Two-component system GacS/GacA, a global response regulator of bacterial physiological behaviors

The signal transduction system of microorganisms helps them adapt to changes in their complex living environment. Two-component system (TCS) is a representative signal transduction system that plays a crucial role in regulating cellular communication and secondary metabolism. In Gram-negative bacteria, an unorthodox TCS consisting of histidine kinase protein GacS (initially called LemA) and response regulatory protein GacA is widespread. It mainly regulates various physiological activities and behaviors of bacteria, such as quorum sensing, secondary metabolism, biofilm formation and motility, through the Gac/Rsm (Regulator of secondary metabolism) signaling cascade pathway. The global regulatory ability of GacS/GacA in cell physiological activities makes it a potential research entry point for developing natural products and addressing antibiotic resistance. In this review, we summarize the progress of research on GacS/GacA from various perspectives, including the reaction mechanism, related regulatory pathways, main functions and GacS/GacA-mediated applications. Hopefully, this review will facilitate further research on GacS/GacA and promote its application in regulating secondary metabolism and as a therapeutic target.