title: The cell death protease Kex1p is essential for hypochlorite-induced apoptosis in yeast.
abstract: Following microbial pathogen invasion, the human immune system of activated phagocytes generates and releases the potent oxidant hypochlorous acid (HOCl), which contributes to the killing of menacing microorganisms. Though tightly controlled, HOCl generation by the myeloperoxidase-hydrogen peroxide-chloride system of neutrophils/monocytes may occur in excess and lead to tissue damage. It is thus of marked importance to delineate the molecular pathways underlying HOCl cytotoxicity in both microbial and human cells. Here, we show that HOCl induces the generation of reactive oxygen species (ROS), apoptotic cell death and the formation of specific HOCl-modified epitopes in the budding yeast Saccharomyces cerevisiae. Interestingly, HOCl cytotoxicity can be prevented by treatment with ROS scavengers, suggesting oxidative stress to mediate the lethal effect. The executing pathway involves the pro-apoptotic protease Kex1p, since its absence diminishes HOCl-induced production of ROS, apoptosis and protein modification. By characterizing HOCl-induced cell death in yeast and identifying a corresponding central executor, these results pave the way for the use of Saccharomyces cerevisiae in HOCl research, not least given that it combines both being a microorganism as well as a model for programmed cell death in higher eukaryotes.
authors: Institute of Molecular Biosciences, University of Graz, Graz, Austria.
authors: Didac
authors: D
authors: Carmona-Gutierrez
authors: Ali
authors: A
authors: Alavian-Ghavanini
authors: Lukas
authors: L
authors: Habernig
authors: Maria Anna
authors: MA
authors: Bauer
authors: Astrid
authors: A
authors: Hammer
authors: Christine
authors: C
authors: Rossmann
authors: Andreas S
authors: AS
authors: Zimmermann
authors: Christoph
authors: C
authors: Ruckenstuhl
authors: Sabrina
authors: S
authors: Büttner
authors: Tobias
authors: T
authors: Eisenberg
authors: Wolfgang
authors: W
authors: Sattler
authors: Ernst
authors: E
authors: Malle
authors: Frank
authors: F
authors: Madeo
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D002268:Carboxypeptidases / Q000378:metabolism*; D000939:Epitopes / Q000737:chemistry / Q000378:metabolism; D006997:Hypochlorous Acid / Q000633:toxicity*; D010766:Phosphorylation; D017382:Reactive Oxygen Species / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000378:metabolism*
chemical_list: D000939:Epitopes; D017382:Reactive Oxygen Species; D006997:Hypochlorous Acid; D002268:Carboxypeptidases; C078874:carboxypeptidase D
keywords: HOCl; Saccharomyces cerevisiae; apoptosis; hypochlorous acid; mitochondria; reactive oxygen species; yeast
references: J Biol Chem. 2002 Jun 7;277(23):20518-26
references: 11925431
references: Aging (Albany NY). 2011 Aug;3(8):716-32
references: 21869457
references: Toxicology. 2010 Apr 11;270(2-3):112-20
references: 20152877
references: Science. 2001 Apr 13;292(5515):288-90
references: 11292860
references: IUBMB Life. 2000 Oct-Nov;50(4-5):259-66
references: 11327319
references: Methods Enzymol. 1986;132:585-93
references: 3547027
references: Biochim Biophys Acta. 2012 Feb;1823(2):420-9
references: 22008466
references: Biochem J. 1999 Dec 1;344 Pt 2:443-9
references: 10567227
references: Arch Biochem Biophys. 2004 Mar 1;423(1):170-81
references: 14871479
references: Cell Cycle. 2010 Oct 1;9(19):3991-6
references: 20935467
references: Mol Cell Biochem. 1982 Dec 10;49(3):143-9
references: 6298593
references: J Cell Biol. 2004 Feb 16;164(4):501-7
references: 14970189
references: J Biol Chem. 2008 Mar 21;283(12):7554-60
