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Curr Opin Microbiol. Author manuscript; available in PMC Apr 1, 2011.
Published in final edited form as:
PMCID: PMC2847643
NIHMSID: NIHMS181166

Global Regulation by the Seven-component Pi Signaling System

Summary

This review concerns how Escherichia coli detects environmental inorganic orthophosphate (Pi) to regulate genes of the phosphate (Pho) regulon by the PhoR/PhoB two-component system (TCS). Pi control by the PhoR/PhoB TCS is a paradigm of a bacterial signal transduction pathway in which occupancy of a cell surface receptor(s) controls gene expression in the cytoplasm. The Pi signaling pathway requires seven proteins, all of which probably interact in a membrane-associated signaling complex. Our latest studies show that Pi signaling involves three distinct processes, which appear to correspond to different states of the sensory histidine kinase PhoR: an inhibition state, an activation state, and a deactivation state. We describe a revised model for Pi signal transduction of the E. coli Pho regulon.

Introduction

How cells respond to environmental (extracellular) signals is of fundamental importance in biology. The control of the Escherichia coli phosphate (Pho) regulon by extracellular inorganic orthophosphate (Pi) is of special interest for it serves as a paradigm for a two-component system (TCS) in which signaling is mediated by an ABC (ATP-binding cassette) transporter, the Pst (phosphate-specific transport) system, in the absence of transport.

The E. coli Pho regulon is comprised of a large number of genes that are co-regulated by environmental Pi, the preferred P source, and that are required for assimilation of a variety of phosphorus (P) sources for growth. Signal transduction by environmental Pi requires seven proteins, which are thought to interact in a membrane-associated signaling complex. These Pi signaling proteins include: (i) two that are members of the large family of TCSs, namely the sensory histidine kinase (HK) PhoR (an integral membrane protein) and its partner DNA-binding response regulator (RR) PhoB (a transcription factor); (ii) four components of the ABC transporter Pst; and (iii) the chaperone-like PhoR/PhoB inhibitory protein called PhoU.

The PhoR HK is required for activation (phosphorylation) of the PhoB RR under conditions of Pi limitation. Other (non-partner) HKs, e. g., the CreC HK of the CreC/CreB TCS, can also activate (phosphorylate) PhoB, both in vivo and in vitro. The finding of such interactions has lead to the suggestion that “cross regulation” can occur between different TCSs, which may play a role in the integration of multiple signals. For example, cross regulation of the PhoR/PhoB TCS may be important for connecting different steps of Pi metabolism [1]. Similar interactions have been seen among non-partner proteins of other TCSs (e. g., the NarX/NarL and NarQ/NarP TCSs [2]). DNA microarray studies have provided further evidence for cross regulation among the BaeS/BaeR, PhoR/PhoB, and CreC/CreB TCSs [3]. Other data suggest that cross regulation of the PhoR/PhoB TCS is likely to be even more extensive [4]. Thus, further studies of the Pho regulon can serve as a model for cross regulation among different TCSs.

This review covers the period from when inorganic orthophosphate (Pi) control of the Escherichia coli phosphate (Pho) regulon was last reviewed in 1996 [1] through 2009. It includes new information on genes controlled by the PhoR/PhoB TCS, cross regulation and stochasticity in the control of Pi-regulated genes, and our current understanding of how environmental Pi regulates the E. coli Pho regulon.

The PhoR/PhoB TCS controls genes for phosphorus assimilation

Estimates for the number of Pi-regulated genes vary widely. Proteome profiles of cells grown under Pi excess and limited conditions revealed nearly 400 proteins (almost 10% of the E. coli proteome) whose amounts varied in response to the environmental P source [5]. Results from DNA microarray experiments have also shown the number of PhoR/PhoB-regulated genes to be large (Y. Jiang, Y. H., and B. L. W., unpublished data). These data are consistent with computational predictions of a large number of PhoB-binding sites on the genome [6]. However, in the absence of direct evidence, it is difficult to provide a complete catalog of Pho regulon genes. To date, only 31 genes (9 transcriptional units: eda, phnCDEFGHIJKLMNOP, phoA, phoBR, phoE, phoH, psiE, pstSCAB-phoU, and ugpBAECQ) have been shown to be directly controlled by the PhoR/PhoB TCS (Table 1). Although strong evidence exists for several others (such as amn, psiF, yidD, and yibD), direct evidence for their control by PhoB is lacking. In this regard, expression of the acid-inducible asr, which had been previously reported to be transcriptionally controlled by the PhoR/PhoB TCS [17], is now known to be instead regulated by the stationary phase sigma factor RpoS [18]. Earlier interpretations from the same investigators were based on indirect effects of the PhoR/PhoB TCS under conditions of Pi limitation.

