# Protein Kinases in Mediating Phage-Bacteria Interactions
## 5 Bacteria HKs in Phage-Bacteria Interactions  
There are surprisingly fewer reports (Table 1; Figure 2) of canonical HK/RRs systems that are involved in phage-bacteria interactions, despite the large body of research of them in bacterial stress response and antibiotic tolerance and resistance [12; 54]. Only three examples were found and described below, i.e., the Rcs, BarA/UvrY and Cpx pathways. Figure 2: Bacterial Histidine Kinases (HK) (in two-component systems, TCS) in mediating phage-bacteria interactions. (**A**) Briefly, _Serratia_ Rcs TCS system balances innate immunity (mediated by changed cell surface structures and nonspecific blockage of phage absorption) and adaptive immunity (mediated by repressed CRISPR-Cas system) [43]. The latter allows horizontal transfer of plasmids containing antibiotic resistance genes from other cells. (**B**) _Marinomonas_ BarA/UvrY-like TCS system PpoS/PpoR regulates expression of both PAM-dependent and -independent CRISPR-Cas systems, avoiding phage escape mutations [9]. (**C**) The Cpx (conjugative pilus expression) TCS system mediates conjugative plasmid transfer and cross-species spread of multidrug resistance genes, besides upregulating efflux pumps to cause antibiotic resistance. Recent study indicates that certain phages can exploit conjugative pili for bacterial infections [45]. For simplicity, all three HKs (in bold) and their cognate response regulators (RRs, with a phosphate Pi) are presented in the similar 3-D architectures with varied colors. (Created in BioRender. [PERSON] (2025) [[https://BioRender.com/efjlk59](https://BioRender.com/efjlk59)]([https://BioRender.com/efjlk59](https://BioRender.com/efjlk59)) (accessed on 1 June 2025)). The Rcs (Regulator of Capsule Synthesis) System: A Multifaceted Envelope Stress Response Pathway [55]  
The Rcs system is a complex bacterial signalling network that responds to diverse envelope stresses, including perturbations in lipopolysaccharide (LPS) charge/fluidity [56; 57; 58], peptidoglycan biosynthesis defects [59], impaired lipoprotein trafficking [60], and loss of periplasmic osmoregulated glycans [61]. Central to this system is the outer membrane lipoprotein RcsF, which acts as a stress sensor. In its unique conformation, RcsF threads through outer membrane proteins (OMPs), positioning its signalling domain in the periplasm to detect LPS alterations via electrostatic interactions and potentially sense peptidoglycan disruptions [58]. Activation of Rcs involves a multi-step phosphorelay distinct from simpler two-component systems: under stress, RcsF relieves IgA-mediated repression of the HK RcsC [62; 63], enabling autophosphorylation and subsequent phosphotransfer through RcsD to the RR RcsB. Phosphorylated RcsB regulates transcription either as a homodimer or by forming heterodimers with auxiliary regulators like RcsA, which is controlled post-translationally via proteolysis and folding dynamics [55]. The Rcs regulon drives diverse physiological adaptations, including upregulation of colonic acid capsule synthesis, biofilm formation [64], and stress resistance (via RpoS activation through the sRNA RprA [65]), while repressing motility genes [66]. RcsB also interacts with non-canonical partners (e.g., BgJl, GadE) [55] to fine-tune responses. Despite its well-characterized roles, many Rcs-regulated genes remain unannotated [55], underscoring the system's complexity in bridging envelope integrity monitoring with global transcriptional reprogramming. The Rcs phosphorelay system in _Serratia_ sp. ATCC 39006 was found to act as a dual regulator of phage defense, balancing innate and adaptive immunity [43] (Figure 2A). Mutations activating Rcs (e.g., \(\Delta\)_igaA/\(\Delta\)modG_) induce cell-surface modifications via RcsB-RcsA, blocking phage adsorption through innate mechanisms, while concurrently suppressing CRISPR-Cas adaptive immunity. Suppressed CRISPR-Cas system instead facilitates plasmid-mediated antibiotic resistance gene transfer.