Coordination of bacterial proteome with metabolism by cyclic AMP signalling

The cyclic AMP (cAMP)-dependent catabolite repression effect in Escherichia coli is among the most intensely studied regulatory processes in biology. However, the physiological function(s) of cAMP signalling and its molecular triggers remain elusive. Here we use a quantitative physiological approach to show that cAMP signalling tightly coordinates the expression of catabolic proteins with biosynthetic and ribosomal proteins, in accordance with the cellular metabolic needs during exponential growth. The expression of carbon catabolic genes increased linearly with decreasing growth rates upon limitation of carbon influx, but decreased linearly with decreasing growth rate upon limitation of nitrogen or sulphur influx. In contrast, the expression of biosynthetic genes showed the opposite linear growth-rate dependence as the catabolic genes. A coarse-grained mathematical model provides a quantitative framework for understanding and predicting gene expression responses to catabolic and anabolic limitations. A scheme of integral feedback control featuring the inhibition of cAMP signalling by metabolic precursors is proposed and validated. These results reveal a key physiological role of cAMP-dependent catabolite repression: to ensure that proteomic resources are spent on distinct metabolic sectors as needed in different nutrient environments. Our findings underscore the power of quantitative physiology in unravelling the underlying functions of complex molecular signalling networks. Cyclic AMP, one of the earliest discovered and most intensely studied signalling molecules in molecular biology, is widely believed to signal the carbon status in mediating catabolite repression in bacteria; here a quantitative approach reveals a much broader physiological role for cAMP signalling, whereby it coordinates the allocation of proteomic resources with the global metabolic needs of the cell, including, for example, nitrogen or sulphur. A global metabolic role for cyclic AMP Cyclic AMP, one of the earliest discovered and most intensely studied signalling molecules in molecular biology, is widely believed to be focused on carbon metabolism in bacteria. Now Terence Hwa and colleagues reveal a much broader physiological role, whereby cAMP signalling orchestrates the allocation of the whole genome's resources in response to global metabolic needs — including, for example, nitrogen and phosphorus. To achieve this rewrite of molecular biology textbooks, the researchers followed an