Table 1
Genes of the E. coli K-12 phosphate regulon

The Pst system is the predominant system for Pi uptake

Nearly all genes directly controlled by the PhoR/PhoB TCS have a role in assimilation of Pi or an alternative P source for growth (Table 1). The most strongly activated promoter pstSp (for the pstSCAB-phoU operon) governs expression of the ABC transporter Pst and PhoU [1]. It had until recently been thought that the Pst system has a role in Pi uptake only under conditions of Pi limitation. A variety of data now show that the Pst system, not the low affinity “phosphate inorganic transporter” PitA, serves as the primary Pi transporter when Pi is in excess. PitA is unlikely to act primarily as a Pi transporter, but rather as a transporter of divalent metal cations (Zn2+) that are transported in complex with Pi [19]. A primary role for PitA as a Zn2+, and not a Pi, transporter is supported by the finding that pitA expression is activated by Zn2+, and not by Pi limitation [20;21]. Likewise, pitB [22;23] probably has no role in Pi uptake in normal cells, as it is not expressed under normal growth conditions.

The PhoB RR acts as a transcription factor for Pho regulon promoters

PhoB belongs to the OmpR/PhoB subfamily, the largest group of RRs. PhoB is comprised of an N-terminal receiver domain and a C-terminal DNA-binding domain. Its activity as transcription factor depends upon its state of phosphorylation (D53) of the PhoB receiver domain. Several structures of PhoB have been determined of both its receiver and DNA-binding domain (without and with Mg++ and DNA; www.prfect.org/EcoliProteins), including those of two “constitutively active” mutants [24-27]. NMR studies have also examined the activation mechanism for receiver domain ([28]; see also [29] in this volume) and the mechanism of DNA binding [30].

The PhoR HK lacks a Pi sensory domain

PhoR acts as the Pi sensory HK and is essential for three distinct processes that control PhoB activity as a transcription factor: inhibition (prevention of PhoB phosphorylation), activation (phosphorylation of PhoB), and deactivation (dephosphorylation of phospho-PhoB). As shown in Fig. 1, PhoR is comprised of five domains (or regions). Its N-terminal transmembrane (TM) domain is required solely for association of PhoR to the membrane. Presumably, membrane localization of PhoR is necessary for interaction with the Pst transporter. PhoR acts as a sensory protein via an interaction between a cytosolic domain of PhoR (possibly its PAS domain; Y.H. and B.L.W., manuscript in preparation) and the Pst transporter (possibly the ABC component PstB; Fig. 2) and/or PhoU.

Fig. 1
Domain organization of PhoR. TM, transmembrane-anchoring domain; CR, positively charged linker region; PAS, Per-Arnt-Sim domain; DHp, dimerization and histidine phosphoacceptor domain; CA, a catalytic domain.
Fig. 2
Model for transmembrane signal transduction by environmental Pi. The signaling processes of inhibition, activation, and deactivation are proposed to correspond to different states of PhoR: an inhibition state (PhoRI), an activation state (PhoRA), and ...

Cross regulation of Pho regulon by non-partner HKs

PhoB can also be activated in the absence of PhoR. Activation of PhoB in the absence of PhoR is due to cross regulation (PhoB phosphorylation; [1]) by non-partner HKs such as CreC [31] or small molecule phosphoryl donor(s) such as acetyl phosphate [32]. When PhoR is absent, the non-partner HKs ArcB, CreC, KdpD, and QseC can lead to moderate activation of PhoB in response to different growth conditions, while the non-partner HKs BaeS and EnvZ can lead to low level activation [4;33]. It should be noted that these studies were carried out by examining gene expression in cultures, in which gene expression levels reflect only population averages and not the dynamics of gene expression in single cells.

