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Cited by 74Tuberculosis Research and EpidemiologyBacterial Genetics and BiotechnologyMycobacterium research and diagnosis

Mycobacterium tuberculosis Ser/Thr Protein Kinase B Mediates an Oxygen-Dependent Replication Switch

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Ortega, Corrie, Liao, Reiling, Anderson, Lindsey N., Rustad, Tige, Ollodart, Anja R., Wright, Aaron T., Sherman, David R., Grundner, Christoph·2014·PLoS Biology
DOI 10.1371/journal.pbio.1001746PMC PMC3883633
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Abstract

The majority of Mycobacterium tuberculosis (Mtb) infections are clinically latent, characterized by drug tolerance and little or no bacterial replication. Low oxygen tension is a major host factor inducing bacteriostasis, but the molecular mechanisms driving oxygen-dependent replication are poorly understood. Here, we tested the role of serine/threonine phosphorylation in the Mtb response to altered oxygen status, using an in vitro model of latency (hypoxia) and reactivation (reaeration). Broad kinase inhibition compromised survival of Mtb in reaeration. Activity-based protein profiling and genetic mutation identified PknB as the kinase critical for surviving hypoxia. Mtb replication was highly sensitive to changes in PknB levels in aerated culture, and even more so in hypoxia. A mutant overexpressing PknB specifically in hypoxia showed a 10-fold loss in viability and gross morphological defects in low oxygen conditions. In contrast, chemically reducing PknB activity during hypoxia specifically compromised resumption of growth during reaeration. These data support a model in which PknB activity is reduced to achieve bacteriostasis, and elevated when replication resumes. Together, these data show that phosphosignaling controls replicative transitions associated with latency and reactivation, that PknB is a major regulator of these transitions, and that PknB could provide a highly vulnerable therapeutic target at every step of the Mtb life cycle-active disease, latency, and reactivation.

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  • PknA and PknB phosphorylate EmbR, activating transcription of embC, embA and embB during growth, thus ensuring that arabinan levels remain high for expansion of the cell wall.

    “PknA and PknB phosphorylate EmbR85, activating tran- scription of embC, embA and embB81 during growth59,72, thus ensuring that arabinan levels remain high for expan- sion of the cell wall.”

    From The mycobacterial cell envelope — a moving target (2020) · cites this paper as [72]

    The Results section, “Aerated Growth Is Sensitive to Changes in PknB Abundance,” shows that PknB kinase activity affects growth. The cited paper does not establish that PknA and PknB phosphorylate EmbR, activate transcription of embC, embA and embB, or maintain arabinan levels for cell-wall expansion; the printed sentence places other citations beside the EmbR and transcription clauses. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • EmbR is also phosphorylated by PknH, which is likely present in both growth and stasis on the basis of transcriptional and mutant survival data.

    “EmbR is also phosphorylated by PknH86, which is likely present in both growth and stasis on the basis of transcriptional and mutant survival data14,72,81.”

    From The mycobacterial cell envelope — a moving target (2020) · cites this paper as [72]

  • As these STPKs are associated with stasis conditions, their phosphorylation of FAS-II enzymes reduces mycolic acid synthesis during stasis and chronic phases of infection.

    “As these STPKs are associated with stasis conditions14,72,94,95, we predict that their phosphorylation of FAS-​II enzymes reduces mycolic acid synthesis during stasis and chronic phases of infection.”

    From The mycobacterial cell envelope — a moving target (2020) · cites this paper as [72]

  • PknB plays a key role in each stage of the complete cycle of growth, stasis and reactivation.

    “This article describes a complete cycle of growth, stasis and reactivation, and shows how the critical cell wall regulator, PknB, plays a key role in each stage.”

    From The mycobacterial cell envelope — a moving target (2020) · cites this paper as [72]

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Authors
Ortega, C., Liao, R., Anderson, L. N., Rustad, T., Ollodart, A. R., Wright, A. T., Sherman, D. R., & Grundner, C.
Affiliations
  • Center for Infectious Disease Research (US)
  • Pacific Northwest National Laboratory (US)
Corresponding author
Grundner, Christoph
ORCID
Venue
PLoS Biology
Publisher
Public Library of Science (PLoS)
Published
2014-01-07
Volume
12
Issue
1
Pages
e1001746
ISSN
  • 1544-9173 (ISSN-L)
  • 1545-7885
DOI
10.1371/journal.pbio.1001746
PMC
PMC3883633
OpenAlex
W2036411910
Cited by
74
References
3
Citations by year
2026: 5 · 2025: 2 · 2024: 3 · 2023: 3 · 2021: 2 · 2020: 10 · 2019: 7 · 2018: 8 · 2017: 17 · 2016: 4 · 2015: 7 · 2014: 6
FWCI
7.97
Type
journal article
Language
en
Open access
Licence
Locations
  • PLoS Biology (publishedVersion, public-domain)
  • Europe PMC (PubMed Central) (publishedVersion, public-domain)
  • PubMed Central (publishedVersion, public-domain)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
  • Figshare (submittedVersion, cc-by)
Funders
  • U.S. Department of Energy (GM103493)
  • Cancer Research Institute
  • Paul G. Allen Family Foundation
  • American Lung Association
  • University of Washington
  • National Institutes of Health (8p41gm103493-10, P41-GM103493, GM103493)
  • Center for AIDS Research, University of Washington (P30 AI027757)
  • National Institute on Aging
  • National Heart, Lung, and Blood Institute
  • National Institute of Mental Health
  • National Institute on Drug Abuse
  • National Cancer Institute (P41 GM103493)
  • National Institute of General Medical Sciences (GM103493, P41-GM103493)
  • National Institute of Allergy and Infectious Diseases (P30AI027757)
  • Laboratory Directed Research and Development
  • Pacific Northwest National Laboratory
Topics
  • Health Sciences › Medicine › Infectious Diseases › Tuberculosis Research and Epidemiology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Bacterial Genetics and Biotechnology
  • Health Sciences › Medicine › Epidemiology › Mycobacterium research and diagnosis
Keywords
Mycobacterium tuberculosis, PknB, serine/threonine kinase, hypoxia, reaeration, latent tuberculosis infection, tuberculosis reactivation, bacterial replication, bacteriostatic activity, oxygen partial pressure, kinase inhibition, therapeutic target
MeSH terms
Anaerobiosis, Anti-Bacterial Agents, Bacterial Proteins, Carbazoles, Mycobacterium tuberculosis, Oxygen, Serine, Threonine, Signal Transduction, Gene Expression Regulation, Bacterial, Indole Alkaloids, Protein Kinase Inhibitors, Proto-Oncogene Proteins c-akt

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