title: Pro-autophagic signal induction by bacterial pore-forming toxins.
abstract: Pore-forming toxins (PFT) comprise a large, structurally heterogeneous group of bacterial protein toxins. Nucleated target cells mount complex responses which allow them to survive moderate membrane damage by PFT. Autophagy has recently been implicated in responses to various PFT, but how this process is triggered is not known, and the significance of the phenomenon is not understood. Here, we show that S. aureus α-toxin, Vibrio cholerae cytolysin, streptolysin O and E. coli haemolysin activate two pathways leading to autophagy. The first pathway is triggered via AMP-activated protein kinase (AMPK). AMPK is a major energy sensor which induces autophagy by inhibiting the target of rapamycin complex 1 (TORC1) in response to a drop of the cellular ATP/AMP-ratio, as is also observed in response to membrane perforation. The second pathway is activated by the conserved eIF2α-kinase GCN2, which causes global translational arrest and promotes autophagy in response to starvation. The latter could be accounted for by impaired amino acid transport into target cells. Notably, PKR, an eIF2α-kinase which has been implicated in autophagy induction during viral infection, was also activated upon membrane perforation, and evidence was obtained that phosphorylation of eIF2α is required for the accumulation of autophagosomes in α-toxin-treated cells. Treatment with 3-methyl-adenine inhibited autophagy and disrupted the ability of cells to recover from sublethal attack by S. aureus α-toxin. We propose that PFT induce pro-autophagic signals through membrane perforation-dependent nutrient and energy depletion, and that an important function of autophagy in this context is to maintain metabolic homoeostasis.
authors.affiliation: Institute of Medical Microbiology and Hygiene, University Medical Center, Johannes Gutenberg-University Mainz, Mainz, Germany.
authors.forename: Nicole
authors.initials: N
authors.lastname: Kloft
authors.forename: Claudia
authors.initials: C
authors.lastname: Neukirch
authors.forename: Wiesia
authors.initials: W
authors.lastname: Bobkiewicz
authors.forename: Gunnaporn
authors.initials: G
authors.lastname: Veerachato
authors.forename: Tim
authors.initials: T
authors.lastname: Busch
authors.forename: Gisela
authors.initials: G
authors.lastname: von Hoven
authors.forename: Klaus
authors.initials: K
authors.lastname: Boller
authors.forename: Matthias
authors.initials: M
authors.lastname: Husmann
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D001343:Autophagy / Q000187:drug effects*; D001427:Bacterial Toxins / Q000633:toxicity*; D002460:Cell Line; D002462:Cell Membrane / Q000187:drug effects*; D006801:Humans; D015603:Keratinocytes / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D001427:Bacterial Toxins; C529271:EIF2AK4 protein, human; D017346:Protein Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases
references.citation: J Cell Biol. 2010 Feb 22;188(4):537-46
references.pmid: 20156962
references.citation: Cell Host Microbe. 2009 Aug 20;6(2):137-49
references.pmid: 19683680
references.citation: Immunity. 2000 Jul;13(1):129-41
references.pmid: 10933401
references.citation: Mol Cell. 2005 Apr 15;18(2):141-2
references.pmid: 15837415
references.citation: J Cell Biol. 2008 Mar 10;180(5):905-14
references.pmid: 18316410
references.citation: Cell. 2007 Apr 6;129(1):195-206
references.pmid: 17418795
references.citation: J Biol Chem. 2004 Jun 11;279(24):25143-8
references.pmid: 15066987
references.citation: Proc Natl Acad Sci U S A. 2002 Jan 8;99(1):190-5
references.pmid: 11756670
references.citation: J Cell Biol. 2001 May 28;153(5):1011-22
references.pmid: 11381086
references.citation: Autophagy. 2007 Jul-Aug;3(4):363-5
references.pmid: 17404497
references.citation: Curr Opin Microbiol. 2007 Feb;10(1):57-61
references.pmid: 17234446
references.citation: J Cell Biol. 2010 Feb 22;188(4):527-36
references.pmid: 20156967
references.citation: Annu Rev Genet. 2009;43:67-93
references.pmid: 19653858
references.citation: Nature. 2005 Aug 25;436(7054):1166-73
references.pmid: 16121183
references.citation: Nat Immunol. 2006 Jun;7(6):644-51
references.pmid: 16680145
references.citation: Microb Pathog. 1994 Sep;17(3):187-201
references.pmid: 7535374
references.citation: J Cell Biol. 1988 Mar;106(3):761-71
references.pmid: 2450098
