title: Oxygen-Dependent Cell-to-Cell Variability in the Output of the Escherichia coli Tor Phosphorelay.
abstract: Escherichia coli senses and responds to trimethylamine-N-oxide (TMAO) in the environment through the TorT-TorS-TorR signal transduction system. The periplasmic protein TorT binds TMAO and stimulates the hybrid kinase TorS to phosphorylate the response regulator TorR through a phosphorelay. Phosphorylated TorR, in turn, activates transcription of the torCAD operon, which encodes the proteins required for anaerobic respiration via reduction of TMAO to trimethylamine. Interestingly, E. coli respires TMAO in both the presence and absence of oxygen, a behavior that is markedly different from the utilization of other alternative electron acceptors by this bacterium. Here we describe an unusual form of regulation by oxygen for this system. While the average level of torCAD transcription is the same for aerobic and anaerobic cultures containing TMAO, the behavior across the population of cells is strikingly different under the two growth conditions. Cellular levels of torCAD transcription in aerobic cultures are highly heterogeneous, in contrast to the relatively homogeneous distribution in anaerobic cultures. Thus, oxygen regulates the variance of the output but not the mean for the Tor system. We further show that this oxygen-dependent variability stems from the phosphorelay.
  
  
  OBJECTIVE
  Trimethylamine-N-oxide (TMAO) is utilized by numerous bacteria as an electron acceptor for anaerobic respiration. In E. coli, expression of the proteins required for TMAO respiration is tightly regulated by a signal transduction system that is activated by TMAO. Curiously, although oxygen is the energetically preferred electron acceptor, TMAO is respired even in the presence of oxygen. Here we describe an interesting and unexpected form of regulation for this system in which oxygen produces highly variable expression of the TMAO utilization proteins across a population of cells without affecting the mean expression of these proteins. To our knowledge, this is the first reported example of a stimulus regulating the variance but not the mean output of a signaling system.
authors.affiliation: Department of Biology, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Manuela
authors.initials: M
authors.lastname: Roggiani
authors.affiliation: Department of Biology, University of Pennsylvania, Philadelphia, Pennsylvania, USA goulian@sas.upenn.edu.
authors.forename: Mark
authors.initials: M
authors.lastname: Goulian
mesh_terms: D000332:Aerobiosis; D003497:Cyclic N-Oxides / Q000494:pharmacology; D004926:Escherichia coli / Q000166:cytology / Q000502:physiology*; D029968:Escherichia coli Proteins / Q000235:genetics / Q000378:metabolism*; D015964:Gene Expression Regulation, Bacterial / Q000187:drug effects / Q000502:physiology*; D054833:Isoindoles / Q000494:pharmacology; D008164:Luminescent Proteins; D009876:Operon; D010100:Oxygen / Q000378:metabolism*; D033903:Periplasmic Proteins / Q000235:genetics / Q000378:metabolism; D010770:Phosphotransferases / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic / Q000502:physiology*
chemical_list: C568286:1,1,3,3-tetramethyl-2,3-dihydro-2-azaphenalen-2-yloxyl; D003497:Cyclic N-Oxides; D029968:Escherichia coli Proteins; D054833:Isoindoles; D008164:Luminescent Proteins; D033903:Periplasmic Proteins; C089364:TorR protein, E coli; C098062:TorT protein, E coli; D014157:Transcription Factors; D010770:Phosphotransferases; C103806:TorS protein, E coli; D010100:Oxygen
references.citation: Nat Genet. 2002 May;31(1):69-73
references.pmid: 11967532
references.citation: EcoSal Plus. 2007 Apr;2(2):null
