title: Phenol-soluble modulin α induces G2/M phase transition delay in eukaryotic HeLa cells.
abstract: Staphylococcus aureus is a gram-positive bacterium responsible for a wide range of infections. Host cell cycle alteration is a sophisticated mechanism used by pathogens to hijack the defense functions of host cells. We previously demonstrated that S. aureus MW2 (USA400) bacteria induced a G2/M phase transition delay in HeLa cells. We demonstrate here that this activity is triggered by culture supernatant compounds. Using size exclusion chromatography of the MW2 supernatant, followed by mass spectroscopy analysis of corresponding peaks, we identified phenol-soluble modulin α (PSMα) peptides as the likely candidates for this effect. Indeed, synthetic PSMα1 and PSMα3 caused a G2/M phase transition delay. The implication of PSMα in cell cycle alteration was confirmed by comparison of S. aureus Los Angeles County clone (LAC) wild-type with the isogenic mutant LAC∆psmα, which lacks the psmα operon encoding PSMα1-4. PSMα-induced G2/M transition delay correlated with a decrease in the defensin genes expression suggesting a diminution of antibacterial functions of epithelial cells. By testing the supernatant of S. aureus human clinical isolates, we found that the degree of G2/M phase transition delay correlated with PSMα1 production. We show that PSMs secreted by S. aureus alter the host cell cycle, revealing a newly identified mechanism for fostering an infection.
authors: *Institut National de la Recherche Agronomique, Unité Mixte de Recherche 1253 STLO, Rennes, France; Agrocampus Ouest, Unité Mixtes de Recherche1253 STLO, Rennes, France; Instituto de Ciências Biológicas- Universidade Federal de Minas Gerais , Belo Horizonte- Minas Gerais, Brazil; Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow, Russia; Centre International de Recherche en Infectiologie, Institut National de la Santé et de la Recherche Médicale U1111, Centre National de la Recherche Scientifique Unité Mixtes de Recherche5308, Université Lyon 1, Lyon, France; Hospices Civil de Lyon, Lyon, France; Laboratory of Human Bacterial Pathogenesis, National Institutes of Health, Bethesda, Maryland, USA; and **Microbial Genetics, University of Tübingen, Tübingen, Germany.
authors: Martine
authors: M
authors: Deplanche
authors: *Institut National de la Recherche Agronomique, Unité Mixte de Recherche 1253 STLO, Rennes, France; Agrocampus Ouest, Unité Mixtes de Recherche1253 STLO, Rennes, France; Instituto de Ciências Biológicas- Universidade Federal de Minas Gerais , Belo Horizonte- Minas Gerais, Brazil; Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow, Russia; Centre International de Recherche en Infectiologie, Institut National de la Santé et de la Recherche Médicale U1111, Centre National de la Recherche Scientifique Unité Mixtes de Recherche5308, Université Lyon 1, Lyon, France; Hospices Civil de Lyon, Lyon, France; Laboratory of Human Bacterial Pathogenesis, National Institutes of Health, Bethesda, Maryland, USA; and **Microbial Genetics, University of Tübingen, Tübingen, Germany.
authors: Rachid Aref El-Aouar
authors: RA
authors: Filho
authors: *Institut National de la Recherche Agronomique, Unité Mixte de Recherche 1253 STLO, Rennes, France; Agrocampus Ouest, Unité Mixtes de Recherche1253 STLO, Rennes, France; Instituto de Ciências Biológicas- Universidade Federal de Minas Gerais , Belo Horizonte- Minas Gerais, Brazil; Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow, Russia; Centre International de Recherche en Infectiologie, Institut National de la Santé et de la Recherche Médicale U1111, Centre National de la Recherche Scientifique Unité Mixtes de Recherche5308, Université Lyon 1, Lyon, France; Hospices Civil de Lyon, Lyon, France; Laboratory of Human Bacterial Pathogenesis, National Institutes of Health, Bethesda, Maryland, USA; and **Microbial Genetics, University of Tübingen, Tübingen, Germany.
