ArticleThe Journal of biological chemistry2016
Mycobacterium tuberculosis WhiB3 Responds to Vacuolar pH-induced Changes in Mycothiol Redox Potential to Modulate Phagosomal Maturation and Virulence.
Article in The Journal of biological chemistry, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 62 papers.
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Who cites it
62 citing papers in PubMed, 102 citations in OpenAlex.
- Transcriptional control of asparagine utilization regulates mycobacterial pH-driven adaptation at the host-pathogen crossroads.The Journal of biological chemistry · 2026Article
- Fighting the invader: strategies against intracellular bacteria.Frontiers in pharmacology · 2026Review
- The Microbial Trojan Horse and Antimicrobial Resistance: Acanthamoeba as an Environmental Reservoir for Multidrug Resistant Bacteria.Environmental microbiology · 2025Article
- Unraveling Mycobacterium tuberculosis acid resistance and pH homeostasis mechanisms.FEBS letters · 2025Review
- A pH-dependent direct sulfhydrylation pathway is required for the pathogenesis of Mycobacterium tuberculosis.Communications biology · 2025Article
- Prevention of tuberculosis in cynomolgus macaques by an attenuated Mycobacterium tuberculosis vaccine candidate.Nature communications · 2025Article
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- Physiological stage-dependent effects ofFrontiers in microbiology · 2025Article
- WhiB-like proteins: Diversity of structure, function and mechanism.Biochimica et biophysica acta. Molecular cell research · 2024Review
- Gene Regulatory Mechanism of Mycobacterium Tuberculosis during Dormancy.Current issues in molecular biology · 2024Review
- TargetingMicrobiology (Reading, England) · 2024Review
- Uncovering the roles ofmSphere · 2024Article
- Lsr2, a pleiotropic regulator at the core of the infectious strategy ofMicrobiology spectrum · 2024Article
- Gallein and isoniazid act synergistically to attenuatebioRxiv : the preprint server for biology · 2024Article
- Gallein potentiates isoniazid's ability to suppressFrontiers in microbiology · 2024Article
- Clinically relevant mutations in the PhoR sensor kinase of host-adaptedMicrobiology spectrum · 2023Article
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- Design, Synthesis, and Evaluation of Novel ΔJournal of medicinal chemistry · 2023Article
- Review
- Mycobacterium tuberculosis whiB3 and Lipid Metabolism Genes Are Regulated by Host Induced Oxidative StressMicroorganisms · 2022Article
2 more citing papers are in PubMed but not listed here.
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
Abstract
The ability of Mycobacterium tuberculosis to resist intraphagosomal stresses, such as oxygen radicals and low pH, is critical for its persistence. Here, we show that a cytoplasmic redox sensor, WhiB3, and the major M. tuberculosis thiol, mycothiol (MSH), are required to resist acidic stress during infection. WhiB3 regulates the expression of genes involved in lipid anabolism, secretion, and redox metabolism, in response to acidic pH. Furthermore, inactivation of the MSH pathway subverted the expression of whiB3 along with other pH-specific genes in M. tuberculosis. Using a genetic biosensor of mycothiol redox potential (EMSH), we demonstrated that a modest decrease in phagosomal pH is sufficient to generate redox heterogeneity in EMSH of the M. tuberculosis population in a WhiB3-dependent manner. Data indicate that M. tuberculosis needs low pH as a signal to alter cytoplasmic EMSH, which activates WhiB3-mediated gene expression and acid resistance. Importantly, WhiB3 regulates intraphagosomal pH by down-regulating the expression of innate immune genes and blocking phagosomal maturation. We show that this block in phagosomal maturation is in part due to WhiB3-dependent production of polyketide lipids. Consistent with these observations, MtbΔwhiB3 displayed intramacrophage survival defect, which can be rescued bypharmacological inhibition of phagosomal acidification. Last, MtbΔwhiB3 displayed marked attenuation in the lungs of guinea pigs. Altogether, our study revealed an intimate link between vacuolar acidification, redox physiology, and virulence in M. tuberculosis and discovered WhiB3 as crucial mediator of phagosomal maturation arrest and acid resistance in M. tuberculosis.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.