Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.


Logo for

Science 304 (5678): 1800-1804

Copyright © 2004 by the American Association for the Advancement of Science

Protein Kinase G from Pathogenic Mycobacteria Promotes Survival Within Macrophages

Anne Walburger,1* Anil Koul,2* Giorgio Ferrari,1* Liem Nguyen,1* Cristina Prescianotto-Baschong,1 Kris Huygen,3 Bert Klebl,2 Charles Thompson,1 Gerald Bacher,2 Jean Pieters1{dagger}

Abstract: Pathogenic mycobacteria resist lysosomal delivery after uptake into macrophages, allowing them to survive intracellularly. We found that the eukaryotic-like serine/threonine protein kinase G from pathogenic mycobacteria was secreted within macrophage phagosomes, inhibiting phagosome-lysosome fusion and mediating intracellular survival of mycobacteria. Inactivation of protein kinase G by gene disruption or chemical inhibition resulted in lysosomal localization and mycobacterial cell death in infected macrophages. Besides identifying a target for the control of mycobacterial infections, these findings suggest that pathogenic mycobacteria have evolved eukaryotic-like signal transduction mechanisms capable of modulating host cell trafficking pathways.

1 Biozentrum, University of Basel, Klingelbergstr. 50/70, CH-4056 Basel, Switzerland.
2 Axxima Pharmaceuticals AG, Max-Lebsche-Platz 32, 81377 Munich, Germany.
3 Pasteur Institute, Engelandstraat 642, B1180 Brussels, Belgium.

Back to Top

* These authors contributed equally to this work.

