G-Protein Control of the Ribosome-Associated Stress Response Protein SpoT

Jiang, Mengxi; Sullivan, Susan M.; Wout, Patrice K.; Maddock, Janine R.

doi:10.1128/jb.00315-07

Cited by 80 publications

(96 citation statements)

References 58 publications

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“…CgtA, the conserved bacterial GTP-binding protein, is an essential protein and has been shown to interact with SpoT in V. cholerae and Escherichia coli. It has been suggested that CgtA most likely modulates the SpoT function to maintain low ppGpp levels (20,21). In addition, DksA, an RNA polymerase binding transcription factor, also plays several important roles in modulating stringent response and regulation of other genes in V. cholerae (22,23).…”

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confidence: 99%

Cholera Toxin Production during Anaerobic Trimethylamine N-Oxide Respiration Is Mediated by Stringent Response in Vibrio cholerae

Park

Yoon

et al. 2014

Journal of Biological Chemistry

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Background: Cholera toxin (CT) production is induced during anaerobic respiration with trimethylamine N-oxide (TMAO) in Vibrio cholerae. Results: A bacterial stringent response to nutrient starvation was activated during anaerobic TMAO respiration and influenced CT production. Conclusion: CT production during anaerobic TMAO respiration is mediated by stringent response in V. cholerae. Significance: A mechanism of TMAO-stimulated CT production is uncovered.

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confidence: 99%

Cholera Toxin Production during Anaerobic Trimethylamine N-Oxide Respiration Is Mediated by Stringent Response in Vibrio cholerae

Park

Yoon

et al. 2014

Journal of Biological Chemistry

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“…In this response, uncharged tRNAs induce the ribosome-associated RelA and/or SpoT proteins to synthesize ppGpp (5)(6)(7). [The term "ppGpp" is used here to describe both the unusual nucleotide guanosine-3′,5′-(bis)pyrophosphate and its pentaphosphate precursor.]…”

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confidence: 99%

Direct regulation of Escherichia coli ribosomal protein promoters by the transcription factors ppGpp and DksA

Lemke

Sanchez-Vazquez²,

Burgos³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

140

144

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We show here that the promoters for many of the Escherichia coli ribosomal protein operons are regulated directly by two transcription factors, the small RNA polymerase-binding protein DksA and the nutritional stress-induced nucleotide ppGpp. ppGpp and DksA work together to inhibit transcription initiation from ribosomal protein promoters in vitro and in vivo. The degree of promoter regulation by ppGpp/DksA varies among the r-protein promoters, but some are inhibited almost as much as rRNA promoters. Thus, many r-protein operons are regulated at the level of transcription in addition to their control by the classic translational feedback systems discovered ∼30 y ago. We conclude that direct control of r-protein promoters and rRNA promoters by the same signal, ppGpp/DksA, makes a major contribution to the balanced and coordinated synthesis rates of all of the ribosomal components.ribosome synthesis | transcriptional control | stringent response | translational control P rotein synthesis is the major consumer of cellular energy in bacteria. Because the number of ribosomes is the primary determinant of the level of translation, and ribosome synthesis itself is an energy-intensive process, there are mechanisms that prevent over-or underinvestment of cellular resources in ribosome synthesis (1). Both ribosomal RNA (rRNA) and ribosomal protein (r-protein) synthesis rates are thereby tightly regulated in Escherichia coli (for reviews, see refs. 2, 3).One of the earliest reported examples of regulation of bacterial ribosome synthesis is a stress response referred to as "the stringent response," in which rRNA transcription is inhibited in cells starved for amino acids or some other nutrients (4). In this response, uncharged tRNAs induce the ribosome-associated RelA and/or SpoT proteins to synthesize ppGpp (5-7). [The term "ppGpp" is used here to describe both the unusual nucleotide guanosine-3′,5′-(bis)pyrophosphate and its pentaphosphate precursor.] ppGpp concentrations change not only after complete starvations but also after less severe shifts in nutritional conditions, coordinating rRNA synthesis with the need for protein synthesis. Shifts to a more favorable nutritional condition result in a decrease in the concentration of ppGpp and a corresponding increase in rRNA promoter activity, whereas shifts to a less favorable condition result in an increase in ppGpp and a corresponding decrease in rRNA transcription (8).ppGpp binds directly to E. coli RNA polymerase (RNAP) and inhibits transcription from rRNA promoters (9), although the identity of the ppGpp binding site on RNAP remains unclear (10). However, for ppGpp to exert its full effect on transcription, RNAP has to be modified by the small protein, DksA (11,12). Unlike ppGpp, DksA is present at high concentrations in cells under all conditions that have been examined (11,13). rRNA transcription initiation is also regulated by the concentration of the first nucleotide in the transcript (8,14) and by at least one DNA binding factor, the 11.2-kDa Fis protein (15). Tog...