references.pmid: 26443585
references.citation: J Biol Chem. 2003 Aug 1;278(31):28787-92
references.pmid: 12766163
references.citation: J Bacteriol. 2004 Aug;186(16):5432-41
references.pmid: 15292145
references.citation: J Bacteriol. 1999 Jan;181(2):508-20
references.pmid: 9882665
references.citation: Science. 1997 Sep 5;277(5331):1453-62
references.pmid: 9278503
references.citation: J Biol Chem. 1998 Jun 26;273(26):16615-20
references.pmid: 9632735
references.citation: Biochim Biophys Acta. 1997 Jul 4;1320(3):217-34
references.pmid: 9230919
references.citation: Proc Natl Acad Sci U S A. 2007 Oct 9;104(41):16305-10
references.pmid: 17909183
references.citation: J Nutr. 1989 May;119(5):800-4
references.pmid: 2723829
references.citation: Trends Microbiol. 1999 Mar;7(3):115-20
references.pmid: 10203840
references.citation: J Bacteriol. 2005 May;187(9):3267-72
references.pmid: 15838055
references.citation: Mol Microbiol. 1995 Sep;17(5):971-80
references.pmid: 8596446
references.citation: J Bacteriol. 2001 Apr;183(8):2691-5
references.pmid: 11274133
references.citation: EMBO J. 2004 Oct 13;23(20):3962-72
references.pmid: 15385959
references.citation: J Bacteriol. 2008 Oct;190(20):6881-93
references.pmid: 18676672
references.citation: Structure. 2012 Apr 4;20(4):729-41
references.pmid: 22483119
references.citation: Science. 2002 Aug 16;297(5584):1183-6
references.pmid: 12183631
references.citation: Mol Syst Biol. 2006;2:2006.0008
references.pmid: 16738554
references.citation: Annu Rev Biochem. 2000;69:183-215
references.pmid: 10966457
references.citation: Mol Microbiol. 2006 Mar;59(6):1767-78
references.pmid: 16553882
references.citation: Science. 1982 Sep 24;217(4566):1214-22
references.pmid: 7112124
references.citation: Food Chem Toxicol. 1999 May;37(5):515-20
references.pmid: 10456680
references.citation: J Biol Chem. 2001 Apr 13;276(15):11545-51
references.pmid: 11056172
references.citation: Hum Mol Genet. 1998 May;7(5):839-45
references.pmid: 9536088
references.citation: Adv Microb Physiol. 2005;50:147-98
references.pmid: 16221580
references.citation: J Bacteriol. 2000 Feb;182(4):961-6
references.pmid: 10648521
references.citation: J Biol Chem. 2008 Aug 1;283(31):21433-40
references.pmid: 18522945
references.citation: Cell Metab. 2013 Jan 8;17(1):49-60
references.pmid: 23312283
references.citation: EMBO Rep. 2013 Apr;14(4):319-27
references.pmid: 23478337
references.citation: Mol Microbiol. 2008 Oct;70(2):494-506
references.pmid: 18761686
references.citation: Annu Rev Microbiol. 1985;39:131-49
references.pmid: 3904597
references.citation: Mol Microbiol. 2007 Oct;66(2):484-94
references.pmid: 17850256
references.citation: Methods Enzymol. 2007;423:458-75
references.pmid: 17609146
references.citation: Mol Microbiol. 1994 Mar;11(6):1169-79
references.pmid: 8022286
references.citation: Mol Microbiol. 1996 Jun;20(6):1297-306
references.pmid: 8809780
references.citation: J Mol Biol. 1997 Apr 11;267(4):770-7
references.pmid: 9135110
references.citation: J Biol Chem. 2006 Dec 15;281(50):38189-99
references.pmid: 17040909
references.citation: Nat Rev Microbiol. 2010 Mar;8(3):207-17
references.pmid: 20157339
references.citation: J Bacteriol. 2001 Nov;183(21):6384-93
references.pmid: 11591683
references.citation: Infect Immun. 2006 Jan;74(1):615-24
references.pmid: 16369018
references.citation: J Bacteriol. 2014 May;196(9):1723-32
references.pmid: 24563035
references.citation: Proc Natl Acad Sci U S A. 2000 Jun 6;97(12):6640-5
references.pmid: 10829079
references.citation: Nat Genet. 2011 Feb;43(2):95-100
references.pmid: 21186354
references.citation: Cell. 2014 Apr 24;157(3):624-35
references.pmid: 24766808