Free-living organisms modulate their gene expression patterns in response to environmental cues. This modulation requires sensors to detect chemical and/or physical signals, and regulators to bring about changes in the levels of gene products. Certain cellular processes require the integration of multiple signals into the decision to promote or inhibit the expression of a given gene product, which raises questions about the mechanisms used by different organisms to connect signal transduction pathways and genetic regulatory circuits.In bacteria, extracellular signals are transduced into the cell predominantly by two-component systems (TCSs) (Hoch 2000;Stock et al. 2000;Mascher et al. 2006;Gao et al. 2007). The prototypical TCS consists of a sensor kinase that responds to specific signals by modifying the phosphorylated state of a cognate response regulator (i.e., the second component) (Fig. 1). Sensor kinases are usually integral membrane proteins that autophosphorylate from ATP at a conserved histidine residue and then transfer the phosphoryl group to a conserved aspartate in the response regulator. Phosphorylation of a response regulator changes the biochemical properties of its output domain, which can participate in DNA binding and transcriptional control, perform enzymatic activities, bind RNA, or engage in protein-protein interactions (Gao et al. 2007). In addition to serving as phosphoryl donors, certain sensor kinases display phosphatase activity toward their cognate phosphorylated regulators.Phosphorelays are a more complex version of the TCS in which a sensor kinase first transfers the phosphoryl group to a response regulator possessing the domain with the conserved aspartate but no output domain (Appleby et al. 1996;Perraud et al. 1999). The response regulator subsequently transfers the phosphoryl group to a histidine-containing phosphotransfer protein, and it is the latter protein that serves as a phosphodonor to the terminal response regulator, which possesses an output domain mediating a cellular response (Fig. 1). In some phosphorelays, the sensor kinase and the response regulator lacking the output domain (and sometimes also the histidine-containing phosphotransfer protein) are fused in a single polypeptide (Appleby et al. 1996).The vast majority of response regulators are active only when phosphorylated (Hoch 2000;Gao et al. 2007). Therefore, any condition or product that affects the phosphorylated state of a response regulator will impact its ability to exert its biological functions. Consequently, the output of a response regulator is determined not only by the presence of the specific signals sensed by its cognate sensor kinase but also by gene products that stimulate or inhibit its phosphorylation. Such products can, in principle, target any one of the various steps leading to phosphorylation of the response regulator, including sensor kinase autophosphorylation, phosphotransfer to the response regulator, dephosphorylation of a phosphorylated response regulator, and the activity of the outpu...

Feedback loops have been identified in a variety of regulatory systems and organisms. While feedback loops of the same type (negative or positive) tend to have properties in common, they can play distinctively diverse roles in different regulatory systems, where they can affect virulence in a pathogenic bacterium, maturation patterns of vertebrate oocytes and transitions through cell cycle phases in eukaryotic cells. This review focuses on the properties and functions of positive feedback in biological systems, including bistability, hysteresis and activation surges.

Complex genetic networks consist of structural modules that determine the levels and timing of a cellular response. While the functional properties of the regulatory architectures that make up these modules have been extensively studied, the evolutionary history of regulatory architectures has remained largely unexplored. Here, we investigate the transition between direct and indirect regulatory pathways governing inducible resistance to the antibiotic polymyxin B in enteric bacteria. We identify a novel regulatory architecture—designated feedforward connector loop—that relies on a regulatory protein that connects signal transduction systems post-translationally, allowing one system to respond to a signal activating another system. The feedforward connector loop is characterized by rapid activation, slow deactivation, and elevated mRNA expression levels in comparison with the direct regulation circuit. Our results suggest that, both functionally and evolutionarily, the feedforward connector loop is the transitional stage between direct transcriptional control and indirect regulation.

Chronic inflammation is rapidly becoming recognized as a key contributor to numerous pathologies. Despite detailed investigations, understanding of the molecular mechanisms regulating inflammation is incomplete. Knowledge of such critical regulatory processes and informative indicators of chronic inflammation is necessary for efficacious therapeutic interventions and diagnostic support to clinicians. We used a computational modeling approach to elucidate the critical factors responsible for chronic inflammation and to identify robust molecular indicators of chronic inflammatory conditions. Our kinetic model successfully captured experimentally observed cell and cytokine dynamics for both acute and chronic inflammatory responses. Using sensitivity analysis, we identified macrophage influx and efflux rate modulation as the strongest inducing factor of chronic inflammation for a wide range of scenarios. Moreover, our model predicted that, among all major inflammatory mediators, IL-6, TGF-β, and PDGF may generally be considered the most sensitive and robust indicators of chronic inflammation, which is supported by existing, but limited, experimental evidence.