<i>Mycobacterium tuberculosis</i> virulence‐regulator PhoP interacts with alternative sigma factor SigE during acid‐stress response

Bansal, Roohi; Kumar, Vijjamarri Anil; Sevalkar, Ritesh Rajesh; Singh, Prabhat Ranjan; Sarkar, Dibyendu

doi:10.1111/mmi.13635

Cited by 58 publications

(83 citation statements)

References 39 publications

(71 reference statements)

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“…Either there is involvement of another protein/factor along with PhoP under heat shock conditions or the regulator during stress undergoes a conformational change which provides the binding energy so that it can now bind to the target promoter(s) on its own. While the DNA binding mechanism of PhoP is well known (23), our knowledge of protein-protein interactions involving the major virulence regulator has been limited to a few examples (15,24). Thus, biochemical studies are required to identify newer working partners of the regulator.…”

Section: Discussionmentioning

confidence: 99%

Functioning of Mycobacterial Heat Shock Repressors Requires the Master Virulence Regulator PhoP

et al. 2019

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A hallmark feature of Mycobacterium tuberculosis pathogenesis lies in the ability of the pathogen to survive within macrophages under a stressful environment. Thus, coordinated regulation of stress proteins is critically important for an effective adaptive response of M. tuberculosis, the failure of which results in elevated immune recognition of the tubercle bacilli with reduced survival during chronic infections. Here, we show that virulence regulator PhoP impacts the global regulation of heat shock proteins, which protect M. tuberculosis against stress generated by macrophages during infection. Our results identify that in addition to classical DNAprotein interactions, newly discovered protein-protein interactions control complex mechanisms of expression of heat shock proteins, an essential pathogenic determinant of M. tuberculosis. While the C-terminal domain of PhoP binds to its target promoters, the N-terminal domain of the regulator interacts with the C-terminal end of the heat shock repressors. Remarkably, our findings delineate a regulatory pathway which involves three major transcription factors, PhoP, HspR, and HrcA, that control in vivo recruitment of the regulators within the target genes and regulate stressspecific expression of heat shock proteins via protein-protein interactions. The results have implications on the mechanism of regulation of PhoP-dependent stress response in M. tuberculosis. IMPORTANCE The regulation of heat shock proteins which protect M. tuberculosis against stress generated by macrophages during infection is poorly understood. In this study, we show that PhoP, a virulence regulator of the tubercle bacilli, controls heat shock-responsive genes, an essential pathogenic determinant of M. tuberculosis. Our results unravel that in addition to classical DNA-protein interactions, complex mechanisms of regulation of heat shock-responsive genes occur through multiple protein-protein interactions. Together, these findings delineate a fundamental regulatory pathway where transcription factors PhoP, HspR, and HrcA interact with each other to control stress-specific expression of heat shock proteins.

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Section: Discussionmentioning

confidence: 99%

Functioning of Mycobacterial Heat Shock Repressors Requires the Master Virulence Regulator PhoP

et al. 2019

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“…Total RNA from Mtb was extracted as described (28) using exponentially growing bacterial cultures grown with or without stress. After extraction with chloroform-isoamyl alcohol, RNA was precipitated with chilled ethanol.…”

Section: Methodsmentioning

confidence: 99%

“…cDNA synthesis and PCR reactions using appropriate PAGE-purified primer pairs (200 nM; see Table S1) were performed in an Applied Biosystems real-time PCR detection system using Superscript III platinum-SYBR green one-step qRT-PCR kit (Invitrogen) and cycling conditions as described (28). For each pair of primers, a standard curve was generated using serially diluted RNA samples, and PCR efficiency was evaluated.…”

Section: Methodsmentioning

confidence: 99%

“…Recently, under anaerobic conditions Δ dosR Mtb was shown to be growth defective at low pH (24). Because PhoP controls pH-driven adaptations of Mtb (25–28), in this study we focused to investigate whether virulence-associated phoP locus is linked to hypoxic response of the tubercle bacilli. Transcript profiling indicates that induction of dosR regulon was subdued in ΔphoP mutant, suggesting that PhoP functions as an activator of hypoxia-inducible genes.…”

Section: Introductionmentioning

confidence: 99%

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Metabolic switching ofMycobacterium tuberculosisduring hypoxia is controlled by the virulence regulator PhoP

