Constitutive activation of two-component systems reveals regulatory network interactions in Streptococcus agalactiae

Cosme Claverie, Francesco Coppolino, Maria-Vittoria Mazzuoli, Cécile Guyonnet, Elise Jacquemet, Rachel Legendre, Odile Sismeiro, Giuseppe Valerio Gaetano, Giuseppe Teti, Patrick Trieu-Cuot, Asmaa Tazi, Concetta Beninati and Arnaud Firon ()
Additional contact information
Cosme Claverie: Biology of Gram-Positive Pathogens
Francesco Coppolino: Biology of Gram-Positive Pathogens
Maria-Vittoria Mazzuoli: Biology of Gram-Positive Pathogens
Cécile Guyonnet: French National Reference Center for Streptococci
Elise Jacquemet: Bioinformatics and Biostatistics Hub
Rachel Legendre: Bioinformatics and Biostatistics Hub
Odile Sismeiro: Biology of Gram-Positive Pathogens
Giuseppe Valerio Gaetano: Department of Human Pathology
Giuseppe Teti: Scylla Biotech Srl
Patrick Trieu-Cuot: Biology of Gram-Positive Pathogens
Asmaa Tazi: French National Reference Center for Streptococci
Concetta Beninati: Department of Human Pathology
Arnaud Firon: Biology of Gram-Positive Pathogens

Nature Communications, 2024, vol. 15, issue 1, 1-12

Abstract: Abstract Bacterial two-component systems (TCSs) are signaling modules that control physiology, adaptation, and host interactions. A typical TCS consists of a histidine kinase (HK) that activates a response regulator via phosphorylation in response to environmental signals. Here, we systematically test the effect of inactivating the conserved phosphatase activity of HKs to activate TCS signaling pathways. Transcriptome analyses of 14 HK mutants in Streptococcus agalactiae, the leading cause of neonatal meningitis, validate the conserved HK phosphatase mechanism and its role in the inhibition of TCS activity in vivo. Constitutive TCS activation, independent of environmental signals, enables high-resolution mapping of the regulons for several TCSs (e.g., SaeRS, BceRS, VncRS, DltRS, HK11030, HK02290) and reveals the functional diversity of TCS signaling pathways, ranging from highly specialized to interconnected global regulatory networks. Targeted analysis shows that the SaeRS-regulated PbsP adhesin acts as a signaling molecule to activate CovRS signaling, thereby linking the major regulators of host-pathogen interactions. Furthermore, constitutive BceRS activation reveals drug-independent activity, suggesting a role in cell envelope homeostasis beyond antimicrobial resistance. This study highlights the versatility of constitutive TCS activation, via phosphatase-deficient HKs, to uncover regulatory networks and biological processes.

Date: 2024
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DOI: 10.1038/s41467-024-53439-3

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