Protein kinase and phosphatase signaling in Mycobacterium tuberculosis physiology and pathogenesis.

Mycobacterium tuberculosis (Mtb), the etiological agent of tuberculosis (TB), evades the antimicrobial defenses of the host and survives within the infected individual through a complex set of strategies. These include active prevention of host cellular killing processes as well as overwhelming adaptive gene expression. In the past decade, we have gained an increased understanding of how mycobacteria not only have the ability to adapt to a changing host environment but also actively interfere with the signaling machinery within the host cell to counteract or inhibit parts of the killing apparatus employed by the macrophage. Mtb is able to sense its environment via a set of phospho-signaling proteins which mediate its response and interaction with the host in a coordinated manner. In this review, we summarize the current knowledge about selected Mtb serine, threonine, and tyrosine kinase and phosphatase signaling proteins, focusing on the protein kinases, PknG and PtkA, and the protein phosphatase, PtpA.

[1]  K. Saxena,et al.  Discovery of Mycobacterium Tuberculosis Protein Tyrosine Phosphatase A (MptpA) Inhibitors Based on Natural Products and a Fragment‐Based Approach , 2005, Chembiochem : a European journal of chemical biology.

[2]  A. Steyn,et al.  Mycobacterium tuberculosis DosS is a redox sensor and DosT is a hypoxia sensor , 2007, Proceedings of the National Academy of Sciences.

[3]  T. Alber,et al.  Prospects for TB Therapeutics Targeting Mycobacterium tuberculosis Phosphosignaling Networks , 2011 .

[4]  R. Husson,et al.  Regulation of the SigH stress response regulon by an essential protein kinase in Mycobacterium tuberculosis , 2008, Proceedings of the National Academy of Sciences.

[5]  G. Blatch,et al.  The tetratricopeptide repeat: a structural motif mediating protein-protein interactions. , 1999, BioEssays : news and reviews in molecular, cellular and developmental biology.

[6]  W. Jacobs,et al.  Mycobacterium tuberculosis transporter MmpL7 is a potential substrate for kinase PknD. , 2006, Biochemical and biophysical research communications.

[7]  Bacterial assimilation of d- and l-2-chloropropionates and occurrence of a new dehalogenase , 1982, Archives of Microbiology.

[8]  S. Roychoudhury,et al.  AlgR2 is an ATP/GTP-dependent protein kinase involved in alginate synthesis by Pseudomonas aeruginosa. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[9]  N. Srinivasan,et al.  EmbR, a regulatory protein with ATPase activity, is a substrate of multiple serine/threonine kinases and phosphatase in Mycobacterium tuberculosis , 2006, The FEBS journal.

[10]  Liem Nguyen,et al.  Protein Kinase G from Pathogenic Mycobacteria Promotes Survival Within Macrophages , 2004, Science.

[11]  H. Bach,et al.  Mycobacterium tuberculosis PtkA is a novel protein tyrosine kinase whose substrate is PtpA. , 2009, The Biochemical journal.

[12]  Gang Liu,et al.  Inhibition of MptpB phosphatase from Mycobacterium tuberculosis impairs mycobacterial survival in macrophages. , 2009, The Journal of antimicrobial chemotherapy.

[13]  D. Schwarzer,et al.  Negative regulation of a protein tyrosine phosphatase by tyrosine phosphorylation. , 2006, Journal of the American Chemical Society.

[14]  Shazia Khan,et al.  PknB-mediated phosphorylation of a novel substrate, N-acetylglucosamine-1-phosphate uridyltransferase, modulates its acetyltransferase activity. , 2009, Journal of molecular biology.

[15]  S. Howell,et al.  An Intramolecular Switch Regulates Phosphoindependent FHA Domain Interactions in Mycobacterium tuberculosis , 2009, Science Signaling.

[16]  R. Kiss,et al.  Signalling inhibitors against Mycobacterium tuberculosis--early days of a new therapeutic concept in tuberculosis. , 2008, Current medicinal chemistry.

[17]  A. Cozzone,et al.  Endogenous protein phosphorylation in Escherichia coli extracts. , 1982, Biochemical and biophysical research communications.

[18]  Y Av-Gay,et al.  The eukaryotic-like Ser/Thr protein kinases of Mycobacterium tuberculosis. , 2000, Trends in microbiology.

[19]  Ramandeep Singh,et al.  Disruption of mptpB impairs the ability of Mycobacterium tuberculosis to survive in guinea pigs , 2003, Molecular microbiology.

[20]  H. Bach,et al.  Mycobacterium avium subsp. paratuberculosis PtpA Is an Endogenous Tyrosine Phosphatase Secreted during Infection , 2006, Infection and Immunity.

