The Yersinia pestis chromosome encodes active addiction toxins.
Toxin-antitoxin (TA) loci consist of two genes in an operon, encoding a stable toxin and an unstable antitoxin. The expression of toxin leads to cell growth arrest and sometimes bacterial death, while the antitoxin prevents the cytotoxic activity of the toxin. In this study, we show that the chromosome of Yersinia pestis, the causative agent of plague, carries 10 putative TA modules and two solitary antitoxins that belong to five different TA families (HigBA, HicAB, RelEB, Phd/Doc, and MqsRA). Two of these toxin genes (higB2 and hicA1) could not be cloned in Escherichia coli unless they were coexpressed with their cognate antitoxin gene, indicating that they are highly toxic for this species. One of these toxin genes (higB2) could, however, be cloned directly and expressed in Y. pestis, where it was highly toxic, while the other one (hicA1) could not, probably because of its extreme toxicity. All eight other toxin genes were successfully cloned into the expression vector pBAD-TOPO. For five of them (higB1, higB3, higB5, hicA2, and tox), no toxic activity was detected in either E. coli or Y. pestis despite their overexpression. The three remaining toxin genes (relE1, higB4, and doc) were toxic for E. coli, and this toxic activity was abolished when the cognate antitoxin was coexpressed, showing that these three TA modules are functional in E. coli. Curiously, only one of these three toxins (RelE1) was active in Y. pestis. Cross-interaction between modules of the same family was observed but occurred only when the antitoxins were almost identical. Therefore, our study demonstrates that of the 10 predicted TA modules encoded by the Y. pestis chromosome, at least 5 are functional in E. coli and/or in Y. pestis. This is the first demonstration of active addiction toxins produced by the plague agent.
Goulard
Céline
C
Yersinia Research Unit, Institut Pasteur, 28 Rue du Dr. Roux, F-75724 Paris Cedex 15, France.
Langrand
Sophie
S
Carniel
Elisabeth
E
Chauvaux
Sylvie
S
D000992:Antitoxins / Q000235:genetics / Q000378:metabolism; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism; D001427:Bacterial Toxins / Q000235:genetics* / Q000378:metabolism*; D002876:Chromosomes, Bacterial / Q000235:genetics*; D004926:Escherichia coli / Q000235:genetics / Q000378:metabolism; D015964:Gene Expression Regulation, Bacterial / Q000502:physiology*; D015010:Yersinia pestis / Q000235:genetics* / Q000378:metabolism*
D000992:Antitoxins; D001426:Bacterial Proteins; D001427:Bacterial Toxins
J Bacteriol. 2009 Feb;191(4):1191-9
19060138
Emerg Infect Dis. 2008 Jun;14(6):941-3
18507908
J Bacteriol. 2003 Mar;185(6):1803-7
12618443
J Biol Chem. 2005 Feb 4;280(5):3143-50
15537630
Cell. 2003 Jan 10;112(1):131-40
12526800
FEMS Immunol Med Microbiol. 2003 Sep 22;38(2):113-6
13129645
Mol Microbiol. 2002 May;44(4):971-9
12010492
Genome Biol. 2007;8(8):R155
17678530
Bull Soc Pathol Exot Filiales. 1963 Nov-Dec;56:1186-93
14153922
Mol Microbiol. 2004 Mar;51(6):1705-17
15009896
J Bacteriol. 2004 Dec;186(24):8295-300
15576778
Mol Cell. 2003 Oct;12(4):913-23
14580342
Genome Biol. 2003;4(12):R81
14659018
Antonie Van Leeuwenhoek. 2005 Apr;87(3):171-7
15803382
Plasmid. 2010 Jan;63(1):31-9
19800365
J Mol Biol. 1997 Nov 7;273(4):826-39
9367775
Infect Immun. 2005 Jun;73(6):3734-9
15908403
Gene. 1990 Mar 1;87(1):133-7
2332165
Proc Natl Acad Sci U S A. 1986 May;83(10):3116-20
3517851
Mol Microbiol. 2006 Oct;62(2):397-411
17020579
J Bacteriol. 2006 May;188(9):3420-3
16621839
BMC Microbiol. 2007 Oct 29;7:96
17963531
Mol Microbiol. 2003 Jun;48(5):1389-400
12787364
Proc Natl Acad Sci U S A. 2001 Dec 4;98(25):14328-33
11717402
Nat Rev Microbiol. 2005 May;3(5):371-82
15864262
Epidemiol Infect. 2007 Jul;135(5):740-8
17156497
Nat Rev Microbiol. 2003 Oct;1(1):55-64
15040180
Wkly Epidemiol Rec. 2009 Feb 5;85(6):40-5
20151494
JAMA. 2000 May 3;283(17):2281-90
10807389
Proc Natl Acad Sci U S A. 2008 Apr 15;105(15):5885-90
18398006
FEMS Microbiol Lett. 2006 Oct;263(1):26-31
16958847
J Biol Chem. 2009 Jan 2;284(1):276-283
18952600
FEMS Microbiol Lett. 2005 Feb 15;243(2):489-96
15686853
Microbiology (Reading). 2007 Sep;153(Pt 9):3112-3124
17768254
Infect Immun. 2008 May;76(5):1804-11
18250178
Mol Microbiol. 1995 Jul;17(2):205-10
7494469
Bull Soc Pathol Exot Filiales. 1963 Nov-Dec;56:1168-82
14156818
J Bacteriol. 2004 Jun;186(11):3663-9
15150257
PLoS Pathog. 2009 Dec;5(12):e1000706
20041169
Nucleic Acids Res. 2005 Feb 17;33(3):966-76
15718296
Nature. 2001 Oct 4;413(6855):523-7
11586360
Clin Microbiol Rev. 1997 Jan;10(1):35-66
8993858
FEMS Microbiol Lett. 2009 Jan;290(1):45-53
19016878
Mol Microbiol. 2008 Aug;69(3):559-69
18485066
Trends Microbiol. 2004 Feb;12(2):66-71
15036322
Bull World Health Organ. 1960;23:313-400
13736873
Biol Direct. 2009 Jun 03;4:19
19493340
Trends Biochem Sci. 2005 Dec;30(12):672-9
16257530
Res Microbiol. 2005 Apr;156(3):403-15
15808945