The ArcAB Two-Component System: Function in Metabolism, Redox Control, and Infection

Abstract

ArcAB, also known as the Arc system, is a member of the two-component system family of bacterial transcriptional regulators and is composed of sensor kinase ArcB and response regulator ArcA. In this review, we describe the structure and function of these proteins and assess the state of the literature regarding ArcAB as a sensor of oxygen consumption. The bacterial quinone pool is the primary modulator of ArcAB activity, but questions remain for how this regulation occurs. This review highlights the role of quinones and their oxidation state in activating and deactivating ArcB and compares competing models of the regulatory mechanism. The cellular processes linked to ArcAB regulation of central metabolic pathways and potential interactions of the Arc system with other regulatory systems are also reviewed. Recent evidence for the function of ArcAB under aerobic conditions is challenging the long-standing characterization of this system as strictly an anaerobic global regulator, and the support for additional ArcAB functionality in this context is explored. Lastly, ArcAB-controlled cellular processes with relevance to infection are assessed.

Keywords: facultative anaerobes; global regulatory networks; metabolic regulation; metabolism; two-component regulatory systems.

FIG 1

Working model of ArcAB in detecting oxygen consumption for redox maintenance. The two-component regulatory system ArcAB responds to changes in oxygen consumption within the bacterial cell. Oxygen consumption can be influenced by a multitude of factors, including oxygen availability and the energetic needs of the cell. As activity at the electron transport chain decreases, quinones (Q) interact with sensor kinase ArcB, causing a conformational change and homodimerization. Now active, ArcB autophosphorylates and transphosphorylates response regulator ArcA via a phosphoryl relay. In turn, phosphorylated ArcA multimerizes and serves as a global transcription factor suppressing aerobic metabolic pathways and promoting fermentation among other processes.

FIG 2

Schematic of ArcA and ArcB domains. Sensor kinase ArcB is composed of two transmembrane domains connected by a short periplasmic domain. This anchor to the membrane is connected to the catalytic region of the protein by a linker. Within this linker are domains involved in interaction with regulators of ArcB and homodimerization. Once active, the atypical tripartite kinase region of ArcB can transphosphorylate ArcA. ArcA is composed of a receiver domain that once phosphorylated causes a conformational change in the helix-turn-helix domain. This change allows the second domain to bind DNA elements for ArcA-mediated transcriptional regulation.

FIG 3

Quinone regulation of ArcAB. Activity of the sensor kinase ArcB is controlled by redox sensitive cysteine residues within its linker domain. Quinones are a major determinant of the oxidation state of the cysteine residues. In reducing conditions (e.g., anaerobic culture), quinones reduces these residues, allowing for ArcB homodimerization. ArcB then functions as a kinase, and a phosphorelay ends with phosphorylation of the phosphotransfer domain of the partner ArcB molecule. In oxidizing conditions (e.g., aerobic culture), quinones oxidize the cysteines, which form disulfide bonds with the corresponding cysteines of a neighboring ArcB molecule. This formation silences ArcB kinase activity and phosphorylation does not occur. Ubiquinone, menaquinone, and demethylmenaquinone can activate or inactivate ArcB kinase activity depending on their own oxidation state and abundance. See the text for further details. Key: C-S-H, reduced cysteine residue; C-S-S-C, disulfide bond; L, linker domain; H₁, primary transmitter domain; D, central receiver domain; H₂, phosphotransfer domain. This model has been adapted from Alvarez et al. (26) and Bekker et al. (119) with permission.

FIG 4

ArcA-mediated responses to hydrogen peroxide. Following reactive oxygen stress from exposure to hydrogen peroxide (H₂O₂), cells utilize ArcA to respond by downregulating porins of H₂O₂ (S. enterica), producing proteins such as Dps to protect DNA from oxidative damage (H. influenzae), and promote maintenance of the outer membrane following ROS damage (S. oneidensis).