{dagger} To whom correspondence should be addressed. E-mail: jean.pieters{at}

Bacterial Serine/Threonine Protein Kinases in Host-Pathogen Interactions.
M. J. Canova and V. Molle (2014)
J. Biol. Chem. 289, 9473-9479
   Abstract »    Full Text »    PDF »
Dormant Mycobacterium tuberculosis Fails To Block Phagosome Maturation and Shows Unexpected Capacity To Stimulate Specific Human T Lymphocytes.
S. Mariotti, M. Pardini, M. C. Gagliardi, R. Teloni, F. Giannoni, M. Fraziano, F. Lozupone, S. Meschini, and R. Nisini (2013)
J. Immunol. 191, 274-282
   Abstract »    Full Text »    PDF »
Mycobacterium tuberculosis Maltosyltransferase GlgE, a Genetically Validated Antituberculosis Target, Is Negatively Regulated by Ser/Thr Phosphorylation.
J. Leiba, K. Syson, G. Baronian, I. Zanella-Cleon, R. Kalscheuer, L. Kremer, S. Bornemann, and V. Molle (2013)
J. Biol. Chem. 288, 16546-16556
   Abstract »    Full Text »    PDF »
Tetratricopeptide Repeat Motifs in the World of Bacterial Pathogens: Role in Virulence Mechanisms.
L. Cerveny, A. Straskova, V. Dankova, A. Hartlova, M. Ceckova, F. Staud, and J. Stulik (2013)
Infect. Immun. 81, 629-635
   Abstract »    Full Text »    PDF »
Mycobacterial Shuttle Vectors Designed for High-Level Protein Expression in Infected Macrophages.
J. L. Eitson, J. J. Medeiros, A. R. Hoover, S. Srivastava, K. T. Roybal, J. A. Ainsa, E. J. Hansen, T. Gumbo, and N. S. C. van Oers (2012)
Appl. Envir. Microbiol. 78, 6829-6837
   Abstract »    Full Text »    PDF »
Mycobacterium tuberculosis Protein Kinase K Enables Growth Adaptation through Translation Control.
V. Malhotra, B. P. Okon, and J. E. Clark-Curtiss (2012)
J. Bacteriol. 194, 4184-4196
   Abstract »    Full Text »    PDF »
G. Arora, A. Sajid, M. D. Arulanandh, A. Singhal, A. R. Mattoo, A. P. Pomerantsev, S. H. Leppla, S. Maiti, and Y. Singh (2012)
J. Biol. Chem. 287, 26749-26763
   Abstract »    Full Text »    PDF »
Urease Activity Represents an Alternative Pathway for Mycobacterium tuberculosis Nitrogen Metabolism.
W. Lin, V. Mathys, E. L. Y. Ang, V. H. Q. Koh, J. M. Martinez Gomez, M. L. T. Ang, S. Z. Zainul Rahim, M. P. Tan, K. Pethe, and S. Alonso (2012)
Infect. Immun. 80, 2771-2779
   Abstract »    Full Text »    PDF »
Phosphorylation of Mycobacterial PcaA Inhibits Mycolic Acid Cyclopropanation: CONSEQUENCES FOR INTRACELLULAR SURVIVAL AND FOR PHAGOSOME MATURATION BLOCK.
R. M. Corrales, V. Molle, J. Leiba, L. Mourey, C. de Chastellier, and L. Kremer (2012)
J. Biol. Chem. 287, 26187-26199
   Abstract »    Full Text »    PDF »
Mycobacterium tuberculosis Eis protein initiates suppression of host immune responses by acetylation of DUSP16/MKP-7.
K. H. Kim, D. R. An, J. Song, J. Y. Yoon, H. S. Kim, H. J. Yoon, H. N. Im, J. Kim, D. J. Kim, S. J. Lee, et al. (2012)
PNAS 109, 7729-7734
   Abstract »    Full Text »    PDF »
The Mycobacterium tuberculosis SecA2 System Subverts Phagosome Maturation To Promote Growth in Macrophages.
J. T. Sullivan, E. F. Young, J. R. McCann, and M. Braunstein (2012)
Infect. Immun. 80, 996-1006
   Abstract »    Full Text »    PDF »
Forkhead-associated (FHA) Domain Containing ABC Transporter Rv1747 Is Positively Regulated by Ser/Thr Phosphorylation in Mycobacterium tuberculosis.
V. L. Spivey, V. Molle, R. H. Whalan, A. Rodgers, J. Leiba, L. Stach, K. B. Walker, S. J. Smerdon, and R. S. Buxton (2011)
