Untangling the Complexity of Two-Component Signal Transduction in Bacteria

Two-component systems (TCSs) are ubiquitous in bacteria and are central to their ability to sense and respond to diverse environmental and intracellular cues. Classically composed of a sensor histidine kinase and a cognate response regulator, TCSs control processes ranging from metabolism and development to virulence and antibiotic resistance. In addition to their biological roles, TCSs are garnering attention in synthetic biology and antimicrobial drug development. While canonical architectures have been extensively studied, increasing evidence highlights the remarkable diversity in their organization and regulation. Despite substantial progress, key questions remain regarding the prevalence and physiological relevance of non-canonical TCSs, the mechanisms ensuring signal fidelity, and the potential for engineering these systems. This review explores non-typical TCSs, focusing on their varied transcriptional regulation, alternative response regulator activities, varied control by phosphorylation, and negative control mechanisms. We discuss how bacteria manage signaling specificity among numerous TCSs through cross-talk, hierarchical interactions, and phosphorelay systems and how these features shape adaptive responses. By synthesizing current understanding and highlighting still existing knowledge gaps, this review offers a novel perspective on TCS diversity, indicating directions for future research and potential translational applications in biotechnology and medicine.