Evolution and Function of the RelA/SpoT Homologue (RSH) Proteins


RelA/SpoT Homologue (RSH) proteins comprise a superfamily of enzymes that synthesise and/or hydrolyse the nucleotide alarmone ppGpp, mediator of the ‘stringent’ response and regulator of cellular metabolism in response to changing environmental conditions. Most of what we know about RSHs comes from the Escherichia coli proteins RelA and SpoT, paralogues that appear to have evolved from duplication of an ancestral Rel gene in the lineage to β‐ and γ‐proteobacteria. Recently, more details have come to light on the evolution of the RSH superfamily, revealing that there is a much greater diversity of RSHs than previously thought.

Key Concepts:

  • Various stress conditions (amino acid, iron and fatty acid starvation, heat shock, etc.) induce the so‐called ‘stringent response’ in bacteria and chloroplasts.

  • The stringent response is mediated by RelA/SpoT Homologue (RSH) proteins that modulate intracellular concentration of the ppGpp alarmone nucleotide.

  • ppGpp exerts its regulatory role by binding and modulating activity of several targets: the RNA polymerase, translational GTPases EF‐G and IF2, lysine decarboxylase Ldc1, polynucleotide phosphorylase, DnaG primase and others.

  • RelA senses amino acid starvation by directly interacting with the 70S ribosome and inspecting the aminoacylation status of the A‐site tRNA, and responds to the presence of deacylated tRNA by synthesising ppGpp.

  • SpoT is a bifunctional enzyme that has both ppGpp synthetic and hydrolytic activities and senses several cues that modulate its net activity.

  • Phylogenetic analyses divide the RSH protein family into 30 subgroups comprising three groups: long RSHs (such as RelA and SpoT), small alarmone synthetases (SASs) and small alarmone hydrolases (SAHs).

  • In addition to bacteria and chloroplasts, RSH proteins have been identified in eukaryotes and isolated species of archaea, however the ppGpp‐mediated stringent response has not yet been identified in these organisms.

  • In eukaryotes, amino acid starvation is sensed by the general amino acid control (GAAC) system that is nonhomologous to the RSH system but is functionally analogous.

Keywords: RelA; SpoT; Rel; ppGpp; stringent response; ribosome; SAS; SAH; RSH; amino acid starvation

Figure 1.

Domain structure of RSHs. In Rsh4, cTP and EFh stand for chloroplast transit peptide and EF hand domain, respectively. Abbreviations for the other RSHs are as discussed in the text.

Figure 2.

Schematic diagram for the evolution of long RSHs in bacteria. Thick grey branches indicate the divergence of bacterial groups, whereas the inner line shows the divergence of long RSH proteins and their functionality, as per the inset box. Reproduced with permission from Atkinson et al..

Figure 3.

Phylogenetic trees of the RSH ppGpp synthetase and hydrolase domains. Trees were generated from maximum likelihood phylogenetic analyses: (a) ppGpp hydrolase (HD) domain‐containing RSHs, and (b) the ppGpp synthetase (SYNTH) domain‐containing RSHs. In both trees, subgroups are labelled and shading behind the branches shows the most common domain structure observed for those groups, as per the legend in the inset box. Symbols on branches indicate bootstrap support, as per the inset box. Branch length is proportional to the number of substitutions per site (see scale bar). Reproduced with permission from Atkinson et al..



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Atkinson, Gemma C, and Hauryliuk, Vasili(Feb 2012) Evolution and Function of the RelA/SpoT Homologue (RSH) Proteins. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0023959]