[21]  A. Mascarello,et al.  Synthetic chalcones as efficient inhibitors of Mycobacterium tuberculosis protein tyrosine phosphatase PtpA. , 2008, Bioorganic & medicinal chemistry letters.

[22]  R. Sankaranarayanan,et al.  Crystal Structure of Low-Molecular-Weight Protein Tyrosine Phosphatase from Mycobacterium tuberculosis at 1.9-Å Resolution , 2005, Journal of bacteriology.

[23]  G. Besra,et al.  The Condensing Activities of the Mycobacterium tuberculosis Type II Fatty Acid Synthase Are Differentially Regulated by Phosphorylation* , 2006, Journal of Biological Chemistry.

[24]  Vojo Deretic,et al.  Cell biology of mycobacterium tuberculosis phagosome. , 2004, Annual review of cell and developmental biology.

[25]  A. Cozzone,et al.  Cells of Escherichia coli Contain a Protein-Tyrosine Kinase, Wzc, and a Phosphotyrosine-Protein Phosphatase, Wzb , 1999, Journal of bacteriology.

[26]  K. Soda,et al.  Purification and Properties of a New Enzyme, dl-2-Haloacid Dehalogenase, from Pseudomonas sp , 1982, Journal of bacteriology.

[27]  U. Klages,et al.  2-Haloacid dehalogenase from a 4-chlorobenzoate-degrading Pseudomonas spec. CBS 3. , 1983, Hoppe-Seyler's Zeitschrift fur physiologische Chemie.

[28]  T. Alber,et al.  Auto‐activation mechanism of the Mycobacterium tuberculosis PknB receptor Ser/Thr kinase , 2008, The EMBO journal.

[29]  Liem Nguyen,et al.  Role of Protein Kinase G in Growth and Glutamine Metabolism of Mycobacterium bovis BCG , 2005, Journal of bacteriology.

[30]  P. Alzari,et al.  Regulation of glutamate metabolism by protein kinases in mycobacteria , 2008, Molecular microbiology.

[31]  J. Mekalanos,et al.  Threonine phosphorylation post-translationally regulates protein secretion in Pseudomonas aeruginosa , 2007, Nature Cell Biology.

[32]  Carl A. Miecskowski,et al.  Structure/Function Studies of Ser/Thr and Tyr Protein Phosphorylation in Mycobacterium tuberculosis , 2006, Journal of Molecular Microbiology and Biotechnology.

[33]  Makoto Suematsu,et al.  Variant tricarboxylic acid cycle in Mycobacterium tuberculosis: identification of alpha-ketoglutarate decarboxylase. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[34]  G. Ramponi,et al.  The Inactivation Mechanism of Low Molecular Weight Phosphotyrosine-protein Phosphatase by H2O2 * , 1998, The Journal of Biological Chemistry.

[35]  R. Morona,et al.  Streptococcus pneumoniae Capsule Biosynthesis Protein CpsB Is a Novel Manganese-Dependent Phosphotyrosine-Protein Phosphatase , 2002, Journal of bacteriology.

[36]  L. Tabernero,et al.  MptpB, a virulence factor from Mycobacterium tuberculosis, exhibits triple-specificity phosphatase activity. , 2007, The Biochemical journal.

[37]  R. Scheller,et al.  Nsec1 Binds a Closed Conformation of Syntaxin1a , 2000, The Journal of cell biology.

[38]  X. Zhao,et al.  WaaP of Pseudomonas aeruginosa Is a Novel Eukaryotic Type Protein-tyrosine Kinase as Well as a Sugar Kinase Essential for the Biosynthesis of Core Lipopolysaccharide* , 2002, The Journal of Biological Chemistry.

[39]  P. Nordlund,et al.  The low M r phosphotyrosine protein phosphatase behaves differently when phosphorylated at Tyr131 or Tyr132 by Src kinase , 1999, FEBS letters.

[40]  Vito Calderone,et al.  The first structure of a bacterial class B Acid phosphatase reveals further structural heterogeneity among phosphatases of the haloacid dehalogenase fold. , 2004, Journal of molecular biology.

[41]  T. Hunter Tyrosine phosphorylation: thirty years and counting. , 2009, Current opinion in cell biology.

[42]  C. Gee,et al.  Structural basis for selective inhibition of Mycobacterium tuberculosis protein tyrosine phosphatase PtpB. , 2007, Structure.

[43]  T. Alber,et al.  Protein tyrosine phosphatase PtpA is not required for Mycobacterium tuberculosis growth in mice. , 2008, FEMS microbiology letters.

[44]  K. Papavinasasundaram,et al.  Deletion of the Mycobacterium tuberculosis pknH Gene Confers a Higher Bacillary Load during the Chronic Phase of Infection in BALB/c Mice , 2005, Journal of bacteriology.