authors: Ludmila
authors: L
authors: Alekseeva
authors: *Institut National de la Recherche Agronomique, Unité Mixte de Recherche 1253 STLO, Rennes, France; Agrocampus Ouest, Unité Mixtes de Recherche1253 STLO, Rennes, France; Instituto de Ciências Biológicas- Universidade Federal de Minas Gerais , Belo Horizonte- Minas Gerais, Brazil; Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow, Russia; Centre International de Recherche en Infectiologie, Institut National de la Santé et de la Recherche Médicale U1111, Centre National de la Recherche Scientifique Unité Mixtes de Recherche5308, Université Lyon 1, Lyon, France; Hospices Civil de Lyon, Lyon, France; Laboratory of Human Bacterial Pathogenesis, National Institutes of Health, Bethesda, Maryland, USA; and **Microbial Genetics, University of Tübingen, Tübingen, Germany.
authors: Emilie
authors: E
authors: Ladier
authors: *Institut National de la Recherche Agronomique, Unité Mixte de Recherche 1253 STLO, Rennes, France; Agrocampus Ouest, Unité Mixtes de Recherche1253 STLO, Rennes, France; Instituto de Ciências Biológicas- Universidade Federal de Minas Gerais , Belo Horizonte- Minas Gerais, Brazil; Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow, Russia; Centre International de Recherche en Infectiologie, Institut National de la Santé et de la Recherche Médicale U1111, Centre National de la Recherche Scientifique Unité Mixtes de Recherche5308, Université Lyon 1, Lyon, France; Hospices Civil de Lyon, Lyon, France; Laboratory of Human Bacterial Pathogenesis, National Institutes of Health, Bethesda, Maryland, USA; and **Microbial Genetics, University of Tübingen, Tübingen, Germany.
authors: Julien
authors: J
authors: Jardin
authors: *Institut National de la Recherche Agronomique, Unité Mixte de Recherche 1253 STLO, Rennes, France; Agrocampus Ouest, Unité Mixtes de Recherche1253 STLO, Rennes, France; Instituto de Ciências Biológicas- Universidade Federal de Minas Gerais , Belo Horizonte- Minas Gerais, Brazil; Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow, Russia; Centre International de Recherche en Infectiologie, Institut National de la Santé et de la Recherche Médicale U1111, Centre National de la Recherche Scientifique Unité Mixtes de Recherche5308, Université Lyon 1, Lyon, France; Hospices Civil de Lyon, Lyon, France; Laboratory of Human Bacterial Pathogenesis, National Institutes of Health, Bethesda, Maryland, USA; and **Microbial Genetics, University of Tübingen, Tübingen, Germany.
authors: Gwénaële
authors: G
authors: Henry
authors: *Institut National de la Recherche Agronomique, Unité Mixte de Recherche 1253 STLO, Rennes, France; Agrocampus Ouest, Unité Mixtes de Recherche1253 STLO, Rennes, France; Instituto de Ciências Biológicas- Universidade Federal de Minas Gerais , Belo Horizonte- Minas Gerais, Brazil; Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow, Russia; Centre International de Recherche en Infectiologie, Institut National de la Santé et de la Recherche Médicale U1111, Centre National de la Recherche Scientifique Unité Mixtes de Recherche5308, Université Lyon 1, Lyon, France; Hospices Civil de Lyon, Lyon, France; Laboratory of Human Bacterial Pathogenesis, National Institutes of Health, Bethesda, Maryland, USA; and **Microbial Genetics, University of Tübingen, Tübingen, Germany.
authors: Vasco
authors: V
authors: Azevedo
authors: *Institut National de la Recherche Agronomique, Unité Mixte de Recherche 1253 STLO, Rennes, France; Agrocampus Ouest, Unité Mixtes de Recherche1253 STLO, Rennes, France; Instituto de Ciências Biológicas- Universidade Federal de Minas Gerais , Belo Horizonte- Minas Gerais, Brazil; Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow, Russia; Centre International de Recherche en Infectiologie, Institut National de la Santé et de la Recherche Médicale U1111, Centre National de la Recherche Scientifique Unité Mixtes de Recherche5308, Université Lyon 1, Lyon, France; Hospices Civil de Lyon, Lyon, France; Laboratory of Human Bacterial Pathogenesis, National Institutes of Health, Bethesda, Maryland, USA; and **Microbial Genetics, University of Tübingen, Tübingen, Germany.
