Linking nutritional status to gene activation and development

Abstract

One of the most daunting challenges in biology is elucidating the mechanisms by which cells sense and respond to changes in their food supply. The reason for the difficulty in addressing this problem even in primitive cells such as bacteria is that nutrient limitation can perturb the complex web of metabolic interactions that govern the physiological state of the cell. Thus, when a cell is deprived of nutrients, how are we to pinpoint the precise cue among the myriad alterations in metabolic intermediates that is responsible for the ensuing adaptive response? And how are we to tie this cue to the molecular mechanisms that execute the resulting changes in gene expression? In some cases, such as the response to growth-limiting levels of an amino acid or a particular carbon source, the specific nutrient is the signal to which the cell responds, and the mechanisms by which the cell perceives this signal and adapts to it are well understood. In other cases, however, in which the general nutritional status of the cell has been perturbed, the challenge of linking nutrient availability to alterations in gene expression has met with success in only a few instances. Here, after a brief review of a few classic examples of nutrient-sensing mechanisms in bacteria, we focus on a wonderfully simple solution, as reported in this issue by Ratnayake-Lecamwasam et al. (2001), to the long-standing problem of how a bacterium responds to nutritional signals that trigger the elaborate adaptive response of spore formation and entry into stationary phase. A classic example of a transcriptional response to a change in the level of a specific nutrient is the trp operon of Escherichia coli. The operon is regulated in part by a repressor whose capacity to bind to the trp operator is determined by direct interaction with tryptophan (Rose et al. 1973). The trp operon also responds to tryptophan levels through a mechanism called attenuation that acts at the level of transcription termination (Oxender et al. 1979). The 5 region of the trp mRNA contains a short open reading frame for a tryptophan-containing leader peptide. When tryptophan, and hence charged tRNA, levels are high, the ribosome translates the leader peptide-coding sequence and allows the formation of a hairpin that terminates transcription. In contrast, when tryptophan levels are low, the ribosome stalls in the short open reading frame, thereby preventing the formation of the transcription termination hairpin. In this example, the response to the levels of a specific nutrient in the medium is determined by the intracellular concentration of the amino acid, which is monitored by the Trp repressor, and the intracellular concentration of charged tRNA, which is sensed by the ribosome as it translates a Trp codon-containing leader sequence. A second classic example of a transcriptional response to a change in the level of a nutrient is the phenomenon of “catabolite repression” in E. coli. In the presence of a readily metabolized carbon source such as glucose, transcription of genes encoding proteins responsible for the catabolism of other carbon sources is inhibited. This inhibition is caused in part by a drop in the intracellular concentration of cAMP, the response to which is mediated by the transcription factor cAMP receptor protein (Busby and Kolb 1996). The level of glucose in the medium is linked to the level of cAMP in the cell by the phosphotransferase system, a sugar transport system in which the uptake from the medium is driven by phosphorylation of the sugar (Saier 1998). In the case of glucose, a phosphoryl group is transferred to the sugar from the phosphorylated form of the phosphotransferase protein IIA. This generates unphosphorylated IIA, which, among other effects, acts allosterically to inhibit the cAMP-generating enzyme, adenylate cyclase. Thus, in this instance a nutrient-specific transport system senses the presence or absence of a sugar, transducing the signal into a second messenger that interacts directly with a transcriptional regulatory protein. As a final example of a transcriptional response to a specific nutrient, we consider the case of ammonium, the favored source of nitrogen for enteric bacteria such as E. coli and Salmonella, which convert ammonium to glutamine via the enzyme glutamine synthetase. These bacteria sense low ammonium levels by monitoring the pool of intracellular glutamine (Ikeda et al. 1996) and respond in part by increasing the transcription of the gene for glutamine synthetase (Magasanik 1999). The molecule that senses glutamine directly is uridyltransferase/uridyl removing enzyme (UTase/UR) (Ninfa and Corresponding author. E-MAIL dworkin2@fas.harvard.edu; FAX: (617) 496-4642 Article and publication are at www.genesdev.org/cgi/doi/10.1101/ gad.892801.