Sigma cascades in prokaryotic regulatory networks

Classical paradigms of prokaryotic transcriptional regulation are simple and elegant. In some cases, modification of an activator leads to DNA binding that enables initiation of transcription by an RNA polymerase. In others, interaction with an inducer relieves inhibition by a DNA-binding repressor. Alternative sigma factors activated under specific stress conditions may compete with the housekeeping sigma factor to direct a core RNA polymerase in the transcription of specific gene subsets. However, as the control of individual genes is examined in greater detail, the situation often becomes more complex. Transcription of individual genes may reflect input from multiple DNA-binding proteins, regulatory cascades, RNA-binding proteins, redox-sensing motifs, and small RNAs or metabolites (1), as well as factors influencing genome structure and local DNA superhelicity (2). One example, the Escherichia coli sodA gene encoding manganese superoxide dismutase, is controlled by at least five transcriptional regulators: SoxS, Fur, ArcA, Fnr, and IHF (3). In this respect, sodA is by no means unusual. Genes encoded by the SPI-1 pathogenicity island required for invasion of host cells by Salmonella are controlled by four transcriptional regulators and modulated by as many as a dozen others (4). Expression of the alternative sigma factor σS is controlled by as many as two dozen regulatory factors at the level of transcription, translation, or proteolysis (5). Microbiologists might be forgiven for wondering whether transcriptional regulatory networks were designed by Rube Goldberg (1883–1970), a cartoonist famous for his invention of inordinately complicated schemes to achieve simple tasks. Microarray technology has revolutionized the ability to comprehensively examine bacterial transcriptional responses to environmental changes and to examine the contribution of specific regulatory loci (6). Such analyses have revealed unanticipated complexity of regulatory phenomena: in E. coli …