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primary topic: Dual functioning by the PhoR sensor is a key determinant to Mycobacterium tuberculosis virulence

Dual functioning by the PhoR sensor is a key determinant to Mycobacterium tuberculosis virulence
type: AcademicArticle
type: Article
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
volume: 19
issue: 12
status: peerReviewed
status: published
author list: authors
type: EPrint
type: ArticleEPrint
is part of: repository
subject: QR Microbiology

Pub Med Central
type: Organization

PLoS Genet.
type: Collection

Partha Paul
type: Person
given name: Partha
family name: Paul

Dibyendu Sarkar
type: Person
given name: Dibyendu
family name: Sarkar

Bhanwar Bamniya
type: Person
given name: Bhanwar
family name: Bamniya

Roohi Bansal
type: Person
given name: Roohi
family name: Bansal

Prabhat Ranjan Singh
type: Person
given name: Prabhat Ranjan
family name: Singh

Khushboo Mehta
type: Person
given name: Khushboo
family name: Mehta

Subramanian Karthikeyan
type: Person
given name: Subramanian
family name: Karthikeyan

Harsh Goar
type: Person
given name: Harsh
family name: Goar

Anil Kumar Vijjamarri
type: Person
given name: Anil Kumar
family name: Vijjamarri

Hina Khan
type: Person
given name: Hina
family name: Khan

HTML Summary of #3399 Dual functioning by the PhoR sensor is a key determinant to Mycobacterium tuberculosis virulence
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primary topic: Dual functioning by the PhoR sensor is a key determinant to Mycobacterium tuberculosis virulence

QR Microbiology
type: Concept