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dc:title "HTML Summary of #3399 \n\nDual functioning by the PhoR sensor is a key determinant to Mycobacterium tuberculosis virulence\n\n";
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bibo: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."^^xsd:string;
bibo:authorList ;
bibo:issue "12";
bibo:status ,
;
bibo:volume "19";
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dct:date "2023-12-15";
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dct:subject ;
dct:title "Dual functioning by the PhoR sensor is a key determinant to Mycobacterium tuberculosis virulence"^^xsd:string;
rdf:type bibo:AcademicArticle,
bibo:Article,
ep:ArticleEPrint,
ep:EPrint;
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skos:prefLabel "QR Microbiology"@en .
foaf:name "Pub Med Central"^^xsd:string;
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foaf:name "Hina Khan"^^xsd:string;
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foaf:name "Subramanian Karthikeyan"^^xsd:string;
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foaf:givenName "Prabhat Ranjan"^^xsd:string;
foaf:name "Prabhat Ranjan Singh"^^xsd:string;
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foaf:name "Partha Paul"^^xsd:string;
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