Attenuation of a DNA cruciform by a conserved regulator directs T3SS1 mediated virulence in Vibrio parahaemolyticus

Abstract Pathogenic Vibrio species account for 3–5 million annual life-threatening human infections. Virulence is driven by bacterial hemolysin and toxin gene expression often positively regulated by the winged helix-turn-helix (wHTH) HlyU transcriptional regulator family and silenced by histone-lik...

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Published in:	Nucleic acids research Vol. 51; no. 12; pp. 6156 - 6171
Main Authors:	Getz, Landon J, Brown, Justin M, Sobot, Lauren, Chow, Alexandra, Mahendrarajah, Jastina, Thomas, Nikhil A
Format:	Journal Article
Language:	English
Published:	England Oxford University Press 07-07-2023
Subjects:	Bacterial Proteins - metabolism DNA, Cruciform - metabolism Escherichia coli - genetics Gene Expression Regulation, Bacterial Gene regulation, Chromatin and Epigenetics Humans Type III Secretion Systems - genetics Vibrio parahaemolyticus - genetics Vibrio parahaemolyticus - metabolism Virulence - genetics
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Summary:	Abstract Pathogenic Vibrio species account for 3–5 million annual life-threatening human infections. Virulence is driven by bacterial hemolysin and toxin gene expression often positively regulated by the winged helix-turn-helix (wHTH) HlyU transcriptional regulator family and silenced by histone-like nucleoid structural protein (H-NS). In the case of Vibrio parahaemolyticus, HlyU is required for virulence gene expression associated with type 3 Secretion System-1 (T3SS1) although its mechanism of action is not understood. Here, we provide evidence for DNA cruciform attenuation mediated by HlyU binding to support concomitant virulence gene expression. Genetic and biochemical experiments revealed that upon HlyU mediated DNA cruciform attenuation, an intergenic cryptic promoter became accessible allowing for exsA mRNA expression and initiation of an ExsA autoactivation feedback loop at a separate ExsA-dependent promoter. Using a heterologous E. coli expression system, we reconstituted the dual promoter elements which revealed that HlyU binding and DNA cruciform attenuation were strictly required to initiate the ExsA autoactivation loop. The data indicate that HlyU acts to attenuate a transcriptional repressive DNA cruciform to support T3SS1 virulence gene expression and reveals a non-canonical extricating gene regulation mechanism in pathogenic Vibrio species. Graphical Abstract Graphical Abstract
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0305-1048 1362-4962
DOI:	10.1093/nar/gkad370