Possible Roles for Basal Levels of (p)ppGpp: Growth Efficiency Vs. Surviving Stress

Abstract

Two (p)ppGpp nucleotide analogs, sometimes abbreviated simply as ppGpp, are widespread in bacteria and plants. Their name alarmone reflects a view of their function as intracellular hormone-like protective alarms that can increase a 100-fold when sensing any of an array of physical or nutritional dangers, such as abrupt starvation, that trigger lifesaving adjustments of global gene expression and physiology. The diversity of mechanisms for stress-specific adjustments of this sort is large and further compounded by almost infinite microbial diversity. The central question raised by this review is whether the small basal levels of (p)ppGpp functioning during balanced growth serve very different roles than alarmone-like functions. Recent discoveries that abrupt amino acid starvation of Escherichia coli , accompanied by very high levels of ppGpp, occasion surprising instabilities of transfer RNA (tRNA), ribosomal RNA (rRNA), and ribosomes raises new questions. Is this destabilization, a mode of regulation linearly related to (p)ppGpp over the entire continuum of (p)ppGpp levels, including balanced growth? Are regulatory mechanisms exerted by basal (p)ppGpp levels fundamentally different than for high levels? There is evidence from studies of other organisms suggesting special regulatory features of basal levels compared to burst of (p)ppGpp. Those differences seem to be important even during bacterial infection, suggesting that unbalancing the basal levels of (p)ppGpp may become a future antibacterial treatment. A simile for this possible functional duality is that (p)ppGpp acts like a car’s brake, able to stop to avoid crashes as well as to slow down to drive safely.

Inducible expression of (pp)pGpp synthetases in Staphylococcus aureus is associated with activation of stress response genes

“…Moreover, the different levels of (pp)pGpp in the cell may also dictate different outcomes. There is now growing evidence that basal level of (pp)pGpp (often below detection limit) are involved to maintain balanced growth whereas high levels are indicative for stress conditions resulting in severe reprogramming of the cell and growth arrest [ 74 , 75 ]. In this context, the induction of rel-Syn likely mirrors stress conditions, whereas relQ induction with low detectable (pp)pGpp synthesis more resembles the proposed basal level.…”

Emerging and divergent roles of pyrophosphorylated nucleotides in bacterial physiology and pathogenesis

“…This decrease in GTP levels reduces transcriptional activation of ribosomal genes that require GTP for initiation [ 57 , 59 ]. These data show that (p)ppGpp fine-tunes core cellular functions like transcription at incremental levels (see [ 60 ] for a recent review on the role of (p)ppGpp at basal levels).…”

“…The efficacy of small molecule inhibitors is also typically tested in whole cell assays against wild type and a mutant strain that is unable to synthesize (p)ppGpp. However, (p)ppGpp-deficient strains are prone to acquiring suppressor mutations that mimic the presence of (p)ppGpp, which may challenge the feasibility of cell-based approaches [ 60 , 124 ].…”

The Ribosome as a Switchboard for Bacterial Stress Response

“…Under optimal growth conditions, GTP is present in millimolar concentrations in the cell, whereas the very low levels of the alarmones (p)ppGpp (guanosine 3′-diphosphate,5′-triphosphate) and ppGpp (guanosine 3′,5′-bispyrophosphate) play essential roles in various aspects of bacterial physiology, modulating growth rate, general metabolism and GTP homeostasis ( Potrykus and Cashel, 2008 ; Potrykus et al, 2011 ; Kriel et al, 2012 ; Hauryliuk et al, 2015 ; Fernández-Coll and Cashel, 2020 ). However, under a variety of stress conditions, including starvation for an essential amino acid, which gives rise to a “stringent response,” many bacteria synthesize large amounts of these alarmones ( Figure 3 ).…”