950869
references.citation: Science. 2000 Nov 3;290(5493):989-92
references.pmid: 11062132
references.citation: Cell. 2000 Nov 10;103(4):645-54
references.pmid: 11106734
references.citation: Int J Mol Med. 2001 Jan;7(1):21-5
references.pmid: 11115603
references.citation: Mol Cell. 2000 Dec;6(6):1389-99
references.pmid: 11163212
references.citation: J Biol Chem. 2001 Apr 27;276(17):13810-6
references.pmid: 11278295
references.citation: Science. 2001 Apr 27;292(5517):727-30
references.pmid: 11326099
references.citation: Genes Dev. 2001 Jun 15;15(12):1481-6
references.pmid: 11410528
references.citation: J Biol Chem. 2001 Sep 7;276(36):34307-17
references.pmid: 11447222
references.citation: Mol Cell. 2001 Sep;8(3):705-11
references.pmid: 11583631
references.citation: J Exp Med. 2001 Nov 5;194(9):1325-37
references.pmid: 11696597
references.citation: J Biol Chem. 2002 Mar 15;277(11):9219-25
references.pmid: 11741880
references.citation: J Cell Sci. 2002 Apr 15;115(Pt 8):1567-74
references.pmid: 11950875
references.citation: Cancer Res. 2002 Jun 15;62(12):3373-6
references.pmid: 12067977
references.citation: Anat Histol Embryol. 2002 Aug;31(4):214-23
references.pmid: 12196263
references.citation: Cancer Cell. 2002 Sep;2(3):183-92
references.pmid: 12242151
references.citation: Physiol Rev. 2002 Oct;82(4):893-922
references.pmid: 12270947
references.citation: Oncogene. 2003 Nov 24;22(53):8590-607
references.pmid: 14634621