[45]  A. Cozzone,et al.  Tyrosine phosphatase MptpA of Mycobacterium tuberculosis inhibits phagocytosis and increases actin polymerization in macrophages. , 2005, Research in microbiology.

[46]  J. Pieters,et al.  Survival of Pathogenic Mycobacteria in Macrophages Is Mediated through Autophosphorylation of Protein Kinase G , 2009, Journal of bacteriology.

[47]  R. Woodard,et al.  Escherichia coli YrbI Is 3-Deoxy-d-manno-octulosonate 8-Phosphate Phosphatase* , 2003, The Journal of Biological Chemistry.

[48]  L. Kremer,et al.  From the Characterization of the Four Serine/Threonine Protein Kinases (PknA/B/G/L) of Corynebacterium glutamicum toward the Role of PknA and PknB in Cell Division* , 2008, Journal of Biological Chemistry.

[49]  J. Sun,et al.  Molecular characterization and transcriptional analysis of type 8 capsule genes in Staphylococcus aureus , 1997, Journal of bacteriology.

[50]  M. Wessels,et al.  Identification of cpsD, a gene essential for type III capsule expression in group B streptococci , 1993, Molecular microbiology.

[51]  L. Cantley,et al.  The Mycobacterium tuberculosis serine/threonine kinases PknA and PknB: substrate identification and regulation of cell shape. , 2005, Genes & development.

[52]  Tom Alber,et al.  Mycobacterium tuberculosis protein tyrosine phosphatase PtpB structure reveals a diverged fold and a buried active site. , 2005, Structure.

[53]  J Wu,et al.  A novel bacterial tyrosine kinase essential for cell division and differentiation. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[54]  Tom Alber,et al.  Mycobacterium tuberculosis serine/threonine kinases PknB, PknD, PknE, and PknF phosphorylate multiple FHA domains , 2005, Protein science : a publication of the Protein Society.

[55]  G. Besra,et al.  The Mycobacterium tuberculosis β-Ketoacyl-Acyl Carrier Protein Synthase III Activity Is Inhibited by Phosphorylation on a Single Threonine Residue* , 2009, Journal of Biological Chemistry.

[56]  Meetu Gupta,et al.  The Mycobacterium tuberculosis Protein Kinase K Modulates Activation of Transcription from the Promoter of Mycobacterial Monooxygenase Operon through Phosphorylation of the Transcriptional Regulator VirS* , 2009, Journal of Biological Chemistry.

[57]  M. Thakur,et al.  GTPase Activity of Mycobacterial FtsZ Is Impaired Due to Its Transphosphorylation by the Eukaryotic-type Ser/Thr Kinase, PknA* , 2006, Journal of Biological Chemistry.

[58]  J. Selengut MDP-1 is a new and distinct member of the haloacid dehalogenase family of aspartate-dependent phosphohydrolases. , 2001, Biochemistry.

[59]  G. Besra,et al.  An FHA phosphoprotein recognition domain mediates protein EmbR phosphorylation by PknH, a Ser/Thr protein kinase from Mycobacterium tuberculosis. , 2003, Biochemistry.

[60]  J. Meyer Clostridial iron-sulphur proteins. , 2000, Journal of molecular microbiology and biotechnology.

[61]  Y. Av‐Gay,et al.  Expression and localization of the Mycobacterium tuberculosis protein tyrosine phosphatase PtpA. , 2002, Research in microbiology.

[62]  S. Horinouchi,et al.  Phosphorylation of the AfsR protein involved in secondary metabolism in Streptomyces species by a eukaryotic-type protein kinase. , 1994, Gene.

[63]  Tom Alber,et al.  M. tuberculosis Ser/Thr Protein Kinase D Phosphorylates an Anti-Anti–Sigma Factor Homolog , 2007, PLoS pathogens.

[64]  J. Bliska,et al.  Identification of p130Cas as a substrate of Yersinia YopH (Yop51), a bacterial protein tyrosine phosphatase that translocates into mammalian cells and targets focal adhesions , 1997, The EMBO journal.

[65]  R. Scheller,et al.  nSec 1 Binds a Closed Conformation of Syntaxin 1 A , 2000 .

[66]  V. Mizrahi,et al.  The Mycobacterium tuberculosis protein serine/threonine kinase PknG is linked to cellular glutamate/glutamine levels and is important for growth in vivo , 2004, Molecular microbiology.

[67]  Martin Cohen-Gonsaud,et al.  The Mycobacterium tuberculosis serine/threonine kinase PknL phosphorylates Rv2175c: Mass spectrometric profiling of the activation loop phosphorylation sites and their role in the recruitment of Rv2175c , 2008, Proteomics.

