Regulation of prokaryotic gene expression involving signal transduction networks
The formation of two cell types with differing developmental fates, a small forespore and a large mother cell, is the first morphological indication of early sporulation in Bacillus subtilis . This apparently simple morphological structure belies the complex network of interconnected regulatory pathways that are activated during late growth in response to nutritional stress and cell cycle related signals. These interconnected regulatory pathways control which genes are expressed and the changing physiological state of the cell, often culminating in the initiation of sporulation. Such signal transduction pathways in Bacillus subtilis cannot be viewed as linear regulatory pathways, but rather as a signal transduction network that gathers diverse input from the environment and intracellular signals, and processes that information to determine which program of late growth response is most appropriate, thus determining the hierarchy of environmental signal responses. Depletion of nutrients, including phosphate, is a stress often encountered by a bacterial cell and results in slowed growth, marking the cessation of exponential growth. Inorganic phosphate (Pi) is the critical limiting nutrient for biological growth in soil, the natural environment of Bacillus subtilis . Soil bacteria, including Bacillus subtilis have evolved complex regulatory systems for utilizing this limited nutrient, which is often present at levels 2 to 3 orders of magnitude lower than those of other required ions.
We have used genes that are transcriptionally activated by phosphate starvation to identify a network of at least three signal transduction systems that have a role in the phosphate deficiency response of Bacillus subtilis . The interconnected pathways involve the PhoP-PhoR system whose primary role is the phosphate deficiency response, the SpoO phosphorelay required for the initiation of sporulation, and a signal transduction system ResD-ResE which controls aerobic and anaerobic respiration. The PhoP-PhoR and ResD-ResE systems positively regulate the Pho response via a positive feedback loop, while the SpoO system represses both activator signal transduction systems, thereby repressing the Pho response.
The physiological importance of the PhoPR two-component system to B. subtilis during phosphate limitation, a situation naturally imposed upon soil organisms, has become increasingly clear (i) as the identity of genes directly regulated by PhoP increases, (ii) as the co-dependency of aerobic respiration and Pho regulon induction is understood and (iii) as emerging evidence of its role in sporulation development unfolds. PhoP is functionally a fascinating protein being capable (i) of either promoter activation or repression, (ii) of functioning with multiple forms of RNA polymerase (Es A or Es E ) and (iii) of executing different patterns of promoter binding depending on its functional role at that promoter and the strength of that promoter.
The studies of two-component regulatory systems have resulted in a massive accumulation of knowledge concerning signal transduction in bacteria. The wealth of information we have gained can now be applied to regulatory networks, involving multiple two-component systems for cross regulation of complex processes. At the same time, information continues to grow at the submolecular level as paradigm systems are being analyzed. Structural information of the two-component proteins, coupled with identification of essential two-component-systems make an attractive target for antibacterial agents.
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