Protein Kinase B (PknB) of Mycobacterium tuberculosis Is Essential for Growth of the Pathogen in Vitro as well as for Survival within the Host

The Mycobacterium tuberculosis protein kinase B (PknB) comprises an intracellular kinase domain, connected through a transmembrane domain to an extracellular region that contains four PASTA domains. The present study describes the comprehensive analysis of different domains of PknB in the context of...

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Bibliographic Details
Published in:The Journal of biological chemistry 2014-05, Vol.289 (20), p.13858-13875
Main Authors: Chawla, Yogesh, Upadhyay, Sandeep, Khan, Shazia, Nagarajan, Sathya Narayanan, Forti, Francesca, Nandicoori, Vinay Kumar
Format: Article
Language:English
Subjects:
Animals
Bacterial Protein Kinases
Cell Growth
Cell Membrane - metabolism
Cell Proliferation
Cell Signaling
Extracellular Space - metabolism
Gene Expression Regulation, Bacterial
Intracellular Space - metabolism
Mice
Microbial Viability
Mycobacteria
Mycobacterium tuberculosis - cytology
Mycobacterium tuberculosis - enzymology
Mycobacterium tuberculosis - genetics
Mycobacterium tuberculosis - physiology
PASTA Domain
PknB
Protein Phosphorylation
Protein Structure, Tertiary
Protein Transport
Protein-Serine-Threonine Kinases - chemistry
Protein-Serine-Threonine Kinases - genetics
Protein-Serine-Threonine Kinases - metabolism
Signal Transduction
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Summary:The Mycobacterium tuberculosis protein kinase B (PknB) comprises an intracellular kinase domain, connected through a transmembrane domain to an extracellular region that contains four PASTA domains. The present study describes the comprehensive analysis of different domains of PknB in the context of viability in avirulent and virulent mycobacteria. We find stringent regulation of PknB expression necessary for cell survival, with depletion or overexpression of PknB leading to cell death. Although PknB-mediated kinase activity is essential for cell survival, active kinase lacking the transmembrane or extracellular domain fails to complement conditional mutants not expressing PknB. By creating chimeric kinases, we find that the intracellular kinase domain has unique functions in the virulent strain, which cannot be substituted by other kinases. Interestingly, we find that although the presence of the C-terminal PASTA domain is dispensable in the avirulent M. smegmatis, all four PASTA domains are essential in M. tuberculosis. The differential behavior of PknB vis-à-vis the number of essential PASTA domains and the specificity of kinase domain functions suggest that PknB-mediated growth and signaling events differ in virulent compared with avirulent mycobacteria. Mouse infection studies performed to determine the role of PknB in mediating pathogen survival in the host demonstrate that PknB is not only critical for growth of the pathogen in vitro but is also essential for the survival of the pathogen in the host. Mycobacterium tuberculosis PknB plays a critical role in modulating cell division and cell wall synthesis. We present a comprehensive evaluation of the importance of various domains of PknB in modulating cell survival The intracellular kinase domain and extracytoplasmic PASTA domains of PknB are essential for cell survival. PknB is essential for both in vitro growth and survival of the pathogen in vivo.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M114.563536