Binary toxin production in Clostridium difficile is regulated by CdtR, a LytTR family response regulator.
Clostridium difficile binary toxin (CDT) is an actin-specific ADP-ribosyltransferase that is produced by various C. difficile isolates, including the "hypervirulent" NAP1/027 epidemic strains. In contrast to the two major toxins from C. difficile, toxin A and toxin B, little is known about the role of CDT in virulence or how C. difficile regulates its production. In this study we have shown that in addition to the cdtA and cdtB toxin structural genes, a functional cdt locus contains a third gene, here designated cdtR, which is predicted to encode a response regulator. By introducing functional binary toxin genes into cdtR(+) and cdtR-negative strains of C. difficile, it was established that the CdtR protein was required for optimal expression of binary toxin. Significantly increased expression of functional binary toxin was observed in the presence of a functional cdtR gene; an internal deletion within cdtR resulted in a reduction in binary toxin production to basal levels. Strains that did not carry intact cdtAB genes or cdtAB pseudogenes also did not have cdtR, with the entire cdt locus, or CdtLoc, being replaced by a conserved 68-bp sequence. These studies have shown for the first time that binary toxin production is subject to strict regulatory control by the response regulator CdtR, which is a member of the LytTR family of response regulators and is related to the AgrA protein from Staphylococcus aureus.
Carter
Glen P
GP
Australian Bacterial Pathogenesis Program, Department of Microbiology, Monash University, Victoria, Australia.
Lyras
Dena
D
Allen
David L
DL
Mackin
Kate E
KE
Howarth
Pauline M
PM
O'Connor
Jennifer R
JR
Rood
Julian I
JI
D036002:ADP Ribose Transferases / Q000096:biosynthesis* / Q000235:genetics; D000595:Amino Acid Sequence; D001426:Bacterial Proteins / Q000096:biosynthesis* / Q000235:genetics; D016360:Clostridioides difficile / Q000502:physiology*; D004269:DNA, Bacterial / Q000737:chemistry / Q000235:genetics; D015964:Gene Expression Regulation, Bacterial / Q000502:physiology*; D005798:Genes, Bacterial; D005809:Genes, Regulator; D005816:Genetic Complementation Test; D008969:Molecular Sequence Data; D017422:Sequence Analysis, DNA; D017384:Sequence Deletion; D017386:Sequence Homology, Amino Acid; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*
D001426:Bacterial Proteins; D004269:DNA, Bacterial; D014157:Transcription Factors; D036002:ADP Ribose Transferases; C410164:actin-specific ADP-ribosyltransferase, Clostridium
FEMS Microbiol Lett. 2000 May 15;186(2):307-12
10802189
Plasmid. 1989 Jul;22(1):59-69
2550984
DNA Seq. 2001;12(2):115-20
11761709
Clin Infect Dis. 2002 Feb 1;34(3):346-53
11774082
Nucleic Acids Res. 2002 Jun 1;30(11):2453-9
12034833
J Bacteriol. 2002 Nov;184(21):5971-8
12374831
Infect Immun. 2002 Nov;70(11):6083-93
12379685
Mol Microbiol. 2002 Oct;46(2):439-52
12406220
Infect Immun. 2003 Apr;71(4):1784-93
12654792
J Clin Microbiol. 2003 Nov;41(11):5227-32
14605169
Mol Microbiol. 1992 Oct;6(20):2905-8
1479882
J Bacteriol. 1994 Mar;176(6):1616-23
8132455
Mol Microbiol. 1994 Jun;12(5):761-77
8052128
Nucleic Acids Res. 1994 Nov 11;22(22):4673-80
7984417
Lancet. 1995 Feb 18;345(8947):455-6
7853976
J Biol Chem. 1995 Jun 9;270(23):13932-6
7775453
Nature. 1995 Jun 8;375(6531):500-3
7777059
Mol Gen Genet. 1995 Aug 30;248(4):446-58
7565609
Mol Microbiol. 1996 Sep;21(6):1227-37
8898391
Gene. 1996 Nov 28;181(1-2):29-38
8973304
Infect Immun. 1997 Apr;65(4):1402-7
9119480
Eur J Biochem. 1997 Mar 15;244(3):735-42
9108241
Mol Microbiol. 1998 Jan;27(1):107-20
9466260
J Antimicrob Chemother. 1998 May;41 Suppl C:5-12
9630369
J Antimicrob Chemother. 1998 May;41 Suppl C:13-9
9630370
J Antimicrob Chemother. 1998 May;41 Suppl C:21-7
9630371
Annu Rev Microbiol. 1998;52:333-60
9891801
Clin Infect Dis. 2005 Jan 15;40(2):265-72
15655746
Infect Control Hosp Epidemiol. 2005 Aug;26(8):672-5
16156321
Lancet. 2005 Sep 24-30;366(9491):1079-84
16182895
N Engl J Med. 2005 Dec 8;353(23):2442-9
16322602
J Infect Dis. 2006 Apr 15;193(8):1143-50
16544255
Euro Surveill. 2005;10(6):E050630.2
16783109
Nat Genet. 2006 Jul;38(7):779-86
16804543
Mol Microbiol. 2006 Sep;61(5):1335-51
16925561
Clin Microbiol Infect. 2006 Oct;12 Suppl 6:2-18
16965399
J Bacteriol. 2006 Oct;188(20):7297-305
17015669
Infect Control Hosp Epidemiol. 2007 Feb;28(2):131-9
17265393
J Med Microbiol. 2007 Mar;56(Pt 3):329-35
17314362
Clin Microbiol Infect. 2007 May;13(5):457-9
17331126
J Clin Microbiol. 2004 May;42(5):1933-9
15131151
CMAJ. 2004 Jul 20;171(2):123
15262874
Microbiol Mol Biol Rev. 2004 Sep;68(3):373-402, table of contents
15353562
J Clin Microbiol. 2004 Sep;42(9):4316-8
15365032
J Mol Biol. 1969 May 14;41(3):459-72
4896022
Nature. 1970 Aug 15;227(5259):680-5
5432063
Antimicrob Agents Chemother. 1981 Jun;19(6):997-1003
7271279
Infect Immun. 1982 Mar;35(3):1032-40
7068210
Antimicrob Agents Chemother. 1983 May;23(5):784-6
6870225
Med Microbiol Immunol. 1987;176(2):79-82
3574240
Antimicrob Agents Chemother. 1987 Jul;31(7):1039-45
2821888
Infect Immun. 1988 Jan;56(1):24-7
3121511
Infect Immun. 1988 Sep;56(9):2299-306
3137166
Mol Gen Genet. 1988 Sep;214(1):177-9
3147372
Gene. 1989 Apr 15;77(1):51-9
2744487
Gene. 1989 Apr 15;77(1):61-8
2744488
Annu Rev Biochem. 2000;69:183-215
10966457