Abstract
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.
Highlights
Nitric oxide (NO) is a highly reactive, toxic, and membrane-permeable radical gas
We previously reported that NO-induced HmpA encoded by VVMO6_RS01375 is crucial for survival under host-derived nitrosative stress and pathogenesis of V. vulnificus during infection (Kim et al, 2019)
We newly identified and characterized an NOresponsive transcriptional regulator NsrR in V. vulnificus (Figure 1)
Summary
Nitric oxide (NO) is a highly reactive, toxic, and membrane-permeable radical gas. As one of the major components of the host innate immune system, NO is produced by inducible NO synthase (iNOS) which is expressed in phagocytes and epithelial cells under infectious conditions (Fang, 2004; Wang et al, 2010). NO produced by iNOS can subsequently be converted into other toxic hmpA Regulation by NsrR in V. vulnificus reactive nitrogen species (RNS) such as nitrogen dioxide (NO2), peroxynitrite (ONOO−), and dinitrogen trioxide (N2O3) which impose the nitrosative stress on pathogens (Fang, 2004; Stern and Zhu, 2014). RNS can cause damage to cellular components, including the metal centers of proteins, membrane lipids and nucleotide bases, and thereby inhibit respiration and interfere with the DNA replication of pathogens (Fang, 2004). Pathogens have evolved sophisticated mechanisms to sense the increased level of RNS and express the proper genes to overcome nitrosative stress in a host (Bang et al, 2006; Stern et al, 2012)
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