J. Biol. Chem. 286, 26198-26209
   Abstract »    Full Text »    PDF »
Relief from Zmp1-Mediated Arrest of Phagosome Maturation Is Associated with Facilitated Presentation and Enhanced Immunogenicity of Mycobacterial Antigens.
P. Johansen, A. Fettelschoss, B. Amstutz, P. Selchow, Y. Waeckerle-Men, P. Keller, V. Deretic, L. Held, T. M. Kundig, E. C. Bottger, et al. (2011)
Clin. Vaccine Immunol. 18, 907-913
   Abstract »    Full Text »    PDF »
Protein Kinase LegK2 Is a Type IV Secretion System Effector Involved in Endoplasmic Reticulum Recruitment and Intracellular Replication of Legionella pneumophila.
E. Hervet, X. Charpentier, A. Vianney, J.-C. Lazzaroni, C. Gilbert, D. Atlan, and P. Doublet (2011)
Infect. Immun. 79, 1936-1950
   Abstract »    Full Text »    PDF »
Helicobacter pylori proinflammatory protein up-regulates NF-{kappa}B as a cell-translocating Ser/Thr kinase.
D. J. Kim, K.-S. Park, J.-H. Kim, S.-H. Yang, J. Y. Yoon, B.-G. Han, H. S. Kim, S. J. Lee, J. Y. Jang, K. H. Kim, et al. (2010)
PNAS 107, 21418-21423
   Abstract »    Full Text »    PDF »
Phosphorylation of Enoyl-Acyl Carrier Protein Reductase InhA Impacts Mycobacterial Growth and Survival.
S. Khan, S. N. Nagarajan, A. Parikh, S. Samantaray, A. Singh, D. Kumar, R. P. Roy, A. Bhatt, and V. K. Nandicoori (2010)
J. Biol. Chem. 285, 37860-37871
   Abstract »    Full Text »    PDF »
Mycobacterium tuberculosis protein kinase K confers survival advantage during early infection in mice and regulates growth in culture and during persistent infection: implications for immune modulation.
V. Malhotra, L. T. Arteaga-Cortes, G. Clay, and J. E. Clark-Curtiss (2010)
Microbiology 156, 2829-2841
   Abstract »    Full Text »    PDF »
Lipid Droplet-associated Proteins Are Involved in the Biosynthesis and Hydrolysis of Triacylglycerol in Mycobacterium bovis Bacillus Calmette-Guerin.
K. L. Low, G. Shui, K. Natter, W. K. Yeo, S. D. Kohlwein, T. Dick, S. P. S. Rao, and M. R. Wenk (2010)
J. Biol. Chem. 285, 21662-21670
   Abstract »    Full Text »    PDF »
Functional characterization of the Mycobacterium tuberculosis serine/threonine kinase PknJ.
J. Jang, A. Stella, F. Boudou, F. Levillain, E. Darthuy, J. Vaubourgeix, C. Wang, F. Bardou, G. Puzo, M. Gilleron, et al. (2010)
Microbiology 156, 1619-1631
   Abstract »    Full Text »    PDF »
Phosphorylation of the Mycobacterium tuberculosis {beta}-Ketoacyl-Acyl Carrier Protein Reductase MabA Regulates Mycolic Acid Biosynthesis.
R. Veyron-Churlet, I. Zanella-Cleon, M. Cohen-Gonsaud, V. Molle, and L. Kremer (2010)
J. Biol. Chem. 285, 12714-12725
   Abstract »    Full Text »    PDF »
Key Residues in Mycobacterium tuberculosis Protein Kinase G Play a Role in Regulating Kinase Activity and Survival in the Host.
D. Tiwari, R. K. Singh, K. Goswami, S. K. Verma, B. Prakash, and V. K. Nandicoori (2009)
J. Biol. Chem. 284, 27467-27479
   Abstract »    Full Text »    PDF »
Protein Kinase G Is Required for Intrinsic Antibiotic Resistance in Mycobacteria.
K. A. Wolff, H. T. Nguyen, R. H. Cartabuke, A. Singh, S. Ogwang, and L. Nguyen (2009)
Antimicrob. Agents Chemother. 53, 3515-3519
   Abstract »    Full Text »    PDF »
Survival of Pathogenic Mycobacteria in Macrophages Is Mediated through Autophosphorylation of Protein Kinase G.
