Serine/Threonine Kinase Signaling in Mycobacteria

Mycobacteria possess a sophisticated network of eukaryotic-type serine/threonine protein kinases (STPKs) that modulate a wide range of cellular processes through reversible phosphorylation. In Mycobacterium tuberculosis, eleven STPKs coordinate cell growth, cell division, cell-wall remodelling and stress responses by phosphorylating key substrates. Surface-associated domains, such as the penicillin binding protein and Ser/Thr kinase associated (PASTA) repeats in PknB, detect peptidoglycan fragments at sites of cell-wall turnover, directing kinase activity to the septum and poles. Kinases such as PknG regulate intracellular metabolism and redox homeostasis under nutrient limitation or hypoxia, thereby contributing to persistence and latency. Convergence with two-component systems further integrates environmental signals, for example through phosphorylation of dormancy regulator DosR by PknH, ensuring precise induction of hypoxia-responsive genes. Multisystem analyses reveal that PknA and PknB jointly orchestrate envelope stress responses, lipid metabolism and protein secretion pathways, highlighting the potential of these kinases as therapeutic targets. Collectively, serine/threonine kinase signalling underpins the pathogen’s ability to adapt to host environments and sustain chronic infection.

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Serine/Threonine Kinase Signaling in Mycobacteria publication trend

The graph below shows the total number of articles in serine/threonine kinase signaling in mycobacteria across all publications each year (not limited to Nature Index journals).

Technical terms

Serine/Threonine Protein Kinase (STPK): An enzyme that transfers a phosphate group from ATP to specific serine or threonine residues on protein substrates, modulating their activity or interactions.

Phosphorylation: A reversible post-translational modification involving the covalent attachment of a phosphate group to amino acid side chains, which alters protein function or localisation.

PASTA Domain: A conserved extracytoplasmic module found in certain STPKs that binds peptidoglycan fragments, guiding kinase localisation to sites of cell-wall synthesis.

Two-Component System: A bacterial signal transduction mechanism comprising a sensor histidine kinase and a response regulator that controls gene expression via phosphorylation.

Phosphoproteome: The complete set of phosphorylated proteins in a cell under defined conditions, often characterised by mass spectrometry.

References

1. The Extracytoplasmic Domain of the Mycobacterium tuberculosis Ser/Thr Kinase PknB Binds Specific Muropeptides and Is Required for PknB Localization. PLOS Pathogens (2011).
2. Protein kinase G confers survival advantage to Mycobacterium tuberculosis during latency-like conditions. Journal of Biological Chemistry (2017).
3. Convergence of Ser/Thr and Two-component Signaling to Coordinate Expression of the Dormancy Regulon in Mycobacterium tuberculosis *[S]. Journal of Biological Chemistry (2010).
4. Multisystem Analysis of Mycobacterium tuberculosis Reveals Kinase-Dependent Remodeling of the Pathogen-Environment Interface. mBio (2018).
5. More than two components: complexities in bacterial phosphosignaling. mSystems (2024).
6. Two Faces of CwlM, an Essential PknB Substrate, in Mycobacterium tuberculosis. Cell Reports (2018).
7. Hanks-Type Serine/Threonine Protein Kinases and Phosphatases in Bacteria: Roles in Signaling and Adaptation to Various Environments. International Journal of Molecular Sciences (2018).