Discretely calibrated regulatory loops controlled by ppGpp partition gene induction across the ‘feast to famine’ gradient in Escherichia coli

Abstract

SummaryBacteria comprehensively reorganize their global gene expression when faced with starvation. The alarmone ppGpp facilitates this massive response by co-ordinating the downregulation of genes of the translation apparatus, and the induction of biosynthetic genes and the general stress response. Such a large reorientation requires the activities of multiple regulators, yet the regulatory network downstream of ppGpp remains poorly defined. Transcription profiling during isoleucine depletion, which leads to gradual starvation (over > 100 min), allowed us to identify genes that required ppGpp, Lrp and RpoS for their induction and to deduce the regulon response times. Although the Lrp and RpoS regulons required ppGpp for their activation, they were not induced simultaneously. The data suggest that metabolic genes, i.e. those of the Lrp regulon, require only a low level of ppGpp for their induction. In contrast, the RpoS regulon was induced only when high levels of ppGpp accumulated. We tested several predictions of a model that explains how bacteria allocate transcriptional resources between metabolism and stress response by discretely tuning two regulatory circuits to different levels of ppGpp. The emergent regulatory structure insures that stress survival circuits are only triggered if homeostatic metabolic networks fail to compensate for environmental deficiencies.

Genome-wide screen identifies host colonization determinants in a bacterial gut symbiont

“…Many genes involved in stress responses confer strong fitness benefits in vivo, suggesting that the bee gut is a challenging environment in which S. alvi is exposed to toxins, low nutrient availability, and fluctuating O 2 , pH, and temperature. Among genes required in vivo were those underlying the ppGpp stringent response and Lrp, a master regulator that is induced by ppGpp upon amino acid starvation in other bacteria (29). In turn, Lrp can modulate expression of various amino acid synthesis enzymes and transporters to ensure cell survival (30).…”

Transfer RNA instability as a stress response inEscherichia coli: Rapid dynamics of the tRNA pool as a function of demand

“…74-77 This initial response is followed by down-regulation of many growth-related genes and up-regulation of the general stress response genes by σ S -bound RNA polymerase. 18,19 …”

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

“…Repression or activation of target genes is dependent on discriminator sequences encoded in the promoter region (12). Furthermore, (p)ppGpp promotes alternative factor usage (64). In Firmicutes, (p)ppGpp is unable to bind to RNAP (8,9).…”

“…This is not to say that the contributions of subtle fluctuations in (p)ppGpp pools to the control of core cellular processes and growth rate have been completely overlooked (59)(60)(61)(62). However, more recently, the notion that (p)ppGpp exerts important regulatory effects at concentrations below those needed to activate the SR has been more thoroughly revisited (10,54,63,64). In an elegant study using cells that were progressively starved, the Conway lab identified two distinct regulatory cascades activated by (p)ppGpp in E. coli (64).…”

“…However, more recently, the notion that (p)ppGpp exerts important regulatory effects at concentrations below those needed to activate the SR has been more thoroughly revisited (10,54,63,64). In an elegant study using cells that were progressively starved, the Conway lab identified two distinct regulatory cascades activated by (p)ppGpp in E. coli (64). First, at slightly elevated (p)ppGpp concentrations, the leucine-responsive protein (Lrp) regulon, a global regulator of genes involved in amino acid biosynthesis and transport, is activated (65).…”