title: A bacterial hemerythrin-like protein MsmHr inhibits the SigF-dependent hydrogen peroxide response in mycobacteria.
abstract: Hydrogen peroxide (H2O2) is one of a variety of reactive oxygen species (ROS) produced by aerobic organisms. Host production of toxic H2O2 in response to pathogen infection is an important classical innate defense mechanism against invading microbes. Understanding the mechanisms by which pathogens, in response to oxidative stress, mediate defense against toxic ROS, can reveal anti-microbial targets and shed light on pathogenic mechanisms. In this study, we provide evidence that a Mycobacterium smegmatis hemerythrin-like protein MSMEG_2415, designated MsmHr, is a H2O2-modulated repressor of the SigF-mediated response to H2O2. Circular dichroism and spectrophotometric analysis of MsmHr revealed properties characteristic of a typical hemerythrin-like protein. An msmHr knockout strain of M. smegmatis mc(2)155 (ΔmsmHr) was more resistant to H2O2 than its parental strain, and overexpression of MsmHr increased mycobacterial susceptibility to H2O2. Mutagenesis studies revealed that the hemerythrin domain of MsmHr is required for the regulation of the H2O2 response observed in the overexpression study. We show that MsmHr inhibits the expression of SigF (MSMEG_1804), an alternative sigma factor that plays an important role in bacterial oxidative stress responses, including those elicited by H2O2, thus providing a mechanistic link between ΔmsmHr and its enhanced resistance to H2O2. Together, these results strongly suggest that MsmHr is involved in the response of mycobacteria to H2O2 by negatively regulating a sigma factor, a function not previously described for hemerythrins.
authors: CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences Beijing, China.
authors: Xiaojing
authors: X
authors: Li
authors: CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences Beijing, China.
authors: Jun
authors: J
authors: Tao
authors: CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences Beijing, China.
authors: Xinling
authors: X
authors: Hu
authors: Departments of Medicine and Microbiology and Immunology, Albert Einstein College of Medicine Bronx, NY, USA.
authors: John
authors: J
authors: Chan
authors: CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences Beijing, China.
authors: Jing
authors: J
authors: Xiao
authors: CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences Beijing, China ; Beijing Key Laboratory of Microbial Drug Resistance and Resistome Beijing, China.
authors: Kaixia
authors: K
authors: Mi
keywords: MsmHr; SigF; hemerythrin-like protein; hydrogen peroxide; mycobacteria
references: Nucleic Acids Res. 2009 Jan;37(Database issue):D387-92
references: 18931379
references: Infect Immun. 2008 Jun;76(6):2478-89
references: 18391009
references: Annu Rev Biochem. 2008;77:755-76
references: 18173371
references: Tuber Lung Dis. 1997;78(1):3-12
references: 9666957
references: Inorg Chem. 2011 Jun 6;50(11):4892-9
references: 21528842
references: J Bacteriol. 1995 Jan;177(1):123-33
references: 8002610
references: Microbiology. 2008 Sep;154(Pt 9):2786-95
references: 18757812
references: J Biol Chem. 2012 Jan 2;287(1):299-310
references: 22069311
references: Bioinformatics. 2006 Jan 15;22(2):195-201
references: 16301204
references: BMC Evol Biol. 2008 Sep 02;8:244
references: 18764950
references: Expert Rev Mol Med. 2011 Dec 16;13:e39
references: 22172201
references: J Am Chem Soc. 2003 Apr 2;125(13):3980-7
references: 12656634
references: Methods. 2001 Dec;25(4):402-8
references: 11846609
references: Proc Natl Acad Sci U S A. 1996 Apr 2;93(7):2790-4
references: 8610119
references: Antimicrob Agents Chemother. 2002 Sep;46(9):2765-71
references: 12183226
references: Free Radic Biol Med. 2012 Oct 15;53(8):1625-41
references: 22921590
references: Nucleic Acids Res. 2012 Nov;40(21):10832-50
references: 22965120
references: Nat Rev Microbiol. 2004 Oct;2(10):820-32
references: 15378046
references: Science. 2009 Oct 30;326(5953):718-21
references: 19762596
references: Proc Natl Acad Sci U S A. 2007 Jul 10;104(28):11568-73
references: 17609369
references: Adv Microb Physiol. 2010;57:43-117
references: 21078441
references: J Clin Microbiol. 2003 Sep;41(9):4471-4
references: 12958298
references: Antimicrob Agents Chemother. 2002 Nov;46(11):3348-55
references: 12384335
references: Genome Biol Evol. 2013;5(7):1435-42
references: 23843190
references: J Bacteriol. 2010 May;192(10):2491-502
references: 20233930
references: Science. 2009 Oct 30;326(5953):722-6
references: 19762597
references: Nature. 1991 Jun 6;351(6326):456-60
references: 1904554
references: J Biol Chem. 2007 Apr 6;282(14):10352-9
references: 17289666
references: Biochemistry. 2012 Oct 30;51(43):8563-70
references: 23057727
references: J Inorg Biochem. 2012 Jun;111:10-7
references: 22484247
references: Methods Enzymol. 1991;204:537-55
references: 1658570
references: FEMS Microbiol Rev. 2006 Nov;30(6):926-41
references: 17064287
references: Adv Microb Physiol. 2012;60:263-324
references: 22633061
references: Biochemistry. 2006 Aug 1;45(30):9023-31
references: 16866347
references: FEMS Microbiol Lett. 2008 Feb;279(2):131-45
references: 18081840
references: FEBS J. 2005 May;272(10):2428-40
references: 15885093
references: J Biol Chem. 2005 Jan 28;280(4):2636-43
references: 15546870
references: Curr Microbiol. 2008 Jun;56(6):574-80
references: 18324436
references: Nat Rev Microbiol. 2013 Jul;11(7):443-54
references: 23712352
references: J Clin Microbiol. 1986 Dec;24(6):976-81
references: 3097069
references: Mol Microbiol. 2002 Sep;45(6):1527-40
references: 12354223
references: Wei Sheng Wu Xue Bao. 2012 Nov 4;52(11):1352-9
references: 23383506
references: J Biol Chem. 2004 Dec 3;279(49):51554-60
references: 15385566
references: Electrophoresis. 1997 Dec;18(15):2714-23
references: 9504803
references: Microbiology. 2002 Oct;148(Pt 10):3007-17
references: 12368434
references: Antimicrob Agents Chemother. 1999 Feb;43(2):218-25
references: 9925509
references: Biochemistry. 2000 May 2;39(17):5117-25
references: 10819979
references: Nucleic Acids Res. 2003 Jul 1;31(13):3381-5
references: 12824332
references: Curr Opin Chem Biol. 2012 Apr;16(1-2):45-53
references: 22483328