Regulatory Themes and Variations by the Stress-Signaling Nucleotide Alarmones (p)ppGpp in Bacteria

Abstract

Bacterial stress-signaling alarmones are important components of a protective network against diverse stresses such as nutrient starvation and antibiotic assault. pppGpp and ppGpp, collectively (p)ppGpp, have well-documented regulatory roles in gene expression and protein translation. Recent work has highlighted another key function of (p)ppGpp: inducing rapid and coordinated changes in cellular metabolism by regulating enzymatic activities, especially those involved in purine nucleotide synthesis. Failure of metabolic regulation by (p)ppGpp results in the loss of coordination between metabolic and macromolecular processes, leading to cellular toxicity. In this review, we document how (p)ppGpp and newly characterized nucleotides pGpp and (p)ppApp directly regulate these enzymatic targets for metabolic remodeling. We examine targets’ common determinants for alarmone interaction as well as their evolutionary diversification. We highlight classical and emerging themes in nucleotide signaling, including oligomerization and allostery along with metabolic interconversion and crosstalk, illustrating how they allow optimized bacterial adaptation to their environmental niches.

The proteomic and transcriptomic landscapes altered by Rgg2/3 activity in Streptococcus pyogenes

“…In prior studies, Steiner and Malke found that RelA ( spy49_1632c ) was responsible for the majority of (p)ppGpp accumulation under amino acid starvation in S. pyogenes , but they also identified two additional putative alarmone synthases ( spy49_0877 and spy49_0687 in NZ131, spy_1125 and spy_0873 in SF370, respectively) (28, 29). RelA is predicted to have two enzymatic activities, serving as a bifunctional synthetase and hydrolase, whereas Spy49_0877 and Spy49_0687 are predicted to encode small alarmone synthases (SASs) that we have named sasA and sasB , respectively, based on orthologous genes in B. subtilis (30, 31). As sasA and sasB have remained untested in S. pyogenes , we took the opportunity to construct deletions of each synthase gene, as well as double and triple knockout combinations with relA (Fig.…”

Direct activation of an innate immune system in bacteria by a viral capsid protein

“…To investigate the molecular basis of phage-induced activation of bacterial immunity, we focused here on toxSAS TA systems, which feature toxins homologous to bacterial small alarmone synthetases (SAS) that pyrophosphorylate purine nucleotides 24 . While most housekeeping alarmone synthetases produce the growth regulator (p)ppGpp 25,26 , toxSAS toxins can synthesize (p)ppApp to deplete ATP 24,27 or pyrophosphorylate tRNAs to inhibit translation 24,28 . Their cognate antitoxins can either bind and neutralize the toxin or act as hydrolases to reverse toxin-catalyzed pyrophosphorylation 24,28 .…”

A guanosine tetraphosphate (ppGpp) mediated brake on photosynthesis is required for acclimation to nitrogen limitation in Arabidopsis

“…Likely candidates for regulating chloroplast stress signaling are the hyperphosphorylated nucleotides guanosine pentaphosphate and tetraphosphate (together referred to as ppGpp) that are synthesized from ATP and GDP/GTP by chloroplast localized enzymes of the RelA SpoT Homologue (RSH) family ( Boniecka et al, 2017 ; Field, 2018 ). In bacteria, where ppGpp was originally discovered, a considerable body of work indicates that ppGpp and related nucleotides interact directly with specific effector enzymes to regulate growth rate and promote stress acclimation ( Ronneau and Hallez, 2019 ; Bange et al, 2021 ; Anderson et al, 2021 ). In plants, ppGpp signaling is less well understood both at the physiological and mechanistic levels.…”