MtsR is a dual regulator that controls virulence genes and metabolic functions in addition to metal homeostasis in the group A streptococcus.
MtsR is a metal-dependent regulator in the group A streptococcus (GAS) that directly represses the transcription of genes involved in haem and metal uptake. While MtsR has been implicated in GAS virulence, the DNA recognition and full regulatory scope exerted by the protein are unknown. In this study we identified the shr promoter (P(shr)) and mapped MtsR binding to a 69 bp segment in P(shr) that overlaps the core promoter elements. A global transcriptional analysis demonstrated that MtsR modulates the expression of 64 genes in GAS, 44 of which were upregulated and 20 were downregulated in the mtsR mutant. MtsR controls genes with diverse functions including metal homeostasis, nucleic acid and amino acid metabolism, and protein fate. Importantly, the MtsR regulon includes mga, emm49 and ska, which are central for GAS pathogenesis. MtsR binding to the promoter region of both negatively and positively regulated genes demonstrates that it functions as a dual regulator. MtsR footprints are large (47-130 bp) and vary between target promoters. A 16 bp motif that consists of an interrupted palindrome is implicated in the DNA recognition by the metalloregulator. In conclusion, we report here that MtsR is a global regulator in GAS that shapes the expression of vital virulence factors and genes involved in metabolic functions and metal transport, and we discuss the implications for the GAS disease process.
Toukoki
Chadia
C
Department of Biology, College of Arts and Sciences, Georgia State University, Atlanta, GA 30303, USA.
Gold
Kathryn M
KM
McIver
Kevin S
KS
Eichenbaum
Zehava
Z
D000595:Amino Acid Sequence; D001483:Base Sequence; D015964:Gene Expression Regulation, Bacterial; D053263:Gene Regulatory Networks; D005809:Genes, Regulator; D006706:Homeostasis / Q000235:genetics; D008670:Metals / Q000378:metabolism; D008969:Molecular Sequence Data; D009876:Operon; D011401:Promoter Regions, Genetic; D018085:Regulon / Q000235:genetics; D013297:Streptococcus pyogenes / Q000235:genetics* / Q000378:metabolism / Q000472:pathogenicity*; D014774:Virulence / Q000235:genetics; D037521:Virulence Factors / Q000235:genetics*
D008670:Metals; D037521:Virulence Factors
Infect Immun. 2002 Sep;70(9):4968-76
12183543
Microbiology (Reading). 2005 Nov;151(Pt 11):3749-3757
16272396
Nucleic Acids Res. 2003 Aug 15;31(16):4689-95
12907708
Mol Microbiol. 2005 Jan;55(1):221-34
15612930
Microbiology (Reading). 2001 Mar;147(Pt 3):653-662
11238972
J Bacteriol. 2000 Oct;182(19):5290-9
10986229
Biochemistry. 2009 Nov 3;48(43):10308-20
19795834
Infect Immun. 2008 Oct;76(10):4659-68
18678666
Mol Microbiol. 2008 Jul;69(2):436-52
18485073
Infect Immun. 1998 Jan;66(1):315-21
9423873
Br J Sports Med. 1999 Jun;33(3):204-7
10378074
Infect Immun. 2003 Mar;71(3):1042-55
12595414
Mol Microbiol. 1998 Oct;30(1):209-19
9786197
Adv Exp Med Biol. 2008;609:29-42
18193655
J Bacteriol. 2008 Aug;190(15):5382-93
18515418
Cell Microbiol. 2009 Jan;11(1):1-12
18710460
J Bacteriol. 2006 Jul;188(14):5033-44
16816176
Biochem Biophys Res Commun. 2003 Mar 21;302(4):722-7
12646229
Infect Immun. 2002 Aug;70(8):4494-500
12117961
Infect Immun. 2005 Sep;73(9):5743-53
16113291
Infect Immun. 2006 Sep;74(9):5132-9
16926405
Infect Immun. 2008 Aug;76(8):3451-63
18490461
J Bacteriol. 2004 Jun;186(12):3928-37
15175307
J Bacteriol. 2010 Mar;192(5):1433-43
19915021
Mol Microbiol. 2007 Feb;63(4):1185-96
17238923
PLoS Pathog. 2006 Jan;2(1):e5
16446783
PLoS Pathog. 2008 Sep 05;4(9):e1000145
18773116
Mol Microbiol. 2001 Nov;42(3):851-65
11722747
Infect Immun. 2006 Feb;74(2):1171-80
16428766
Microbiology (Reading). 2009 May;155(Pt 5):1569-1579
19372167
J Biol Chem. 2006 Jul 28;281(30):20761-20771
16717094
Infect Immun. 1995 Nov;63(11):4540-2
7591100
Infect Immun. 2000 Aug;68(8):4441-51
10899841
J Bacteriol. 2002 Dec;184(24):6882-92
12446639
FEMS Microbiol Lett. 2003 Dec 5;229(1):97-101
14659548
Infect Immun. 2009 Jul;77(7):2840-8
19398546
Mol Microbiol. 2007 Dec;66(5):1056-65
18001346
BMC Microbiol. 2008 Jan 23;8:15
18215300
Appl Environ Microbiol. 1998 Aug;64(8):2763-9
9687428
Proc Natl Acad Sci U S A. 2006 May 2;103(18):7059-64
16636287
Infect Immun. 2003 Apr;71(4):2199-207
12654842
BMC Microbiol. 2005 Oct 14;5:62
16225685
Nucleic Acids Res. 2008 Jul 1;36(Web Server issue):W423-6
18477636
FEMS Microbiol Lett. 1991 Aug 1;66(2):219-24
1936949
Mol Microbiol. 2005 Jun;56(5):1195-207
15882414
Med Microbiol Immunol. 1995 Oct;184(3):139-46
8577315
J Bacteriol. 2008 Jul;190(14):4849-58
18502861
J Mol Biol. 2002 Sep 20;322(3):521-32
12225746
Trends Microbiol. 2007 Jul;15(7):318-25
17524649
Mol Microbiol. 2006 Oct;62(2):491-508
16965517
Proc Natl Acad Sci U S A. 1994 Sep 27;91(20):9646-50
7937822
Proc Natl Acad Sci U S A. 2001 Aug 28;98(18):10416-21
11517341
Microbiology (Reading). 2008 Apr;154(Pt 4):1132-1143
18375805
J Bacteriol. 2009 Jan;191(2):673-7
18996992
Clin Microbiol Rev. 2000 Jul;13(3):470-511
10885988
Proc Natl Acad Sci U S A. 2010 Jan 12;107(2):888-93
20080771
Mol Microbiol. 2000 Oct;38(1):140-53
11029696
BMC Genomics. 2006 Feb 09;7:21
16469103
Nucleic Acids Res. 1998 Aug 1;26(15):3584-90
9671823
Infect Immun. 2008 Nov;76(11):5006-15
18710861
Proc Natl Acad Sci U S A. 2002 Oct 15;99(21):13855-60
12370433
Mol Microbiol. 2001 Jan;39(2):392-406
11136460
J Bacteriol. 1994 Feb;176(4):1141-9
8106325
Infect Immun. 2003 May;71(5):2656-64
12704140
Microbiology (Reading). 2009 Feb;155(Pt 2):566-575
19202105
Contrib Microbiol. 2009;16:103-119
19494581