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“…Interestingly, (p)ppGpp synthesis by SpoT is induced by unique signals not sensed by RelA, which include carbon, fatty acid, and iron starvation (32)(33)(34). In addition, SpoT interacts with the GTPbinding protein CgtA (35,36), which has been proposed to promote hydrolase activity, thereby maintaining low (p)ppGpp levels under nutrient-rich conditions (37). However, the effects of CgtA on basal (p)ppGpp pools are quantitatively minor and deserve further verification.…”

Section: Changing Paradigms: the Discovery Of "Short" Rela/spot Homologsmentioning

confidence: 99%

Many Means to a Common End: the Intricacies of (p)ppGpp Metabolism and Its Control of Bacterial Homeostasis

2015

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In nearly all bacterial species examined so far, amino acid starvation triggers the rapid accumulation of the nucleotide second messenger (p)ppGpp, the effector of the stringent response. While for years the enzymes involved in (p)ppGpp metabolism and the significance of (p)ppGpp accumulation to stress survival were considered well defined, a recent surge of interest in the field has uncovered an unanticipated level of diversity in how bacteria metabolize and utilize (p)ppGpp to rapidly synchronize a variety of biological processes important for growth and stress survival. In addition to the classic activation of the stringent response, it has become evident that (p)ppGpp exerts differential effects on cell physiology in an incremental manner rather than simply acting as a biphasic switch that controls growth or stasis. Of particular interest is the intimate relationship of (p)ppGpp with persister cell formation and virulence, which has spurred the pursuit of (p)ppGpp inhibitors as a means to control recalcitrant infections. Here, we present an overview of the enzymes responsible for (p)ppGpp metabolism, elaborate on the intricacies that link basal production of (p)ppGpp to bacterial homeostasis, and discuss the implications of targeting (p)ppGpp synthesis as a means to disrupt long-term bacterial survival strategies. While analyzing nucleotide extracts of Escherichia coli, Cashel and Gallant visualized two spots by thin-layer chromatography that could be implicated in the inhibition of stable RNA accumulation provoked by amino acid starvation, which they dubbed "magic spots" (1). These magic spots were later identified as the hyperphosphorylated guanosine derivatives ppGpp (GDP, 3=-diphosphate) and pppGpp (GTP, 3=-diphosphate), collectively referred to as (p)ppGpp, or alarmones (2, 3). Subsequent studies revealed that (p)ppGpp is responsible for activation of the stringent response (SR), a highly conserved stress response to nutrient starvation (4, 5). Generally speaking, accumulation of (p)ppGpp induces large-scale transcriptional alterations leading to general repression of genes required for rapid growth, such as rRNA genes, and concomitant activation of genes involved in amino acid biosynthesis, nutrient acquisition, and stress survival. In addition to transcriptional control, (p)ppGpp has been shown to directly inhibit the activity of several enzymes, including DNA primase, translation factors, and enzymes involved in GTP biosynthesis (6) (Fig. 1). Ultimately, the SR reallocates cellular resources toward adaptation to a semidormant state, facilitating survival under unfavorable conditions (5, 7). Although initially defined as a response to amino acid and carbon starvation, the term SR has since been expanded to include any regulatory effect exerted by cellular (p)ppGpp accumulation irrespective of the triggering mechanism (4).The broad physiological alterations induced by (p)ppGpp accumulation rely heavily upon transcriptional alterations. In Gammaproteobacteria, such as the Gram-negative paradigmatic orga...

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G-Protein Control of the Ribosome-Associated Stress Response Protein SpoT

Cited by 80 publications

References 58 publications

Cholera Toxin Production during Anaerobic Trimethylamine N-Oxide Respiration Is Mediated by Stringent Response in Vibrio cholerae

Cholera Toxin Production during Anaerobic Trimethylamine N-Oxide Respiration Is Mediated by Stringent Response in Vibrio cholerae

Direct regulation of Escherichia coli ribosomal protein promoters by the transcription factors ppGpp and DksA

Many Means to a Common End: the Intricacies of (p)ppGpp Metabolism and Its Control of Bacterial Homeostasis

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