creators_name: Singh, Prabhat Ranjan
creators_name: Goar, Harsh
creators_name: Paul, Partha
creators_name: Mehta, Khushboo
creators_name: Bamniya, Bhanwar
creators_name: Vijjamarri, Anil Kumar
creators_name: Bansal, Roohi
creators_name: Khan, Hina
creators_name: Karthikeyan, Subramanian
creators_name: Sarkar, Dibyendu
type: article
datestamp: 2026-03-25 08:22:48
lastmod: 2026-03-25 08:22:48
metadata_visibility: show
title: Dual functioning by the PhoR sensor is a key determinant to Mycobacterium tuberculosis virulence
ispublished: pub
subjects: QR
note: Copyright of this article belongs to Pub Med Central
abstract: 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.
date: 2023-12-15
date_type: published
publication: PLoS Genet.
volume: 19
number: 12
publisher: Pub Med Central
pagerange: e1011070
refereed: TRUE
official_url: https://pmc.ncbi.nlm.nih.gov/articles/PMC10723718/
citation:   Singh, Prabhat Ranjan and Goar, Harsh and Paul, Partha and Mehta, Khushboo and Bamniya, Bhanwar and Vijjamarri, Anil Kumar and Bansal, Roohi and Khan, Hina and Karthikeyan, Subramanian and Sarkar, Dibyendu  (2023) Dual functioning by the PhoR sensor is a key determinant to Mycobacterium tuberculosis virulence.  PLoS Genet., 19 (12).  e1011070.