TY  - JOUR
N1  - Copyright of this article belongs to Pub Med Central
ID  - open3399
UR  - https://pmc.ncbi.nlm.nih.gov/articles/PMC10723718/
IS  - 12
A1  - Singh, Prabhat Ranjan
A1  - Goar, Harsh
A1  - Paul, Partha
A1  - Mehta, Khushboo
A1  - Bamniya, Bhanwar
A1  - Vijjamarri, Anil Kumar
A1  - Bansal, Roohi
A1  - Khan, Hina
A1  - Karthikeyan, Subramanian
A1  - Sarkar, Dibyendu
Y1  - 2023/12/15/
N2  - 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.
PB  - Pub Med Central
JF  - PLoS Genet.
VL  - 19
TI  - Dual functioning by the PhoR sensor is a key determinant to Mycobacterium tuberculosis virulence
ER  -