authors: Anderson
authors: A
authors: Miyoshi
authors: *Institut National de la Recherche Agronomique, Unité Mixte de Recherche 1253 STLO, Rennes, France; Agrocampus Ouest, Unité Mixtes de Recherche1253 STLO, Rennes, France; Instituto de Ciências Biológicas- Universidade Federal de Minas Gerais , Belo Horizonte- Minas Gerais, Brazil; Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow, Russia; Centre International de Recherche en Infectiologie, Institut National de la Santé et de la Recherche Médicale U1111, Centre National de la Recherche Scientifique Unité Mixtes de Recherche5308, Université Lyon 1, Lyon, France; Hospices Civil de Lyon, Lyon, France; Laboratory of Human Bacterial Pathogenesis, National Institutes of Health, Bethesda, Maryland, USA; and **Microbial Genetics, University of Tübingen, Tübingen, Germany.
authors: Laetitia
authors: L
authors: Beraud
authors: *Institut National de la Recherche Agronomique, Unité Mixte de Recherche 1253 STLO, Rennes, France; Agrocampus Ouest, Unité Mixtes de Recherche1253 STLO, Rennes, France; Instituto de Ciências Biológicas- Universidade Federal de Minas Gerais , Belo Horizonte- Minas Gerais, Brazil; Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow, Russia; Centre International de Recherche en Infectiologie, Institut National de la Santé et de la Recherche Médicale U1111, Centre National de la Recherche Scientifique Unité Mixtes de Recherche5308, Université Lyon 1, Lyon, France; Hospices Civil de Lyon, Lyon, France; Laboratory of Human Bacterial Pathogenesis, National Institutes of Health, Bethesda, Maryland, USA; and **Microbial Genetics, University of Tübingen, Tübingen, Germany.
authors: Frederic
authors: F
authors: Laurent
authors: *Institut National de la Recherche Agronomique, Unité Mixte de Recherche 1253 STLO, Rennes, France; Agrocampus Ouest, Unité Mixtes de Recherche1253 STLO, Rennes, France; Instituto de Ciências Biológicas- Universidade Federal de Minas Gerais , Belo Horizonte- Minas Gerais, Brazil; Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow, Russia; Centre International de Recherche en Infectiologie, Institut National de la Santé et de la Recherche Médicale U1111, Centre National de la Recherche Scientifique Unité Mixtes de Recherche5308, Université Lyon 1, Lyon, France; Hospices Civil de Lyon, Lyon, France; Laboratory of Human Bacterial Pathogenesis, National Institutes of Health, Bethesda, Maryland, USA; and **Microbial Genetics, University of Tübingen, Tübingen, Germany.
authors: Gerard
authors: G
authors: Lina
authors: *Institut National de la Recherche Agronomique, Unité Mixte de Recherche 1253 STLO, Rennes, France; Agrocampus Ouest, Unité Mixtes de Recherche1253 STLO, Rennes, France; Instituto de Ciências Biológicas- Universidade Federal de Minas Gerais , Belo Horizonte- Minas Gerais, Brazil; Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow, Russia; Centre International de Recherche en Infectiologie, Institut National de la Santé et de la Recherche Médicale U1111, Centre National de la Recherche Scientifique Unité Mixtes de Recherche5308, Université Lyon 1, Lyon, France; Hospices Civil de Lyon, Lyon, France; Laboratory of Human Bacterial Pathogenesis, National Institutes of Health, Bethesda, Maryland, USA; and **Microbial Genetics, University of Tübingen, Tübingen, Germany.
