Nitric oxide (NO) is an important antimicrobial effector produced by the host innate immune system to counteract invading pathogens. To survive and establish a successful
infection, a fulminating human pathogen Vibrio vulnificus expresses the
hmpA gene encoding an
NO dioxygenase in an NO-responsive manner. In this study, we identified an Rrf2-family transcriptional regulator NsrR that is predicted to contain the Fe-S cluster coordinated by three
cysteine residues. Transcriptome analysis showed that NsrR controls the expression of multiple genes potentially involved in nitrosative stress responses. Particularly, NsrR acts as a strong repressor of
hmpA transcription and relieves the repression of
hmpA upon exposure to NO. Notably, nsrR and
hmpA are transcribed divergently, and their promoter regions overlap with each other. Molecular
biological analyses revealed that NsrR directly binds to this overlapping promoter region, which is alleviated by loss of the Fe-S cluster, leading to the subsequent derepression of
hmpA under nitrosative stress. We further found that a
leucine-responsive regulatory protein (Lrp) negatively regulates
hmpA in an NsrR-dependent manner by directly binding to the promoter region, presumably resulting in
a DNA conformation change to support the repression by NsrR. Meanwhile, a
cyclic AMP receptor protein (CRP) positively regulates
hmpA probably through repression of nsrR and lrp by directly binding to each promoter region in a sequential cascade. Altogether, this collaborative regulation of NsrR along with Lrp and CRP enables an elaborate control of
hmpA transcription, contributing to survival under host-derived nitrosative stress and thereby the pathogenesis of V. vulnificus.