N. Scherr, P. Muller, D. Perisa, B. Combaluzier, P. Jeno, and J. Pieters (2009)
J. Bacteriol. 191, 4546-4554
   Abstract »    Full Text »    PDF »
Cutinase-like proteins of Mycobacterium tuberculosis: characterization of their variable enzymatic functions and active site identification.
N. P. West, F. M. E. Chow, E. J. Randall, J. Wu, J. Chen, J. M. C. Ribeiro, and W. J. Britton (2009)
FASEB J 23, 1694-1704
   Abstract »    Full Text »    PDF »
The Mycobacterium tuberculosis Protein Kinase K Modulates Activation of Transcription from the Promoter of Mycobacterial Monooxygenase Operon through Phosphorylation of the Transcriptional Regulator VirS.
P. Kumar, D. Kumar, A. Parikh, D. Rananaware, M. Gupta, Y. Singh, and V. K. Nandicoori (2009)
J. Biol. Chem. 284, 11090-11099
   Abstract »    Full Text »    PDF »
An Intramolecular Switch Regulates Phosphoindependent FHA Domain Interactions in Mycobacterium tuberculosis.
T. J. Nott, G. Kelly, L. Stach, J. Li, S. Westcott, D. Patel, D. M. Hunt, S. Howell, R. S. Buxton, H. M. O'Hare, et al. (2009)
Science Signaling 2, ra12
   Abstract »    Full Text »    PDF »
The Mycobacterium tuberculosis {beta}-Ketoacyl-Acyl Carrier Protein Synthase III Activity Is Inhibited by Phosphorylation on a Single Threonine Residue.
R. Veyron-Churlet, V. Molle, R. C. Taylor, A. K. Brown, G. S. Besra, I. Zanella-Cleon, K. Futterer, and L. Kremer (2009)
J. Biol. Chem. 284, 6414-6424
   Abstract »    Full Text »    PDF »
Comparative Genomics Reveal Extensive Transposon-Mediated Genomic Plasticity and Diversity among Potential Effector Proteins within the Genus Coxiella.
P. A. Beare, N. Unsworth, M. Andoh, D. E. Voth, A. Omsland, S. D. Gilk, K. P. Williams, B. W. Sobral, J. J. Kupko III, S. F. Porcella, et al. (2009)
Infect. Immun. 77, 642-656
   Abstract »    Full Text »    PDF »
LspA inactivation in Mycobacterium tuberculosis results in attenuation without affecting phagosome maturation arrest.
S. K. Rampini, P. Selchow, C. Keller, S. Ehlers, E. C. Bottger, and P. Sander (2008)
Microbiology 154, 2991-3001
   Abstract »    Full Text »    PDF »
Susceptibility to nontuberculous mycobacterial lung disease.
P. Sexton and A. C. Harrison (2008)
Eur. Respir. J. 31, 1322-1333
   Abstract »    Full Text »    PDF »
Interdomain Interaction Reconstitutes the Functionality of PknA, a Eukaryotic Type Ser/Thr Kinase from Mycobacterium tuberculosis.
M. Thakur, R. Chaba, A. K. Mondal, and P. K. Chakraborti (2008)
J. Biol. Chem. 283, 8023-8033
   Abstract »    Full Text »    PDF »
Demonstration of Allelic Exchange in the Slow-Growing Bacterium Mycobacterium avium subsp. paratuberculosis, and Generation of Mutants with Deletions at the pknG, relA, and lsr2 Loci.
K. T. Park, J. L. Dahl, J. P. Bannantine, R. G. Barletta, J. Ahn, A. J. Allen, M. J. Hamilton, and W. C. Davis (2008)
Appl. Envir. Microbiol. 74, 1687-1695
   Abstract »    Full Text »    PDF »
Bacterial Growth and Cell Division: a Mycobacterial Perspective.
E. C. Hett and E. J. Rubin (2008)
Microbiol. Mol. Biol. Rev. 72, 126-156
   Abstract »    Full Text »    PDF »
RNA Interference in J774 Macrophages Reveals a Role for Coronin 1 in Mycobacterial Trafficking but Not in Actin-dependent Processes.
R. Jayachandran, J. Gatfield, J. Massner, I. Albrecht, B. Zanolari, and J. Pieters (2008)
Mol. Biol. Cell 19, 1241-1251
