Sequestration of histidine kinases by non-cognate response regulators establishes a threshold level of stimulation for bacterial two-component signaling

Gaurav D. Sankhe, Rubesh Raja, Devendra Pratap Singh, Sneha Bheemireddy, Subinoy Rana, P. J. Athira, Narendra M. Dixit () and Deepak Kumar Saini ()
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Gaurav D. Sankhe: Indian Institute of Science
Rubesh Raja: Indian Institute of Science
Devendra Pratap Singh: Indian Institute of Science
Sneha Bheemireddy: Indian Institute of Science
Subinoy Rana: Indian Institute of Science
P. J. Athira: Indian Institute of Science
Narendra M. Dixit: Indian Institute of Science
Deepak Kumar Saini: Indian Institute of Science

Nature Communications, 2023, vol. 14, issue 1, 1-16

Abstract: Abstract Bacterial two-component systems (TCSs) consist of a sensor histidine kinase (HK) that perceives a specific signal, and a cognate response regulator (RR) that modulates the expression of target genes. Positive autoregulation improves TCS sensitivity to stimuli, but may trigger disproportionately large responses to weak signals, compromising bacterial fitness. Here, we combine experiments and mathematical modelling to reveal a general design that prevents such disproportionate responses: phosphorylated HKs (HK~Ps) can be sequestered by non-cognate RRs. We study five TCSs of Mycobacterium tuberculosis and find, for all of them, non-cognate RRs that show higher affinity than cognate RRs for HK~Ps. Indeed, in vitro assays show that HK~Ps preferentially bind higher affinity non-cognate RRs and get sequestered. Mathematical modelling indicates that this sequestration would introduce a ‘threshold’ stimulus strength for eliciting responses, thereby preventing responses to weak signals. Finally, we construct tunable expression systems in Mycobacterium bovis BCG to show that higher affinity non-cognate RRs suppress responses in vivo.

Date: 2023
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DOI: 10.1038/s41467-023-40095-2

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