(p)ppGpp-dependent activation of gene expression during nutrient limitation

Abstract As rapidly growing bacteria begin to exhaust nutrients, their growth rate slows, ultimately leading to stasis or quiescence. Adaptation to nutrient limitation requires widespread metabolic remodeling that leads to lower cellular energy consumption. Examples of such changes include attenuated transcription of genes encoding ribosome components, in part mediated by the phosphorylated nucleotides guanosine tetra- and penta-phosphate, collectively (p)ppGpp. In addition, genes encoding proteins that facilitate survival nutrient limitation exhibit increased expression. An example is the hpf gene, encoding a broadly conserved protein responsible for protecting the ribosome from degradation under conditions limiting for ribosome synthesis. Here we show that (p)ppGpp plays a key role in the transcriptional activation of hpf as B. subtilis cells exit rapid growth. Specifically, we demonstrate that hpf transcription during nutrient limitation requires an RNA polymerase holoenzyme containing the alternative sigma factor σH, encoded by sigH, whose expression is normally inhibited by the AbrB repressor. However, when global protein synthesis decreases, in part dependent on (p)ppGpp, AbrB levels fall, leading to increased sigH transcription and, consequently, hpf activation. This mechanism couples a key physiological consequence of nutrient limitation – reduced protein synthesis – with specific gene activation, thereby linking transcriptional and translational regulation. Finally, we demonstrate that (p)ppGpp is necessary for the gene expression underlying the elaboration of developmental fates including sporulation and genetic competence. Importance Bacteria often experience nutrient limitation and, in response, they attenuate energetically costly metabolic processes like protein synthesis. At the same time, however, they stimulate the expression of a subset of proteins that facilitate survival under this condition. This study identifies a new molecular mechanism in the model Gram-positive bacterium Bacillus subtilis responsible for gene expression in response to nutrient limitation that couples reduced global protein synthesis with increased transcription of specific genes. This mechanism mediates the elaboration of developmental fates including sporulation and genetic competence that are known responses to nutrient limitation in this organism.