CodY, a global regulator of stationary phase and virulence in Gram-positive bacteria

Many Gram-positive bacteria encode a homolog of Bacillus subtilis CodY, a protein that controls more than a hundred genes that are typically repressed during rapid growth and induced when cells experience nutrient deprivation. In B. subtilis, the repressor function of CodY is activated by interaction with two different effectors, GTP and isoleucine, which independently and additively increase the affinity of CodY for its target sites. In at least some pathogenic Gram-positive bacteria, major virulence factor genes are among the targets of CodY.

Introduction

The ability to adapt efficiently to a wide range of environmental changes, especially to alterations in nutritional quality, distinguishes bacteria from more complex organisms. A large part of the typical bacterial genome encodes proteins involved in sensing, moving towards, transporting and metabolizing a variety of nutrients that can serve as sources of carbon, nitrogen, phosphorus or sulfur. Such nutritional adaptation genes are often subject to multiple forms of regulation to enable their levels of expression to respond to multiple signals. For instance, the response to a particular sugar is usually controlled by at least two regulatory systems, one responding to the specific sugar and the other reflecting the global carbon availability [1, 2].

The stringent response to amino acid limitation was one of the earliest described global systems of regulation in bacteria [3]. When amino acid limitation becomes severe, cells shut off the synthesis of rRNA and ribosomal proteins while maintaining the synthesis of at least some types of mRNA. The signal for this response is the binding of uncharged tRNA to the ribosome and the consequent activation of RelA, a ribosome-bound enzyme that converts GTP to pppGpp. The exact mechanism by which pppGpp changes the rate of transcription of various genes has remained controversial, despite decades of research in this area. Direct interaction of pppGpp or its product ppGpp with RNA polymerase is thought to be responsible for many of the effects of pppGpp.

Pathogenic bacteria have a more complex response to nutritional limitation. When such bacteria inhabit a host organism, they do not necessarily provoke damage to the host. If certain nutrients are limited, however, the bacterial invaders are likely to induce the synthesis of proteins and other factors that damage the host to liberate the required nutrients [4]. In that sense, such killing of eukaryotic cells is functionally related to the propensity of bacteria to produce antibiotics and bacteriocins that kill competitor bacteria. That is, bacteria can profit by killing both prokaryotic and eukaryotic competitors.

Endospore formation is another adaptation to nutrient limitation. Found primarily in the Gram-positive genera Bacillus and Clostridium, endosporulation is a response to the limitation of sources of carbon, nitrogen or phosphorus [5, 6]. Unlike other responses to nutrient limitation, however, sporulation does not in any way help the cell to find new sources of nutrients. Instead, the sporulating cell stops growing, while creating within itself a protected environment for its genome.

Although the relationship between nutrient limitation and sporulation has been known for 50 years, the specific metabolic signals to which cells respond when making the decision to sporulate and the mechanisms by which these signals are sensed are still not fully understood. As early as 1977, Freese and co-workers presented compelling evidence that a decrease in the intracellular pool of GTP correlates well with the entry into stationary phase and the onset of sporulation [7, 8, 9, 10, 11]. Nucleotides are particularly attractive as signal compounds for the initiation of sporulation because their synthesis depends upon adequate supplies of carbon, nitrogen and phosphorus. The drop in GTP has been attributed to the induction of the stringent response [11, 12]. The RelA-dependent synthesis of pppGpp not only reduces the GTP pool directly but also leads to a reduction in de novo biosynthesis of GTP by way of inhibition of inosine monophosphate dehydrogenase (Figure 1) [11].

In this review, I discuss recent findings showing the pervasive role of CodY as a regulator of metabolism, sporulation and virulence in Gram-positive bacteria.