authors: François
authors: F
authors: Vandenesch
authors: *Institut National de la Recherche Agronomique, Unité Mixte de Recherche 1253 STLO, Rennes, France; Agrocampus Ouest, Unité Mixtes de Recherche1253 STLO, Rennes, France; Instituto de Ciências Biológicas- Universidade Federal de Minas Gerais , Belo Horizonte- Minas Gerais, Brazil; Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow, Russia; Centre International de Recherche en Infectiologie, Institut National de la Santé et de la Recherche Médicale U1111, Centre National de la Recherche Scientifique Unité Mixtes de Recherche5308, Université Lyon 1, Lyon, France; Hospices Civil de Lyon, Lyon, France; Laboratory of Human Bacterial Pathogenesis, National Institutes of Health, Bethesda, Maryland, USA; and **Microbial Genetics, University of Tübingen, Tübingen, Germany.
authors: Jean-Paul
authors: JP
authors: Steghens
authors: *Institut National de la Recherche Agronomique, Unité Mixte de Recherche 1253 STLO, Rennes, France; Agrocampus Ouest, Unité Mixtes de Recherche1253 STLO, Rennes, France; Instituto de Ciências Biológicas- Universidade Federal de Minas Gerais , Belo Horizonte- Minas Gerais, Brazil; Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow, Russia; Centre International de Recherche en Infectiologie, Institut National de la Santé et de la Recherche Médicale U1111, Centre National de la Recherche Scientifique Unité Mixtes de Recherche5308, Université Lyon 1, Lyon, France; Hospices Civil de Lyon, Lyon, France; Laboratory of Human Bacterial Pathogenesis, National Institutes of Health, Bethesda, Maryland, USA; and **Microbial Genetics, University of Tübingen, Tübingen, Germany.
authors: Yves
authors: Y
authors: Le Loir
authors: *Institut National de la Recherche Agronomique, Unité Mixte de Recherche 1253 STLO, Rennes, France; Agrocampus Ouest, Unité Mixtes de Recherche1253 STLO, Rennes, France; Instituto de Ciências Biológicas- Universidade Federal de Minas Gerais , Belo Horizonte- Minas Gerais, Brazil; Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow, Russia; Centre International de Recherche en Infectiologie, Institut National de la Santé et de la Recherche Médicale U1111, Centre National de la Recherche Scientifique Unité Mixtes de Recherche5308, Université Lyon 1, Lyon, France; Hospices Civil de Lyon, Lyon, France; Laboratory of Human Bacterial Pathogenesis, National Institutes of Health, Bethesda, Maryland, USA; and **Microbial Genetics, University of Tübingen, Tübingen, Germany.
authors: Michael
authors: M
authors: Otto
authors: *Institut National de la Recherche Agronomique, Unité Mixte de Recherche 1253 STLO, Rennes, France; Agrocampus Ouest, Unité Mixtes de Recherche1253 STLO, Rennes, France; Instituto de Ciências Biológicas- Universidade Federal de Minas Gerais , Belo Horizonte- Minas Gerais, Brazil; Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow, Russia; Centre International de Recherche en Infectiologie, Institut National de la Santé et de la Recherche Médicale U1111, Centre National de la Recherche Scientifique Unité Mixtes de Recherche5308, Université Lyon 1, Lyon, France; Hospices Civil de Lyon, Lyon, France; Laboratory of Human Bacterial Pathogenesis, National Institutes of Health, Bethesda, Maryland, USA; and **Microbial Genetics, University of Tübingen, Tübingen, Germany.
authors: Friedrich
authors: F
authors: Götz
authors: *Institut National de la Recherche Agronomique, Unité Mixte de Recherche 1253 STLO, Rennes, France; Agrocampus Ouest, Unité Mixtes de Recherche1253 STLO, Rennes, France; Instituto de Ciências Biológicas- Universidade Federal de Minas Gerais , Belo Horizonte- Minas Gerais, Brazil; Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow, Russia; Centre International de Recherche en Infectiologie, Institut National de la Santé et de la Recherche Médicale U1111, Centre National de la Recherche Scientifique Unité Mixtes de Recherche5308, Université Lyon 1, Lyon, France; Hospices Civil de Lyon, Lyon, France; Laboratory of Human Bacterial Pathogenesis, National Institutes of Health, Bethesda, Maryland, USA; and **Microbial Genetics, University of Tübingen, Tübingen, Germany nadia.berkova@rennes.inra.fr.
