title: Interplay among cyclic diguanylate, HapR, and the general stress response regulator (RpoS) in the regulation of Vibrio cholerae hemagglutinin/protease.
abstract: Vibrio cholerae secretes the Zn-dependent metalloprotease hemagglutinin (HA)/protease (mucinase), which is encoded by hapA and displays a broad range of potential pathogenic activities. Expression of HA/protease has a stringent requirement for the quorum-sensing regulator HapR and the general stress response regulator RpoS. Here we report that the second messenger cyclic diguanylic acid (c-di-GMP) regulates the production of HA/protease in a negative manner. Overexpression of a diguanylate cyclase to increase the cellular c-di-GMP pool resulted in diminished expression of HA/protease and its positive regulator, HapR. The effect of c-di-GMP on HapR was independent of LuxO but was abolished by deletion of the c-di-GMP binding protein VpsT, the LuxR-type regulator VqmA, or a single-base mutation in the hapR promoter that prevents autorepression. Though expression of HapR had a positive effect on RpoS biosynthesis, direct manipulation of the c-di-GMP pool at a high cell density did not significantly impact RpoS expression in the wild-type genetic background. In contrast, increasing the c-di-GMP pool severely inhibited RpoS expression in a ΔhapR mutant that is locked in a regulatory state mimicking low cell density. Based on the above findings, we propose a model for the interplay between HapR, RpoS, and c-di-GMP in the regulation of HA/protease expression.
authors.affiliation: Southern Research Institute, 2000 Ninth Avenue South, Birmingham, Alabama 35205, USA.
authors.forename: Hongxia
authors.initials: H
authors.lastname: Wang
authors.forename: Jian-He
authors.initials: JH
authors.lastname: Wu
authors.forename: Julio C
authors.initials: JC
authors.lastname: Ayala
authors.forename: Jorge A
authors.initials: JA
authors.lastname: Benitez
authors.forename: Anisia J
authors.initials: AJ
authors.lastname: Silva
mesh_terms: D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism*; D006152:Cyclic GMP / Q000031:analogs & derivatives / Q000378:metabolism; D015964:Gene Expression Regulation, Bacterial; D015971:Gene Expression Regulation, Enzymologic; D008666:Metalloendopeptidases / Q000235:genetics* / Q000378:metabolism; D012808:Sigma Factor / Q000235:genetics / Q000378:metabolism*; D014734:Vibrio cholerae / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism
chemical_list: D001426:Bacterial Proteins; D012808:Sigma Factor; C069567:sigma factor KatF protein, Bacteria; C062025:bis(3',5')-cyclic diguanylic acid; D008666:Metalloendopeptidases; C039814:hemagglutinin-protease; D006152:Cyclic GMP