Two-component systems (TCSs) are highly conserved signaling mechanisms that allow cells to sense and respond to diverse inter- or intracellular stimuli [1]. These systems comprise a sensor histidine kinase (HK) and a response regulator (RR) that work in tandem through a series of phosphorylation and dephosphorylation events. Consequently, this process culminates in alterations in protein–DNA-binding affinities, resulting in changes of gene expression [2]. These changes modulate metabolic processes and cellular behavior, enabling organisms to adapt to fluctuating environments [3]. Many bacterial species possess an extensive array of two-component pathways, often numbering in the dozens or even hundreds, granting them the capacity to respond to a wide spectrum of signals. Although prominent in bacteria, these signaling systems are pervasive throughout all domains of life [4].

TCSs are believed to have evolved in ancient prokaryotic cells from modular one-component regulators, consisting of a single protein harboring an input domain and an output domain [5]. Over time, additional protein components were acquired, enhancing sensing capabilities and enabling more intricate physiological responses 5, 6. This evolutionary process has yielded an extensive array of modular signaling devices with unique sensory capacities and diverse signaling mechanisms [7], providing bacteria the means to adapt and thrive in virtually any ecological niche.

Here, we review recent studies that examine how distinct environments have contributed to the diversity of TCS signaling circuits, influencing gene expression and cell behavior.