references.citation: J Biol Chem. 2004 May 28;279(22):22820-32
references.pmid: 15010461
references.citation: Cell Calcium. 2009 Feb;45(2):165-76
references.pmid: 18922576
references.citation: PLoS Pathog. 2009 Dec;5(12):e1000689
references.pmid: 20011506
references.citation: Proc Natl Acad Sci U S A. 2004 Jul 27;101(30):10995-1000
references.pmid: 15256590
references.citation: Trends Microbiol. 2009 Feb;17(2):59-65
references.pmid: 19208480
references.citation: Immunity. 2005 May;22(5):633-42
references.pmid: 15894280
references.citation: Biochim Biophys Acta. 2009 Oct;1790(10):1067-74
references.pmid: 19539012
references.citation: EMBO J. 2006 Apr 19;25(8):1730-40
references.pmid: 16601681
references.citation: Arch Microbiol. 1996 Feb;165(2):73-9
references.pmid: 8593102
references.citation: Biochem Soc Symp. 1985;50:221-33
references.pmid: 2428369
references.citation: Biochem Soc Trans. 2006 Feb;34(Pt 1):7-11
references.pmid: 16246168
references.citation: J Biol Chem. 2001 Aug 17;276(33):30753-60
references.pmid: 11408481
references.citation: FASEB J. 2002 Feb;16(2):237-9
references.pmid: 11744625
references.citation: Nature. 2008 Jul 17;454(7202):287-8
references.pmid: 18633406
references.citation: Mol Cell. 2003 Mar;11(3):619-33
references.pmid: 12667446
references.citation: PLoS Pathog. 2008 Oct;4(10):e1000176
references.pmid: 18846208
references.citation: Biochem Biophys Res Commun. 2004 Jan 9;313(2):453-8
references.pmid: 14684184
references.citation: EMBO J. 2000 Aug 15;19(16):4292-7
references.pmid: 10944112
references.citation: J Biol Chem. 2006 Sep 29;281(39):28822-30
references.pmid: 16893899
references.citation: Cell. 2006 Sep 22;126(6):1135-45
references.pmid: 16990137
references.citation: Cell Microbiol. 2008 Sep;10(9):1801-14
references.pmid: 18466345
references.citation: Eur J Biochem. 1996 Feb 15;236(1):34-9
references.pmid: 8617283
references.citation: Int J Med Microbiol. 2010 Feb;300(2-3):170-5
references.pmid: 19781990
references.citation: Biochem Biophys Res Commun. 2006 Jun 16;344(4):1128-34
references.pmid: 16643845
references.citation: Biochem Soc Trans. 2009 Feb;37(Pt 1):232-6
references.pmid: 19143638
references.citation: Mol Cell. 2000 Nov;6(5):1099-108
references.pmid: 11106749
references.citation: Cell. 2010 Feb 5;140(3):313-26
references.pmid: 20144757
references.citation: Cell Microbiol. 2006 Oct;8(10):1591-600
references.pmid: 16984414
references.citation: Cell Microbiol. 2008 Apr;10(4):985-93
references.pmid: 18067608
references.citation: J Biol Chem. 1995 Feb 17;270(7):3100-6
references.pmid: 7531699
references.citation: Proc Natl Acad Sci U S A. 2007 Feb 6;104(6):1829-34
references.pmid: 17267617
references.citation: Biochem J. 2003 Jul 1;373(Pt 1):1-18
references.pmid: 12879880
references.citation: PLoS One. 2010 Mar 02;5(3):e9494
references.pmid: 20209166
references.citation: J Virol. 2005 Apr;79(7):4033-42
references.pmid: 15767405
references.citation: J Biol Chem. 1995 Sep 29;270(39):23065-71
references.pmid: 7559447
references.citation: Philos Trans R Soc Lond B Biol Sci. 1984 Sep 6;306(1129):311-24
references.pmid: 6149576
references.citation: FEBS Lett. 2009 Jan 22;583(2):337-44
references.pmid: 19101547
references.citation: Am J Physiol Endocrinol Metab. 2009 Apr;296(4):E592-602
references.pmid: 18765678
references.citation: Biochem Biophys Res Commun. 2009 Aug 7;385(4):503-6
references.pmid: 19497299
references.citation: Proc Natl Acad Sci U S A. 1998 Nov 24;95(24):14511-6
references.pmid: 9826731
references.citation: Infect Immun. 1994 Apr;62(4):1304-12
references.pmid: 8132337
references.citation: Autophagy. 2010 Jan;6(1):110-25
references.pmid: 20110774
references.citation: Infect Immun. 1993 Dec;61(12):4972-9
references.pmid: 8225571
references.citation: Cell Mol Life Sci. 2008 Feb;65(3):493-507
references.pmid: 17989920
references.citation: Infect Immun. 1994 Jun;62(6):2249-56
references.pmid: 8188346
references.citation: PLoS One. 2010 Jan 06;5(1):e8610
references.pmid: 20062534
references.citation: J Biol Chem. 2007 Jan 26;282(4):2695-706
references.pmid: 17135247
references.citation: Traffic. 2008 Feb;9(2):230-50
references.pmid: 17999726
references.citation: Biochemistry. 1999 Nov 16;38(46):15204-11
references.pmid: 10563803
references.citation: Infect Immun. 2001 Apr;69(4):2630-5
references.pmid: 11254628
references.citation: Cell Death Differ. 2005 Aug;12(8):1107-14
references.pmid: 15846374