title: Binary toxin production in Clostridium difficile is regulated by CdtR, a LytTR family response regulator.
abstract: 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.
authors: Australian Bacterial Pathogenesis Program, Department of Microbiology, Monash University, Victoria, Australia.
authors: Glen P
authors: GP
authors: Carter
authors: Dena
authors: D
authors: Lyras
authors: David L
authors: DL
authors: Allen
authors: Kate E
authors: KE
authors: Mackin
authors: Pauline M
authors: PM
authors: Howarth
authors: Jennifer R
authors: JR
authors: O'Connor
authors: Julian I
authors: JI
authors: Rood
mesh_terms: 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*
chemical_list: D001426:Bacterial Proteins; D004269:DNA, Bacterial; D014157:Transcription Factors; D036002:ADP Ribose Transferases; C410164:actin-specific ADP-ribosyltransferase, Clostridium
references: FEMS Microbiol Lett. 2000 May 15;186(2):307-12
references: 10802189
references: Plasmid. 1989 Jul;22(1):59-69
references: 2550984
references: DNA Seq. 2001;12(2):115-20
references: 11761709
references: Clin Infect Dis. 2002 Feb 1;34(3):346-53
references: 11774082
references: Nucleic Acids Res. 2002 Jun 1;30(11):2453-9
references: 12034833
references: J Bacteriol. 2002 Nov;184(21):5971-8
references: 12374831
references: Infect Immun. 2002 Nov;70(11):6083-93
references: 12379685
references: Mol Microbiol. 2002 Oct;46(2):439-52
references: 12406220
references: Infect Immun. 2003 Apr;71(4):1784-93
references: 12654792
references: J Clin Microbiol. 2003 Nov;41(11):5227-32
references: 14605169
references: Mol Microbiol. 1992 Oct;6(20):2905-8
references: 1479882
references: J Bacteriol. 1994 Mar;176(6):1616-23
references: 8132455
references: Mol Microbiol. 1994 Jun;12(5):761-77
references: 8052128
references: Nucleic Acids Res. 1994 Nov 11;22(22):4673-80
references: 7984417
references: Lancet. 1995 Feb 18;345(8947):455-6
references: 7853976
references: J Biol Chem. 1995 Jun 9;270(23):13932-6
references: 7775453
references: Nature. 1995 Jun 8;375(6531):500-3
references: 7777059
references: Mol Gen Genet. 1995 Aug 30;248(4):446-58
references: 7565609
references: Mol Microbiol. 1996 Sep;21(6):1227-37
references: 8898391
references: Gene. 1996 Nov 28;181(1-2):29-38
references: 8973304
references: Infect Immun. 1997 Apr;65(4):1402-7
references: 9119480
references: Eur J Biochem. 1997 Mar 15;244(3):735-42
references: 9108241
references: Mol Microbiol. 1998 Jan;27(1):107-20
references: 9466260
references: J Antimicrob Chemother. 1998 May;41 Suppl C:5-12
references: 9630369
references: J Antimicrob Chemother. 1998 May;41 Suppl C:13-9
references: 9630370
references: J Antimicrob Chemother. 1998 May;41 Suppl C:21-7
references: 9630371
references: Annu Rev Microbiol. 1998;52:333-60
references: 9891801
references: Clin Infect Dis. 2005 Jan 15;40(2):265-72
references: 15655746
references: Infect Control Hosp Epidemiol. 2005 Aug;26(8):672-5
references: 16156321
references: Lancet. 2005 Sep 24-30;366(9491):1079-84
references: 16182895
references: N Engl J Med. 2005 Dec 8;353(23):2442-9
references: 16322602
references: J Infect Dis. 2006 Apr 15;193(8):1143-50
references: 16544255
references: Euro Surveill. 2005;10(6):E050630.2
references: 16783109
references: Nat Genet. 2006 Jul;38(7):779-86
references: 16804543
references: Mol Microbiol. 2006 Sep;61(5):1335-51
references: 16925561
references: Clin Microbiol Infect. 2006 Oct;12 Suppl 6:2-18
references: 16965399
references: J Bacteriol. 2006 Oct;188(20):7297-305
references: 17015669
references: Infect Control Hosp Epidemiol. 2007 Feb;28(2):131-9
references: 17265393
references: J Med Microbiol. 2007 Mar;56(Pt 3):329-35
references: 17314362
references: Clin Microbiol Infect. 2007 May;13(5):457-9
references: 17331126
references: J Clin Microbiol. 2004 May;42(5):1933-9
references: 15131151
references: CMAJ. 2004 Jul 20;171(2):123
references: 15262874
references: Microbiol Mol Biol Rev. 2004 Sep;68(3):373-402, table of contents
references: 15353562
references: J Clin Microbiol. 2004 Sep;42(9):4316-8
references: 15365032
references: J Mol Biol. 1969 May 14;41(3):459-72
references: 4896022
references: Nature. 1970 Aug 15;227(5259):680-5
references: 5432063
references: Antimicrob Agents Chemother. 1981 Jun;19(6):997-1003
references: 7271279
references: Infect Immun. 1982 Mar;35(3):1032-40
references: 7068210
references: Antimicrob Agents Chemother. 1983 May;23(5):784-6
references: 6870225
references: Med Microbiol Immunol. 1987;176(2):79-82
references: 3574240
references: Antimicrob Agents Chemother. 1987 Jul;31(7):1039-45
references: 2821888
references: Infect Immun. 1988 Jan;56(1):24-7
references: 3121511
references: Infect Immun. 1988 Sep;56(9):2299-306
references: 3137166
references: Mol Gen Genet. 1988 Sep;214(1):177-9
references: 3147372
references: Gene. 1989 Apr 15;77(1):51-9
references: 2744487
references: Gene. 1989 Apr 15;77(1):61-8
references: 2744488
references: Annu Rev Biochem. 2000;69:183-215
references: 10966457