Abstract
Both iron starvation and excess are detrimental to cellular life, especially for animal and plant pathogens since they always live in iron-limited environments produced by host immune responses. However, how organisms sense and respond to iron is incompletely understood. Herein, we reveal that in the phytopathogenic bacterium Xanthomonas campestris pv. campestris, VgrS (also named ColS) is a membrane-bound receptor histidine kinase that senses extracytoplasmic iron limitation in the periplasm, while its cognate response regulator, VgrR (ColR), detects intracellular iron excess. Under iron-depleted conditions, dissociation of Fe3+ from the periplasmic sensor region of VgrS activates the VgrS autophosphorylation and subsequent phosphotransfer to VgrR, an OmpR-family transcription factor that regulates bacterial responses to take up iron. VgrR-VgrS regulon and the consensus DNA binding motif of the transcription factor VgrR were dissected by comparative proteomic and ChIP-seq analyses, which revealed that in reacting to iron-depleted environments, VgrR directly or indirectly controls the expressions of hundreds of genes that are involved in various physiological cascades, especially those associated with iron-uptake. Among them, we demonstrated that the phosphorylated VgrR tightly represses the transcription of a special TonB-dependent receptor gene, tdvA. This regulation is a critical prerequisite for efficient iron uptake and bacterial virulence since activation of tdvA transcription is detrimental to these processes. When the intracellular iron accumulates, the VgrR-Fe2+ interaction dissociates not only the binding between VgrR and the tdvA promoter, but also the interaction between VgrR and VgrS. This relieves the repression in tdvA transcription to impede continuous iron uptake and avoids possible toxic effects of excessive iron accumulation. Our results revealed a signaling system that directly senses both extracytoplasmic and intracellular iron to modulate bacterial iron homeostasis.
Highlights
As the fourth most abundant element in the Earth’s crust, iron is a metal essential for all cellular life
The biological function of iron is like a “double-edge sword” to all cellular life since iron starvation or iron excess leads to cell death
For animal and plant pathogens, they have to compete for iron with their hosts since iron-limitation generally is an immune response against microbial infection
Summary
As the fourth most abundant element in the Earth’s crust, iron is a metal essential for all cellular life. Either iron limitiation or iron excess is harmful to organisms. The ferrous iron (Fe2+) acts as a cofactor that is required for essential physiological processes such as respiration, photosynthesis, energy metabolism and biosynthesis of multiple macromolecules [1]. Excess iron can be extremely toxic to cells because it catalyzes the generation of highly reactive damaging hydroxyl radicals from superoxide and hydrogen peroxide [2]. Iron should be exported outside cells or chelated to quench its toxic activity [3, 4]. How cellular organisms precisely balance the two opposite processes to achieve iron homeostasis remains unknown
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