Review Article | Published:

ppGpp: magic beyond RNA polymerase

Nature Reviews Microbiology volume 10, pages 203212 (2012) | Download Citation

Abstract

During stress, bacteria undergo extensive physiological transformations, many of which are coordinated by ppGpp. Although ppGpp is best known for enhancing cellular resilience by redirecting the RNA polymerase (RNAP) to certain genes, it also acts as a signal in many other cellular processes in bacteria. After a brief overview of ppGpp biosynthesis and its impact on promoter selection by RNAP, we discuss how bacteria exploit ppGpp to modulate the synthesis, stability or activity of proteins or regulatory RNAs that are crucial in challenging environments, using mechanisms beyond the direct regulation of RNAP activity.

Key points

  • To tolerate stress, many bacteria rely on the signalling nucleotides guanosine tetraphosphate and guanosine pentaphosphate (collectively referred to as ppGpp) to coordinate physiological adaptations.

  • A wealth of genetic, molecular and biochemical studies have determined that ppGpp and DnaK suppressor (DksA) bind directly to RNA polymerase (RNAP) to regulate promoter selection.

  • Beyond altering promoter selection by RNAP, ppGpp also modulates the expression, stability, oligomerization and activity of a variety of proteins and regulatory RNAs by direct and indirect mechanisms.

  • In addition to increasing the pool of RNAP that is available to alternative σ-factors in Escherichia coli, ppGpp increases the stability of the stationary phase σ-factor, σS, and the activity of the envelope stress σ-factor, σE.

  • By inducing expression of the Legionella pneumophila regulatory RNAs RsmY and RsmZ, ppGpp relieves carbon storage regulator (CsrA)-mediated repression of the translation of mRNAs that are important for transmission.

  • By binding to Salmonella enterica subsp. enterica serovar Typhimurium and Francisella tularensis transcription factors, ppGpp enhances oligomerization and promotes the formation of particular protein complexes, resulting in activation of virulence factor expression.

  • ppGpp binds to and inhibits the activity of a variety of enzymes — namely, polynucleotide phosphorylase of actinomycetes, lysine decarboxylase of E. coli, inosine monophosphate dehydrogenase of gammaproteobacteria and firmicutes, and the Bacillus subtilis phosphodiesterase YybT, which degrades cyclic di-AMP.

  • The synthesis of ppGpp also alters the amount or the impact of other regulatory nucleotides, including GTP (an inhibitor of the CodY repressor of firmicutes) and cyclic di-GMP (an inducer of biofilm matrix production by E. coli).

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Acknowledgements

The authors' research on virulence regulation in L. pneumophila has been supported by the US National Institutes of Health (grant 2 R01 AI44212 to M.S.S.) and the University of Michigan, Ann Arbor, USA (a Rackham Predoctoral Fellowship to Z.D.D.).

Author information

Affiliations

  1. Department of Microbiology, University of Washington, Health Sciences Building K116, 1959 NE Pacific St., Box 357710, Seattle, Washington 98195-7710, USA.

    • Zachary D. Dalebroux
  2. Department of Microbiology & Immunology, University of Michigan Medical School, 6733 Medical Science Building II, 1150 West Medical Center Drive, Ann Arbor, Michigan 48109–5620, USA.

    • Michele S. Swanson

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Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Michele S. Swanson.

Glossary

Stringent response

A stress response coordinated by guanosine tetraphosphate and guanosine pentaphosphate, in which cells rapidly inhibit synthesis of stable RNA, ribosomes and proteins, leading to growth arrest.

Adaptor

In the context of post-translational regulation of protein stability, a protein that binds another protein and chaperones it to the proteasome for degradation; an example of such an adaptor is regulator of σS protein RssB.

Proteasome

A cytoplasmic complex that unfolds and degrades proteins.

Anti-adaptor

In the context of post-translational regulation of protein stability, a protein that binds an adaptor and blocks its chaperone activity; examples of anti-adaptors are IraP and IraD.

Discriminator

The DNA sequence between the −10-box hexamer of a promoter and the transcriptional start site at nucleotide + 1. Promoters that are activated by guanosine tetraphosphate and guanosine pentaphosphate acting with DnaK suppressor (DksA) are typically AT-rich in this region, whereas repressed targets are typically GC-rich.

Serine hydroxamate

A structural analogue of L-serine that induces the stringent response by inhibiting charging of seryl-tRNA synthetase.

rpoB

The gene encoding the β-subunit of RNA polymerase; this subunit is involved in transcription initiation through its interaction with the σ-factor. The commonly used antibiotic rifampicin targets this β-subunit to inhibit transcription, and mutations in rpoB commonly confer rifampicin resistance.

Regulon

All of the genes and operons for which expression is controlled by a particular regulatory protein.

Stringent starvation protein A

A protein that is synthesized in response to amino acid starvation and associates with RNA polymerase to control transcription. It promotes survival during acid stress and nutrient limitation in bacteria.

DNA primase

An enzyme that generates short RNA primers that are elongated by DNA polymerase during chromosome replication. DNA primase is essential for the replication of chromosomes and plasmids.

Second messenger

A molecule that relays signals from a receiver or receptor by exerting an effect on a downstream cellular factor or process.

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