Correction: Mycobacterium tuberculosis Universal Stress Protein Rv2623 Regulates Bacillary Growth by ATP-Binding: Requirement for Establishing Chronic Persistent Infection

Abstract

Tuberculous latency and reactivation play a significant role in the pathogenesis of tuberculosis, yet the mechanisms that regulate these processes remain unclear. The Mycobacterium tuberculosis universal stress protein (USP) homolog, rv2623, is among the most highly induced genes when the tubercle bacillus is subjected to hypoxia and nitrosative stress, conditions thought to promote latency. Induction of rv2623 also occurs when M. tuberculosis encounters conditions associated with growth arrest, such as the intracellular milieu of macrophages and in the lungs of mice with chronic tuberculosis. Therefore, we tested the hypothesis that Rv2623 regulates tuberculosis latency. We observed that an Rv2623-deficient mutant fails to establish chronic tuberculous infection in guinea pigs and mice, exhibiting a hypervirulence phenotype associated with increased bacterial burden and mortality. Consistent with this in vivo growth-regulatory role, constitutive overexpression of rv2623 attenuates mycobacterial growth in vitro. Biochemical analysis of purified Rv2623 suggested that this mycobacterial USP binds ATP, and the 2.9-A ˚-resolution crystal structure revealed that Rv2623 engages ATP in a novel nucleotide-binding pocket. Structure-guided mutagenesis yielded Rv2623 mutants with reduced ATP-binding capacity. Analysis of mycobacteria overexpressing these mutants revealed that the in vitro growth-inhibitory property of Rv2623 correlates with its ability to bind ATP. Together, the results indicate that i) M. tuberculosis Rv2623 regulates mycobacterial growth in vitro and in vivo, and ii) Rv2623 is required for the entry of the tubercle bacillus into the chronic phase of infection in the host; in addition, iii) Rv2623 binds ATP; and iv) the growth-regulatory attribute of this USP is dependent on its ATP-binding activity. We propose that Rv2623 may function as an ATP-dependent signaling intermediate in a pathway that promotes persistent infection.

The ATP-Binding Cassette (ABC) Transport Systems in Mycobacterium tuberculosis: Structure, Function, and Possible Targets for Therapeutics

“…Although still not clear, this transporter has been associated with the translocation of bacterial cell wall components such as lipo-oligosaccharides or phosphatidyl-myo-inositol-mannosides (PIMs), antibiotic extrusion, and cell wall synthesis or remodeling [102]. Interestingly, the phosphorylated protein Rv2623 (USP) binds to Rv1747, modulating the number of PIMs in the cellular envelope [106]. Its function is essential during the infection and pathogenesis of the bacteria [84,104,106].…”

“…Interestingly, the phosphorylated protein Rv2623 (USP) binds to Rv1747, modulating the number of PIMs in the cellular envelope [106]. Its function is essential during the infection and pathogenesis of the bacteria [84,104,106]. Rv1473 NBD Macrolides efflux [92,93] Rv2477c NBD Macrolides efflux [93] The membrane-spanning (RfbD) and nucleotide-binding domains (RfbE) share homology with components of O-antigen and lipopolysaccharide exporter from different species [94,95].…”

Host- and Age-Dependent Transcriptional Changes in Mycobacterium tuberculosis Cell Envelope Biosynthesis Genes after Exposure to Human Alveolar Lining Fluid

“…Key genes such as Rv1747, thought to participate in the export of PIMs to the cell envelope through negative regulation by stress protein Rv2623 [43], were highly downregulated in M.tb exposed to A-ALFs (fold changes of 0.11, 0.14, and 0.09 for A 1 , A 2 , and A 3 , respectively). Indeed, an ∆Rv2623 mutant showed enhanced PIM expression and was hypervirulent in mice [73], while ∆Rv1747 had decreased levels of PIMs and was growthattenuated [74]. Our data suggest that contact with functional A-ALF reduces the expression of PIM transporter Rv1747 through increased expression of Rv2623, modulating the export of immunomodulatory PIMs and potentially influencing bacterial growth and virulence.…”

Universal Stress Proteins as New Targets for Environmental and Therapeutic Interventions of Schistosomiasis

“…USPs have been shown to be present among a diverse group of organisms such as bacteria, protists, fungi and plants (Table 1) [48,49,50,51,52,53,54,55,56,57,58,59], assisting them to tolerate different environmental and adverse conditions such as high salinity, high temperatures, drought and toxic chemicals [49]. Originally, universal stress protein A was first discovered in Escherichia coli but lately, genes encoding proteins with the USP domain (Pfam Identifier: PF00582) have recently been shown to be present in the S. mansoni , S. japonicum and S. haematobium species [17,49,60].…”