Dual functioning by the PhoR sensor is a key determinant to < i > Mycobacterium tuberculosis < /i > virulence

by Prabhat Ranjan Singh, Harsh Goar, Partha Paul, Khushboo Mehta, Bhanwar Bamniya, Anil Kumar Vijjamarri, Roohi Bansal, Hina Khan, Subramanian Karthikeyan, Dibyendu Sarkar PhoP-PhoR, one of the 12 two-component systems (TCSs) that empowerM.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-deletedM.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 kin...
Source: PLoS Genetics - Category: Genetics & Stem Cells Authors: Source Type: research