Singh

Kumar

Sarkar

2019

Preprint

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25Mycobacterium tuberculosis (Mtb) retains the unique ability to establish an asymptomatic 26 latent infection. A fundamental question in mycobacterial physiology is to understand the 27 mechanisms involved in hypoxic stress, a critical player in persistence. Here, we show that the 28 virulence regulator PhoP responds to hypoxia, the dormancy signal and effectively integrates 29 hypoxia with nitrogen metabolism. We also provide evidence to demonstrate that both under 30 nitrogen limiting conditions and during hypoxia, phoP locus controls key genes involved in 31 nitrogen metabolism. Consistently, under hypoxia phoP shows growth attenuation even with 32 surplus nitrogen, the alternate electron acceptor, and complementation of the mutant restores 33 bacterial growth. Together, our observations provide new biological insights into the role of 34 PhoP in integrating nitrogen metabolism with hypoxia by the assistance of the hypoxia regulator 35DosR. The results have significant implications on the mechanism of intracellular survival and 36 growth of the tubercle bacilli under a hypoxic environment within the phagosome. 37 38 Importance 39Mtb retains the unique ability to establish an asymptomatic latent infection. To understand the 40 mechanisms involved in hypoxic stress which plays a critical role in persistence, we show that 41 the virulence regulator PhoP responds to hypoxia, the dormancy signal. In keeping with this, 42 phoP was shown to play a major role in Mtb growth under hypoxia even in presence of surplus 43 nitrogen, the alternate electron acceptor. Our results showing regulation of hypoxia-responsive 44 genes provide new biological insights into role of the virulence regulator in metabolic switching 45 by sensing hypoxia and integrating nitrogen metabolism with hypoxia by the assistance of the 46 hypoxia regulator DosR. 47 48 49 A hallmark of tuberculosis is the unique ability of Mtb to establish an asymptomatic 50 latent infection and persist within granulomas in a dormant form, sometimes for a very long 51 time, before reactivation to cause the active disease. As survival and persistence in this 52 environment depends on the sensing of signals and ability to induce a robust adaptive response, 53 one of the major aspects to understand latent TB relates to understanding molecular mechanism 54 of adaptation of the tubercle bacilli in response to environmental stress. 55 56 Despite its requirement of oxygen for growth, during latency Mtb can survive without 57 oxygen for a surprisingly long time. Thus, two in vivo conditions are often linked to latent TB. 58These are hypoxia and exposure to immune effectors such as nitric oxide (NO) (1-3). The ability 59 to produce reactive nitrogen species (RNS) by host-inducible nitric oxide synthase (iNOS) 60 contributes to TB infections by its effect on both the host and the pathogen (4). Therefore, 61 functional iNOS expression could be detected in the lung macrophages of human TB patients (5, 62 6). Consistently, hypoxia and nitric oxide dependent bacterial adaptation...

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“…Interestingly, SigE regulates gene expression specifically during the post-exponential growth phase of Synechococcus species (Gruber and Bryant 1998). Thus, as a cell surface stressrelated transcription factor, SigE is important for bacterial growth and stress resistance, with diverse effects on cell sporulation (Shuler et al 1995;Wong et al 1995;AlHinai et al 2014;Casonato et al 2014;Kirk et al 2014), granuloma formation (Giacomini et al 2006), phagocytosis by macrophages (Ando et al 2003), cell wall integrity (Paget et al 1999), fatty acid metabolism (Manganelli et al 2001), carotenoid biosynthesis (Hakkila et al 2013), nitrogen starvation and sugar catabolism (Osanai et al 2005a), and responses to various stresses, including acid (Bansal et al 2017), oxidative (Bagchi and Ghosh 2006;Pacheco et al 2012), heat (Pettersson et al 2015), and salt (Koskinen et al 2016) stresses.…”

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confidence: 99%

Sigma factor FaSigE positively regulates strawberry fruit ripening by ABA

et al. 2017

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Mycobacterium tuberculosis virulence‐regulator PhoP interacts with alternative sigma factor SigE during acid‐stress response

Cited by 58 publications

References 39 publications

Functioning of Mycobacterial Heat Shock Repressors Requires the Master Virulence Regulator PhoP

Functioning of Mycobacterial Heat Shock Repressors Requires the Master Virulence Regulator PhoP

Metabolic switching ofMycobacterium tuberculosisduring hypoxia is controlled by the virulence regulator PhoP

Sigma factor FaSigE positively regulates strawberry fruit ripening by ABA

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