   Abstract »    Full Text »    PDF »
HIV Impairs TNF-{alpha} Mediated Macrophage Apoptotic Response to Mycobacterium tuberculosis.
N. R. Patel, J. Zhu, S. D. Tachado, J. Zhang, Z. Wan, J. Saukkonen, and H. Koziel (2007)
J. Immunol. 179, 6973-6980
   Abstract »    Full Text »    PDF »
Antigen 84, an Effector of Pleiomorphism in Mycobacterium smegmatis.
L. Nguyen, N. Scherr, J. Gatfield, A. Walburger, J. Pieters, and C. J. Thompson (2007)
J. Bacteriol. 189, 7896-7910
   Abstract »    Full Text »    PDF »
Inhibition of Phagosome Maturation by Mycobacteria Does Not Interfere with Presentation of Mycobacterial Antigens by MHC Molecules.
L. Majlessi, B. Combaluzier, I. Albrecht, J. E. Garcia, C. Nouze, J. Pieters, and C. Leclerc (2007)
J. Immunol. 179, 1825-1833
   Abstract »    Full Text »    PDF »
A vesicle surface tyrosine kinase regulates phagosome maturation.
J. Fang, J. A. Brzostowski, S. Ou, N. Isik, V. Nair, and T. Jin (2007)
J. Cell Biol. 178, 411-423
   Abstract »    Full Text »    PDF »
Structural basis for the specific inhibition of protein kinase G, a virulence factor of Mycobacterium tuberculosis.
N. Scherr, S. Honnappa, G. Kunz, P. Mueller, R. Jayachandran, F. Winkler, J. Pieters, and M. O. Steinmetz (2007)
PNAS 104, 12151-12156
   Abstract »    Full Text »    PDF »
A Genetic Screen for Mycobacterium tuberculosis Mutants Defective for Phagosome Maturation Arrest Identifies Components of the ESX-1 Secretion System.
J. A. MacGurn and J. S. Cox (2007)
Infect. Immun. 75, 2668-2678
   Abstract »    Full Text »    PDF »
Eukaryotic-Type Serine/Threonine Protein Kinase StkP Is a Global Regulator of Gene Expression in Streptococcus pneumoniae.
L. Saskova, L. Novakova, M. Basler, and P. Branny (2007)
J. Bacteriol. 189, 4168-4179
   Abstract »    Full Text »    PDF »
Serine threonine protein kinases of mycobacterial genus: phylogeny to function.
A. Narayan, P. Sachdeva, K. Sharma, A. K. Saini, A. K. Tyagi, and Y. Singh (2007)
Physiol Genomics 29, 66-75
   Abstract »    Full Text »    PDF »
A Mycobacterial Gene Involved in Synthesis of an Outer Cell Envelope Lipid Is a Key Factor in Prevention of Phagosome Maturation.
N. Robinson, M. Wolke, K. Ernestus, and G. Plum (2007)
Infect. Immun. 75, 581-591
   Abstract »    Full Text »    PDF »
The Ser/Thr Protein Kinase PknB Is Essential for Sustaining Mycobacterial Growth.
P. Fernandez, B. Saint-Joanis, N. Barilone, M. Jackson, B. Gicquel, S. T. Cole, and P. M. Alzari (2006)
J. Bacteriol. 188, 7778-7784
   Abstract »    Full Text »    PDF »
Control of Listeria Superoxide Dismutase by Phosphorylation.
C. Archambaud, M.-A. Nahori, J. Pizarro-Cerda, P. Cossart, and O. Dussurget (2006)
J. Biol. Chem. 281, 31812-31822
   Abstract »    Full Text »    PDF »
The Condensing Activities of the Mycobacterium tuberculosis Type II Fatty Acid Synthase Are Differentially Regulated by Phosphorylation.
V. Molle, A. K. Brown, G. S. Besra, A. J. Cozzone, and L. Kremer (2006)
J. Biol. Chem. 281, 30094-30103
   Abstract »    Full Text »    PDF »
Trypanosoma cruzi Modulates the Expression of Rabs and Alters the Endocytosis in Mouse Cardiomyocytes In Vitro.
D. G. J. Batista, C. F. Silva, R. A. Mota, L. C. Costa, M. N. L. Meirelles, M. Meuser-Batista, and M. N. C. Soeiro (2006)
Journal of Histochemistry & Cytochemistry 54, 605-614
   Abstract »    Full Text »    PDF »
