Advertisement

Host Signal Transduction and Protein Kinases Implicated in Legionella Infection

  • Andrew D. Hempstead
  • Ralph R. Isberg
Chapter
Part of the Current Topics in Microbiology and Immunology book series (CT MICROBIOLOGY, volume 376)

Abstract

Modulation of the phosphorylation status of proteins by both kinases and phosphatases plays an important role in cellular signal transduction. Challenge of host cells by Legionella pneumophila manipulates the phosphorylation state of multiple host factors. These changes play roles in bacterial uptake, vacuole modification, cellular survival, and the immune response. In addition to modification by host cell kinases in response to the bacterium, L. pneumophila translocates bacterial kinases into the host cell that may contribute to further signaling modifications. Proper regulation of host cell signaling by L. pneumophila is necessary for its ability to replicate intracellulary, while avoiding host defenses.

Keywords

Tyrosine Phosphorylation MAPK Signaling MAPK Activation Caffeic Acid Phenethyl Ester Intracellular Growth 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Abbreviations

BMDMs

Bone marrow-derived macrophages

CAPE

Caffeic acid phenethyl ester

CR3

Complement receptor 3

DAG

Diacylglycerol

Dusp

Dual-specificity protein phosphatase

hBD-2

Human β-defensin-2

IDTS

Icm/Dot translocated substrates

IκB

Inhibitor of κB

Icm/Dot

Intracellular multiplication/defect in organelle trafficking

IKK

IκB kinase

LCV

Legionella-containing vacuole

LF

Lethal factor

MAPKK

MAPK kinase

MAPKKK

MAPK kinase kinase

MAPK

Mitogen-activated protein kinase

NF-κB

Nuclear factor kappa-light-chain-enhancer of activated B cells

NLR

Nucleotide-binding oligomerization domain like receptor

PAMP

Pathogen-associated molecular pattern

PRR

Pattern recognition receptor

PI3K

Phosphoinositide 3-kinase

PGE2

Prostaglandin E2

PKB/Akt

Protein kinase B

PKC

Protein kinase C

TLR

Toll-like receptor

T4SS

Type IV secretion system

TPK

Tyrosine protein kinase

References

  1. Adams SA, Robson SC, Gathiram V, Jackson TF, Pillay TS et al (1993) Immunological similarity between the 170 kD amoebic adherence glycoprotein and human beta 2 integrins. Lancet 341:17–19PubMedCrossRefGoogle Scholar
  2. Abu-Zant A, Jones S, Asare R, Suttles J, Price C et al (2007) Anti-apoptotic signaling by the Dot/Icm secretion system of L. pneumophila. Cell Microbiol 9:246–264PubMedCrossRefGoogle Scholar
  3. Backert S, Tegtmeyer N, Selbach M (2010) The versatility of Helicobacter pylori CagA effector protein functions: the master key hypothesis. Helicobacter 15:163–176PubMedCrossRefGoogle Scholar
  4. Bardill JP, Miller JL, Vogel JP (2005) IcmS-dependent translocation of SdeA into macrophages by the Legionella pneumophila type IV secretion system. Mol Microbiol 56:90–103PubMedCrossRefGoogle Scholar
  5. Bartfeld S, Engels C, Bauer B, Aurass P, Flieger A et al (2009) Temporal resolution of two-tracked NF-kappaB activation by Legionella pneumophila. Cell Microbiol 11:1638–1651PubMedCrossRefGoogle Scholar
  6. Berger KH, Isberg RR (1993) Two distinct defects in intracellular growth complemented by a single genetic locus in Legionella pneumophila. Mol Microbiol 7:7–19PubMedCrossRefGoogle Scholar
  7. Black JD (2000) Protein kinase C-mediated regulation of the cell cycle. Front Biosci 5:D406–D423PubMedCrossRefGoogle Scholar
  8. Blom N, Gammeltoft S, Brunak S (1999) Sequence and structure-based prediction of eukaryotic protein phosphorylation sites. J Mol Biol 294:1351–1362PubMedCrossRefGoogle Scholar