Stochastic expression of the Pho regulon

Single-cell profiling by using flow cytometry to monitor gene expression in single cells has revealed an unforeseen stochastic, “all-or-none,” character for activation of PhoB by non-partner HKs [4]. Modeling has shown that stochastic behavior can result not only from TCSs that have a positive feedback loop (i. e., phospho-PhoB leads to autoamplification of PhoB synthesis) but also from systems in which the rate of HK translation initiation is limited (as appears to be the case for PhoR [34]). Accordingly, the low amounts of PhoR resulting from low rates of PhoR translation are expected to lead to the formation of occasional cells in a population having no PhoR protein. Activation of PhoB by non-partner HKs in these cells would lead to stochastic activation of PhoB and to the emergence of multiple stable phenotypes within a population of genetically identical cells. Such behavior at the cellular level is likely to be of fundamental importance not only in the recovery of cells from periods of stress but also in persistence, host-phage interactions and pathogenesis [35-38]. While other TCSs have not been similarly tested for stochasticity, it is reasonable to propose that several are likely to exhibit similar bimodal expression patterns. Two characteristics that appear to be important for stochastic behavior are: (i) the presence of an autoregulatory loop controlling expression of the TCS; and (ii) low translation rates for the HK mRNA [34].

The Pst transporter is required for Pi signal transduction

Early studies showed that the Pst transporter is essential for detecting environmental Pi. Also, recent data show that PhoR detects Pi only indirectly (Y.H. and B.L.W., manuscript in preparation). Further, the Pst system but not Pi uptake per se is essential for Pi signaling by the Pst system [1]. By analogy to the ABC (MalEFGK) transporter for maltose [39], we propose that the Pst transporter exists in two distinct states: in one state, the Pst transporter is both transport and signaling active; and in the other, the Pst transporter is both transport and signaling inactive. These states would correspond to closed (transport active) conformation when Pi is bound and an open (resting state) conformation in the absence of bound Pi. Thus, mutations of the Pst system that abolish Pi uptake without affecting Pi signaling block uptake but yet allow formation of the closed and open conformations [1].

A model for Pi signaling

Mechanistically, Pi signaling is a negative process. Excess Pi is required for turning the system off. Activation is the default state and results under conditions of Pi limitation. The Pst transporter is essential for inhibition, as well as deactivation [1]. Deactivation resets the PhoR/PhoB system to its inhibition state (Fig. 2). That activation (phosphorylation) of PhoB leads to a conformational change in PhoB has been shown by examination of the structural changes brought about by phosphoryl group analog BeF3- [28] and the structure of constitutively active PhoB proteins [27].

Like the Pst transporter, PhoU also has an obligatory role in both inhibition and deactivation of PhoB. The finding that PhoU-like proteins from Aquifex aeolicus and Thermotoga maritima share structural similarity with proteins belonging to the eukaryotic chaperone Hsp70 family [13;14] support a chaperone-like role for PhoU. The action of PhoU as an accessory protein is fully compatible with PhoU being a chaperone. Accordingly, PhoU probably acts together with PhoR to promote autodephosphorylation of PhoB-P [40].

A caveat of Pi signaling by the proposed PhoR/PhoB/PstSCAB/PhoU complex is that individual complexes can exist in different states within a cell. Accordingly, when Pi is in excess, all complexes probably exist in the transport and signaling active state, in which PhoR would be in the inhibition state. Under conditions of Pi limitation, these complexes probably exist in different states within the same cell. That is, under these conditions, some complexes would be in the transport and signaling inactive (PhoR activation) state. Other complexes would be in the transport and signaling active (PhoR inhibition) state. The existence of complexes in both states within the same cell would be necessary to permit simultaneous activation of PhoR/PhoB-regulated genes and growth on limiting amounts of Pi.

Conclusions

Much new information has been learned about the molecular control of the Pho regulon over the past decade, especially with respect to signaling by environmental Pi. Three areas are likely to contribute substantial new information about the Pho regulon and its control in the future (Box 1).

Box 1. Key problems for future studies of the PhoR/PhoB TCS

  • The advent of genome-wide mRNA analysis by deep sequencing (RNA-seq) coupled with chromatin immunoprecipitation (ChIP-seq) can provide unprecedented sensitivity and specificity for protein-DNA interactions on a genome-wide scale [41]. Application of such technology to Pi signal transduction should provide comprehensive identification of genes controlled by the PhoR/PhoB TCS.
  • Studying single-cell gene expression by the PhoR/PhoB TCS under diverse environmental conditions is likely to provide definitive results regarding the role of cross regulation among different TCSs.
  • Studying the different states of the proposed seven-component Pi signaling complex is likely to require development of new technologies that enable examination of single protein complexes inside living cells that are similar to ones now being used to study activities of other machines at the single molecule level [42].

Acknowledgments

Research from this laboratory has been supported by NIH GM62662 and GM83296.

Footnotes

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