Cathepsin L maturation and activity is impaired in macrophages harboring M. avium and M. tuberculosis.
R. M Nepal, S. Mampe, B. Shaffer, A. H Erickson, and P. Bryant (2006)
Int. Immunol. 18, 931-939
   Abstract »    Full Text »    PDF »
Corynebacterial Protein Kinase G Controls 2-Oxoglutarate Dehydrogenase Activity via the Phosphorylation Status of the OdhI Protein.
A. Niebisch, A. Kabus, C. Schultz, B. Weil, and M. Bott (2006)
J. Biol. Chem. 281, 12300-12307
   Abstract »    Full Text »    PDF »
Transcriptional Control of the Mycobacterial embCAB Operon by PknH through a Regulatory Protein, EmbR, In Vivo.
K. Sharma, M. Gupta, M. Pathak, N. Gupta, A. Koul, S. Sarangi, R. Baweja, and Y. Singh (2006)
J. Bacteriol. 188, 2936-2944
   Abstract »    Full Text »    PDF »
Evidence for Acquisition of Legionella Type IV Secretion Substrates via Interdomain Horizontal Gene Transfer.
K. S. de Felipe, S. Pampou, O. S. Jovanovic, C. D. Pericone, S. F. Ye, S. Kalachikov, and H. A. Shuman (2005)
J. Bacteriol. 187, 7716-7726
   Abstract »    Full Text »    PDF »
Vaccines for Tuberculosis: Novel Concepts and Recent Progress.
T. M. Doherty and P. Andersen (2005)
Clin. Microbiol. Rev. 18, 687-702
   Abstract »    Full Text »    PDF »
Ancestral antibiotic resistance in Mycobacterium tuberculosis.
R. P. Morris, L. Nguyen, J. Gatfield, K. Visconti, K. Nguyen, D. Schnappinger, S. Ehrt, Y. Liu, L. Heifets, J. Pieters, et al. (2005)
PNAS 102, 12200-12205
   Abstract »    Full Text »    PDF »
Deletion of the Mycobacterium tuberculosis pknH Gene Confers a Higher Bacillary Load during the Chronic Phase of Infection in BALB/c Mice.
K. G. Papavinasasundaram, B. Chan, J.-H. Chung, M. J. Colston, E. O. Davis, and Y. Av-Gay (2005)
J. Bacteriol. 187, 5751-5760
   Abstract »    Full Text »    PDF »
Role of Protein Kinase G in Growth and Glutamine Metabolism of Mycobacterium bovis BCG.
L. Nguyen, A. Walburger, E. Houben, A. Koul, S. Muller, M. Morbitzer, B. Klebl, G. Ferrari, and J. Pieters (2005)
J. Bacteriol. 187, 5852-5856
   Abstract »    Full Text »    PDF »
An ABC Transporter Containing a Forkhead-Associated Domain Interacts with a Serine-Threonine Protein Kinase and Is Required for Growth of Mycobacterium tuberculosis in Mice.
J. M. Curry, R. Whalan, D. M. Hunt, K. Gohil, M. Strom, L. Rickman, M. J. Colston, S. J. Smerdon, and R. S. Buxton (2005)
Infect. Immun. 73, 4471-4477
   Abstract »    Full Text »    PDF »
The Mycobacterium tuberculosis serine/threonine kinases PknA and PknB: substrate identification and regulation of cell shape.
C.-M. Kang, D. W. Abbott, S. T. Park, C. C. Dascher, L. C. Cantley, and R. N. Husson (2005)
Genes & Dev. 19, 1692-1704
   Abstract »    Full Text »    PDF »
Nuclear Localization and in Situ DNA Damage by Mycobacterium tuberculosis Nucleoside-diphosphate Kinase.
A. K. Saini, K. Maithal, P. Chand, S. Chowdhury, R. Vohra, A. Goyal, G. P. Dubey, P. Chopra, R. Chandra, A. K. Tyagi, et al. (2004)
J. Biol. Chem. 279, 50142-50149
   Abstract »    Full Text »    PDF »
Isolation of Mycobacterium tuberculosis mutants defective in the arrest of phagosome maturation.
K. Pethe, D. L. Swenson, S. Alonso, J. Anderson, C. Wang, and D. G. Russell (2004)
PNAS 101, 13642-13647
   Abstract »    Full Text »    PDF »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882