  9. Burstein D, Zusman T, Degtyar E, Viner R, Segal G et al (2009) Genome-scale identification of Legionella pneumophila effectors using a machine learning approach. PLoS Pathog 5:e1000508PubMedCrossRefGoogle Scholar
  10. Caffrey DR, O’Neill LA, Shields DC (1999) The evolution of the MAP kinase pathways: coduplication of interacting proteins leads to new signaling cascades. J Mol Evol 49:567–582PubMedCrossRefGoogle Scholar
  11. Cambronne ED, Roy CR (2007) The Legionella pneumophila IcmSW complex interacts with multiple Dot/Icm effectors to facilitate type IV translocation. PLoS Pathog 3:e188PubMedCrossRefGoogle Scholar
  12. Cargnello M, Roux PP (2011) Activation and function of the MAPKs and their substrates, the MAPK-activated protein kinases. Microbiol Mol Biol Rev 75:50–83PubMedCrossRefGoogle Scholar
  13. Charpentier X, Gabay JE, Reyes M, Zhu JW, Weiss A et al (2009) Chemical genetics reveals bacterial and host cell functions critical for type IV effector translocation by Legionella pneumophila. PLoS Pathog 5:e1000501PubMedCrossRefGoogle Scholar
  14. Chin AI, Dempsey PW, Bruhn K, Miller JF, Xu Y et al (2002) Involvement of receptor-interacting protein 2 in innate and adaptive immune responses. Nature 416:190–194PubMedCrossRefGoogle Scholar
  15. Coers J, Kagan JC, Matthews M, Nagai H, Zuckman DM et al (2000) Identification of Icm protein complexes that play distinct roles in the biogenesis of an organelle permissive for Legionella pneumophila intracellular growth. Mol Microbiol 38:719–736PubMedCrossRefGoogle Scholar
  16. Cohen P (2001) The role of protein phosphorylation in human health and disease. The Sir Hans Krebs Medal Lecture. Eur J Biochem 268:5001–5010PubMedCrossRefGoogle Scholar
  17. Coxon PY, Summersgill JT, Ramirez JA, Miller RD (1998) Signal transduction during Legionella pneumophila entry into human monocytes. Infect Immun 66:2905–2913PubMedGoogle Scholar
  18. de Felipe KS, Glover RT, Charpentier X, Anderson OR, Reyes M et al (2008) Legionella eukaryotic-like type IV substrates interfere with organelle trafficking. PLoS Pathog 4:e10000117CrossRefGoogle Scholar
  19. de Felipe KS, Pampou S, Jovanovic OS, Pericone CD, Ye SF et al (2005) Evidence for acquisition of Legionella type IV secretion substrates via interdomain horizontal gene transfer. J Bacteriol 187:7716–7726PubMedCrossRefGoogle Scholar
  20. Dorer MS, Kirton D, Bader JS, Isberg RR (2006) RNA interference analysis of Legionella in Drosophila cells: exploitation of early secretory apparatus dynamics. PLoS Pathog 2:e34PubMedCrossRefGoogle Scholar
  21. Duesbery NS, Webb CP, Leppla SH, Gordon VM, Klimpel KR et al (1998) Proteolytic inactivation of MAP-kinase-kinase by anthrax lethal factor. Science 280:734–737PubMedCrossRefGoogle Scholar
  22. Fields BS (1996) The molecular ecology of legionellae. Trends Microbiol 4:286–290PubMedCrossRefGoogle Scholar
  23. Fields BS, Nerad TA, Sawyer TK, King CH, Barbaree JM et al (1990) Characterization of an axenic strain of Hartmannella vermiformis obtained from an investigation of nosocomial legionellosis. J Protozool 37:581–583PubMedCrossRefGoogle Scholar
  24. Fontana MF, Banga S, Barry KC, Shen X, Tan Y et al (2011) Secreted bacterial effectors that inhibit host protein synthesis are critical for induction of the innate immune response to virulent Legionella pneumophila. PLoS Pathog 7:e1001289PubMedCrossRefGoogle Scholar
