title: The propeptide of yeast cathepsin D inhibits programmed necrosis.
abstract: The lysosomal endoprotease cathepsin D (CatD) is an essential player in general protein turnover and specific peptide processing. CatD-deficiency is associated with neurodegenerative diseases, whereas elevated CatD levels correlate with tumor malignancy and cancer cell survival. Here, we show that the CatD ortholog of the budding yeast Saccharomyces cerevisiae (Pep4p) harbors a dual cytoprotective function, composed of an anti-apoptotic part, conferred by its proteolytic capacity, and an anti-necrotic part, which resides in the protein's proteolytically inactive propeptide. Thus, deletion of PEP4 resulted in both apoptotic and necrotic cell death during chronological aging. Conversely, prolonged overexpression of Pep4p extended chronological lifespan specifically through the protein's anti-necrotic function. This function, which triggered histone hypoacetylation, was dependent on polyamine biosynthesis and was exerted via enhanced intracellular levels of putrescine, spermidine and its precursor S-adenosyl-methionine. Altogether, these data discriminate two pro-survival functions of yeast CatD and provide first insight into the physiological regulation of programmed necrosis in yeast.
authors: Institute of Molecular Biosciences, University of Graz, Graz, Austria.
authors: D
authors: D
authors: Carmona-Gutiérrez
authors: M A
authors: MA
authors: Bauer
authors: J
authors: J
authors: Ring
authors: H
authors: H
authors: Knauer
authors: T
authors: T
authors: Eisenberg
authors: S
authors: S
authors: Büttner
authors: C
authors: C
authors: Ruckenstuhl
authors: A
authors: A
authors: Reisenbichler
authors: C
authors: C
authors: Magnes
authors: G N
authors: GN
authors: Rechberger
authors: R
authors: R
authors: Birner-Gruenberger
authors: H
authors: H
authors: Jungwirth
authors: K-U
authors: KU
authors: Fröhlich
authors: F
authors: F
authors: Sinner
authors: G
authors: G
authors: Kroemer
authors: F
authors: F
authors: Madeo
references: J Neurosci. 2000 Sep 15;20(18):6898-906
references: 10995834
references: Cell Death Differ. 2009 Jan;16(1):94-102
references: 19079287
references: Mol Cell Biol. 1986 Jul;6(7):2490-9
references: 3023936
references: Nature. 2009 Jun 11;459(7248):802-7
references: 19516333
references: Autophagy. 2007 May-Jun;3(3):181-206
references: 17224625
references: Mol Biol Cell. 2002 Aug;13(8):2598-606
references: 12181332
references: Cell Death Differ. 2010 May;17(5):763-73
references: 20075938
references: Nat Rev Cancer. 2004 Oct;4(10):781-92
references: 15510159
references: J Cell Biol. 2004 Feb 16;164(4):501-7
references: 14970189
references: Carcinogenesis. 2008 Oct;29(10):1869-77
references: 18566016
references: Nature. 2000 Nov 9;408(6809):239-47
references: 11089981
references: J Cell Biol. 1999 May 17;145(4):757-67
references: 10330404
references: J Biol Chem. 1989 Sep 25;264(27):16037-45
references: 2674123
references: Cell. 2006 Jul 28;126(2):257-68
references: 16873059
references: Eur J Biochem. 1995 Jul 1;231(1):115-25
references: 7628461
references: Science. 2001 Apr 13;292(5515):288-90
references: 11292860
references: Mol Cancer Ther. 2005 May;4(5):733-42
references: 15897237
references: Genes Dev. 2006 Jan 1;20(1):1-15
references: 16391229
references: Science. 2010 Apr 16;328(5976):321-6
references: 20395504
references: Int J Oncol. 2008 Feb;32(2):491-8
references: 18202773
references: Biochem J. 1994 Nov 1;303 ( Pt 3):775-80
references: 7980446
references: Mol Microbiol. 2010 Jun;76(6):1398-410
references: 20345665
references: FASEB J. 2001 Jul;15(9):1592-4
references: 11427496
references: Mol Cell. 2002 Apr;9(4):911-7
references: 11983181
references: Methods Enzymol. 2008;451:33-42
references: 19185711
references: Crit Rev Oncol Hematol. 2008 Oct;68(1):12-28
references: 18396408
references: Brain. 2006 Jun;129(Pt 6):1438-45
references: 16670177
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: Cell Death Differ. 2003 Nov;10(11):1253-9
references: 14576777
references: J Cell Biol. 2004 Sep 27;166(7):1055-67
references: 15452146
references: Nat Cell Biol. 2009 Nov;11(11):1305-14
references: 19801973
references: Apoptosis. 2010 Mar;15(3):257-68
references: 20238475
references: Cancer Lett. 2006 Jun 18;237(2):167-79
references: 16046058
references: Mol Cell. 2007 Jan 26;25(2):233-46
references: 17244531
references: Mol Cell Neurosci. 2003 Feb;22(2):146-61
references: 12676526
references: Cell. 2005 Nov 18;123(4):655-67
references: 16286010
references: Curr Mol Med. 2008 May;8(3):207-20
references: 18473820
references: J Neurosci. 2007 Feb 21;27(8):2081-90
references: 17314303
references: J Cell Biol. 1997 Nov 3;139(3):729-34
references: 9348289