references: 18192273
references: J Cell Biol. 2004 Sep 27;166(7):969-74
references: 15381687
references: J Leukoc Biol. 2005 May;77(5):598-625
references: 15689384
references: Eur J Biochem. 2000 Jul;267(14):4495-503
references: 10880973
references: Cell Death Dis. 2011 May 19;2:e161
references: 21593793
references: J Lipid Res. 2008 Apr;49(4):782-9
references: 18202433
references: Kidney Int. 2003 Dec;64(6):1956-67
references: 14633118
references: Biochim Biophys Acta. 2006 Apr;1761(4):392-415
references: 16698314
references: Cell Cycle. 2007 May 2;6(9):1072-6
references: 17471024
references: Mol Cell. 2012 Jun 8;46(5):561-72
references: 22633370
references: Free Radic Biol Med. 1991;10(2):101-9
references: 1849864
references: Biochem J. 1999 Jun 1;340 ( Pt 2):539-48
references: 10333500
references: Mol Cell. 2012 Jun 8;46(5):552-4
references: 22681882
references: EMBO J. 2011 Jun 14;30(14):2779-92
references: 21673659
references: J Inorg Biochem. 2010 Jul;104(7):759-64
references: 20400181
references: Mol Cell. 2006 Oct 20;24(2):211-20
references: 17052455
references: Cell Cycle. 2011 Nov 15;10(22):3973-8
references: 22071627
references: Cell Rep. 2012 Aug 30;2(2):257-69
references: 22854025
references: Am J Physiol Heart Circ Physiol. 2001 Oct;281(4):H1469-75
references: 11557534
references: Biochem Biophys Res Commun. 2012 Aug 24;425(2):157-61
references: 22819842
references: Biol Pharm Bull. 2007 Feb;30(2):324-30
references: 17268074
references: Free Radic Biol Med. 2005 Jun 15;38(12):1571-84
references: 15917186
references: Antioxid Redox Signal. 2002 Feb;4(1):5-15
references: 11970838
references: Cell Cycle. 2010 Oct;9(20):4046
references: 20980804
references: Cell Cycle. 2013 Jan 15;12(2):346-52
references: 23255134
references: Infect Immun. 1986 Mar;51(3):731-5
references: 3005171
references: PLoS Biol. 2012;10(3):e1001281
references: 22412352
references: Biochem Biophys Res Commun. 2011 Jul 15;410(4):895-900
references: 21708126
references: Yeast. 2011 Aug;28(8):595-609
references: 21761455
references: Curr Med Chem. 2006;13(27):3271-90
references: 17168851
references: J Clin Invest. 2004 Aug;114(4):529-41
references: 15314690
references: Mol Cell. 2002 Apr;9(4):911-7
references: 11983181
references: Cell Cycle. 2012 Sep 15;11(18):3472-80
references: 22918244
references: Aging (Albany NY). 2009 Dec 23;1(12):961-70
references: 20157579
references: Cell. 2005 Jan 14;120(1):25-36
references: 15652479
references: J Cell Sci. 2004 Jan 1;117(Pt 1):115-26
references: 14657274
references: J Biol Chem. 2008 Jul 4;283(27):19151-63
references: 18474590
references: Mol Biol Cell. 2002 Aug;13(8):2598-606
references: 12181332
references: Arterioscler Thromb Vasc Biol. 1995 Jul;15(7):982-9
references: 7541296
references: Mol Microbiol. 2001 Mar;39(5):1166-73
references: 11251834
references: Cell Signal. 2007 Apr;19(4):705-14
references: 17107772
references: Cell Death Differ. 2010 May;17(5):763-73
references: 20075938
references: Nat Cell Biol. 2009 Nov;11(11):1305-14
references: 19801973
references: Apoptosis. 2010 Mar;15(3):257-68
references: 20238475
references: Mutagenesis. 2004 Mar;19(2):157-62
references: 14981163
references: Cell Signal. 2007 Feb;19(2):219-28
references: 16959471
references: Mol Cell. 2007 Jan 26;25(2):233-46
references: 17244531
references: Cell Cycle. 2010 Jul 15;9(14):2836-42
references: 20647757
references: Mol Biol Cell. 2006 Apr;17(4):1802-11
references: 16436509
references: Arterioscler Thromb Vasc Biol. 2004 Jul;24(7):1309-14
references: 15142860
references: J Cell Biol. 1997 Nov 3;139(3):729-34
references: 9348289