[68]  M. Thakur,et al.  Ability of PknA, a mycobacterial eukaryotic-type serine/threonine kinase, to transphosphorylate MurD, a ligase involved in the process of peptidoglycan biosynthesis. , 2008, The Biochemical journal.

[69]  P. Johnson,et al.  Protein tyrosine phosphorylation in Mycobacterium tuberculosis. , 1994, FEMS microbiology letters.

[70]  T. Mustelin,et al.  Regulation of the Low Molecular Weight Phosphotyrosine Phosphatase by Phosphorylation at Tyrosines 131 and 132* , 1997, The Journal of Biological Chemistry.

[71]  S. Sau,et al.  The Staphylococcus aureus allelic genetic loci for serotype 5 and 8 capsule expression contain the type-specific genes flanked by common genes. , 1997, Microbiology.

[72]  H. Bach,et al.  Mycobacterium tuberculosis virulence is mediated by PtpA dephosphorylation of human vacuolar protein sorting 33B. , 2008, Cell host & microbe.

[73]  Jason M. Link,et al.  MglA, a small GTPase, interacts with a tyrosine kinase to control type IV pili‐mediated motility and development of Myxococcus xanthus , 2002, Molecular microbiology.

[74]  K. Saxena,et al.  Discovery of a new class of inhibitors of Mycobacterium tuberculosis protein tyrosine phosphatase B by biology-oriented synthesis. , 2008, Angewandte Chemie.

[75]  G. Ramponi,et al.  Low molecular weight protein tyrosine phosphatases: small, but smart , 2002, Cellular and Molecular Life Sciences CMLS.

[76]  T. Alber,et al.  Fragment-based substrate activity screening method for the identification of potent inhibitors of the Mycobacterium tuberculosis phosphatase PtpB. , 2007, Journal of the American Chemical Society.

[77]  V. Molle,et al.  Two FHA domains on an ABC transporter, Rv1747, mediate its phosphorylation by PknF, a Ser/Thr protein kinase from Mycobacterium tuberculosis. , 2004, FEMS microbiology letters.

[78]  Michael Bott,et al.  Corynebacterial Protein Kinase G Controls 2-Oxoglutarate Dehydrogenase Activity via the Phosphorylation Status of the OdhI Protein* , 2006, Journal of Biological Chemistry.

[79]  A. Ullrich,et al.  Cloning and Characterization of Secretory Tyrosine Phosphatases of Mycobacterium tuberculosis , 2000, Journal of bacteriology.

[80]  M. Steinmetz,et al.  Structural basis for the specific inhibition of protein kinase G, a virulence factor of Mycobacterium tuberculosis , 2007, Proceedings of the National Academy of Sciences.

[81]  S. Cole,et al.  Proteomic identification of M. tuberculosis protein kinase substrates: PknB recruits GarA, a FHA domain-containing protein, through activation loop-mediated interactions. , 2005, Journal of molecular biology.

[82]  W. Wickner,et al.  A Ypt/Rab effector complex containing the Sec1 homolog Vps33p is required for homotypic vacuole fusion. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[83]  Marco Bellinzoni,et al.  Mycobacterial Ser/Thr protein kinases and phosphatases: physiological roles and therapeutic potential. , 2008, Biochimica et biophysica acta.

[84]  L. Kremer,et al.  The Mycobacterium tuberculosis GroEL1 Chaperone Is a Substrate of Ser/Thr Protein Kinases , 2009, Journal of bacteriology.

[85]  J. Belisle,et al.  Mechanism of phagolysosome biogenesis block by viable Mycobacterium tuberculosis. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[86]  M. Bott,et al.  Glutamate production by Corynebacterium glutamicum: dependence on the oxoglutarate dehydrogenase inhibitor protein OdhI and protein kinase PknG , 2007, Applied Microbiology and Biotechnology.

[87]  Hong Soon-Kwang,et al.  Phosphorylation of the AfsR protein involved in secondary metabolism in Streptomyces species by a eukary otic-type protein kinase , 1994 .

[88]  K. Papavinasasundaram,et al.  Novel substrates of Mycobacterium tuberculosis PknH Ser/Thr kinase. , 2007, Biochemical and biophysical research communications.

[89]  C. Thompson,et al.  Differential expression of a virulence factor in pathogenic and non-pathogenic mycobacteria , 2009, Molecular microbiology.

[90]  V. Deretic,et al.  Reactive nitrogen and oxygen intermediates and bacterial defenses: unusual adaptations in Mycobacterium tuberculosis. , 2002, Antioxidants & redox signaling.

[91]  B. Bloom,et al.  Killing of virulent Mycobacterium tuberculosis by reactive nitrogen intermediates produced by activated murine macrophages , 1992, The Journal of experimental medicine.