authors: Nadia
authors: N
authors: Berkova
mesh_terms: D001427:Bacterial Toxins / Q000494:pharmacology*; D015153:Blotting, Western; D049109:Cell Proliferation; D002478:Cells, Cultured; D017077:Culture Media, Conditioned / Q000494:pharmacology*; D005434:Flow Cytometry; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects*; D006367:HeLa Cells; D006801:Humans; D059566:M Phase Cell Cycle Checkpoints / Q000187:drug effects*; D010446:Peptide Fragments / Q000494:pharmacology*; D019800:Phenol / Q000737:chemistry*; D013203:Staphylococcal Infections / Q000382:microbiology; D013211:Staphylococcus aureus / Q000502:physiology*; D053719:Tandem Mass Spectrometry
chemical_list: D001427:Bacterial Toxins; D017077:Culture Media, Conditioned; D010446:Peptide Fragments; D019800:Phenol
keywords: Staphylococcus aureus; cell cycle alteration; defensins; innate immune response; toxin
references: Methods. 2001 Dec;25(4):402-8
references: 11846609
references: Bioinformatics. 2004 Jun 12;20(9):1466-7
references: 14976030
references: J Antimicrob Chemother. 1986 Jul;18 Suppl A:1-12
references: 3091562
references: Pediatr Infect Dis J. 1988 Nov;7(11):791-5
references: 3231500
references: J Cell Physiol. 1989 May;139(2):424-31
references: 2654144
references: J Biol Chem. 1992 Feb 5;267(4):2600-4
references: 1733958
references: Trends Microbiol. 2005 Mar;13(3):103-10
references: 15737728
references: Int Immunol. 2006 Jan;18(1):139-50
references: 16357007
references: Science. 2006 Aug 11;313(5788):848-51
references: 16902142
references: Cell Microbiol. 2006 Oct;8(10):1591-600
references: 16984414
references: J Cell Biol. 2007 Apr 23;177(2):253-64
references: 17452529
references: Nature. 2007 Oct 18;449(7164):827-34
references: 17943119
references: Nat Med. 2007 Dec;13(12):1510-4
references: 17994102
references: Mol Cell. 2008 Oct 10;32(1):150-8
references: 18851841
references: J Microbiol Methods. 2009 Oct;79(1):131-6
references: 19735677
references: J Immunol. 2010 Jun 15;184(12):6688-94
references: 20483750
references: Infect Immun. 2010 Jul;78(7):3112-7
references: 20404083
references: EMBO Mol Med. 2011 Mar;3(3):129-41
references: 21268281
references: Trends Microbiol. 2011 Apr;19(4):184-90
references: 21227700
references: Nat Rev Immunol. 2011 Aug;11(8):505-18
references: 21720387
references: J Virol. 2011 Oct;85(19):10300-9
references: 21795354
references: J Exp Med. 2011 Oct 24;208(11):2263-77
references: 21967767
references: Invest Ophthalmol Vis Sci. 2012 Feb;53(2):757-61
references: 22232436
references: Microbes Infect. 2012 Apr;14(4):380-6
references: 22178792
references: PLoS Pathog. 2012;8(3):e1002606
references: 22457627
references: J Infect Dis. 2012 May 15;205(10):1483-5
references: 22457276
references: PLoS One. 2012;7(8):e42660
references: 22900037
references: PLoS One. 2013;8(2):e56964
references: 23457644
references: PLoS One. 2013;8(5):e63279
references: 23717407
references: Nat Rev Microbiol. 2013 Oct;11(10):667-73
references: 24018382
references: Nat Rev Microbiol. 2014 Jan;12(1):49-62
references: 24336184
references: J Infect Dis. 2014 Feb 15;209(4):588-99
references: 24470577
references: Cell Microbiol. 2014 Apr;16(4):451-65
references: 24164701
references: J Dermatol Sci. 2014 Aug;75(2):94-9
references: 24831548