<> "The repository administrator has not yet configured an RDF license."^^ . <> . . . "Dual functioning by the PhoR sensor is a key determinant to Mycobacterium tuberculosis virulence"^^ . "PhoP-PhoR, one of the 12 two-component systems (TCSs) that empower M. tuberculosis to sense and adapt to diverse environmental conditions, remains essential for virulence, and therefore, represents a major target to develop novel anti-TB therapies. Although both PhoP and PhoR have been structurally characterized, the signal(s) that this TCS responds to remains unknown. Here, we show that PhoR is a sensor of acidic pH/high salt conditions, which subsequently activate PhoP via phosphorylation. In keeping with this, transcriptomic data uncover that acidic pH- inducible expression of PhoP regulon is significantly inhibited in a PhoR-deleted M. tuberculosis. Strikingly, a set of PhoP regulon genes displayed a low pH-dependent activation even in the absence of PhoR, suggesting the presence of non-canonical mechanism(s) of PhoP activation. Using genome-wide interaction-based screening coupled with phosphorylation assays, we identify a non-canonical mechanism of PhoP phosphorylation by the sensor kinase PrrB. To investigate how level of P~PhoP is regulated, we discovered that in addition to its kinase activity PhoR functions as a phosphatase of P~PhoP. Our subsequent results identify the motif/residues responsible for kinase/phosphatase dual functioning of PhoR. Collectively, these results uncover that contrasting kinase and phosphatase functions of PhoR determine the homeostatic mechanism of regulation of intra-mycobacterial P~PhoP which controls the final output of the PhoP regulon. Together, these results connect PhoR to pH-dependent activation of PhoP with downstream functioning of the regulator. Thus, PhoR plays a central role in mycobacterial adaptation to low pH conditions within the host macrophage phagosome, and a PhoR-deleted M. tuberculosis remains significantly attenuated in macrophages and animal models."^^ . "2023-12-15" . "19" . "12" . . "Pub Med Central"^^ . . . "PLoS Genet."^^ . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . "Partha"^^ . "Paul"^^ . "Partha Paul"^^ . . "Dibyendu"^^ . "Sarkar"^^ . "Dibyendu Sarkar"^^ . . "Bhanwar"^^ . "Bamniya"^^ . "Bhanwar Bamniya"^^ . . "Roohi"^^ . "Bansal"^^ . "Roohi Bansal"^^ . . "Prabhat Ranjan"^^ . "Singh"^^ . "Prabhat Ranjan Singh"^^ . . "Khushboo"^^ . "Mehta"^^ . "Khushboo Mehta"^^ . . "Subramanian"^^ . "Karthikeyan"^^ . "Subramanian Karthikeyan"^^ . . "Harsh"^^ . "Goar"^^ . "Harsh Goar"^^ . . "Anil Kumar"^^ . "Vijjamarri"^^ . "Anil Kumar Vijjamarri"^^ . . "Hina"^^ . "Khan"^^ . "Hina Khan"^^ . . . . . "HTML Summary of #3399 \n\nDual functioning by the PhoR sensor is a key determinant to Mycobacterium tuberculosis virulence\n\n" . "text/html" . . . "QR Microbiology"@en . .