  25. Fontana MF, Shin S, Vance RE (2012) Activation of host mitogen-activated protein kinases by secreted Legionella pneumophila effectors that inhibit host protein translation. Infect Immun 80:3570–3575PubMedCrossRefGoogle Scholar
  26. Franco IS, Shohdy N, Shuman HA (2012) The Legionella pneumophila effector VipA is an actin nucleator that alters host cell organelle trafficking. PLoS Pathog 8:e1002546PubMedCrossRefGoogle Scholar
  27. Franke TF, Yang SI, Chan TO, Datta K, Kazlauskas A et al (1995) The protein kinase encoded by the Akt proto-oncogene is a target of the PDGF-activated phosphatidylinositol 3-kinase. Cell 81:727–736PubMedCrossRefGoogle Scholar
  28. Fritz JH, Ferrero RL, Philpott DJ, Girardin SE (2006) Nod-like proteins in immunity, inflammation and disease. Nat Immunol 7:1250–1257PubMedCrossRefGoogle Scholar
  29. Garcia-Garcia E, Rosales C (2002) Signal transduction during Fc receptor-mediated phagocytosis. J Leukoc Biol 72:1092–1108PubMedGoogle Scholar
  30. Gaskins C, Maeda M, Firtel RA (1994) Identification and functional analysis of a developmentally regulated extracellular signal-regulated kinase gene in Dictyostelium discoideum. Mol Cell Biol 14:6996–7012PubMedGoogle Scholar
  31. Ge J, Xu H, Li T, Zhou Y, Zhang Z et al (2009) A Legionella type IV effector activates the NF-kappaB pathway by phosphorylating the IkappaB family of inhibitors. Proc Natl Acad Sci U S A 106:13725–13730PubMedCrossRefGoogle Scholar
  32. Ghayur T, Hugunin M, Talanian RV, Ratnofsky S, Quinlan C et al (1996) Proteolytic activation of protein kinase C delta by an ICE/CED 3-like protease induces characteristics of apoptosis. J Exp Med 184:2399–2404PubMedCrossRefGoogle Scholar
  33. Girardin SE, Tournebize R, Mavris M, Page AL, Li X et al (2001) CARD4/Nod1 mediates NF-kappaB and JNK activation by invasive Shigella flexneri. EMBO Rep 2:736–742PubMedCrossRefGoogle Scholar
  34. Guan KL, Dixon JE (1990) Protein tyrosine phosphatase activity of an essential virulence determinant in Yersinia. Science 249:553–556PubMedCrossRefGoogle Scholar
  35. Haenssler E, Isberg RR (2011) Control of host cell phosphorylation by Legionella pneumophila. Front Microbiol 2:64PubMedCrossRefGoogle Scholar
  36. Hayden MS, Ghosh S (2012) NF-kappaB, the first quarter-century: remarkable progress and outstanding questions. Genes Dev 26:203–234PubMedCrossRefGoogle Scholar
  37. Hervet E, Charpentier X, Vianney A, Lazzaroni JC, Gilbert C et al (2011) Protein kinase LegK2 is a type IV secretion system effector involved in endoplasmic reticulum recruitment and intracellular replication of Legionella pneumophila. Infect Immun 79:1936–1950PubMedCrossRefGoogle Scholar
  38. Huang G, Shi LZ, Chi H (2009) Regulation of JNK and p38 MAPK in the immune system: signal integration, propagation and termination. Cytokine 48:161–169PubMedCrossRefGoogle Scholar
  39. Huang L, Boyd D, Amyot WM, Hempstead AD, Luo ZQ et al (2011) The E Block motif is associated with Legionella pneumophila translocated substrates. Cell Microbiol 13:227–245PubMedCrossRefGoogle Scholar
  40. Johnson GL, Lapadat R (2002) Mitogen-activated protein kinase pathways mediated by ERK, JNK, and p38 protein kinases. Science 298:1911–1912PubMedCrossRefGoogle Scholar
  41. Kawai T, Akira S (2007) TLR signaling. Semin Immunol 19:24–32PubMedCrossRefGoogle Scholar
  42. Kelliher MA, Grimm S, Ishida Y, Kuo F, Stanger BZ et al (1998) The death domain kinase RIP mediates the TNF-induced NF-kappaB signal. Immunity 8:297–303PubMedCrossRefGoogle Scholar
  43. Khelef N, Shuman HA, Maxfield FR (2001) Phagocytosis of wild-type Legionella pneumophila occurs through a wortmannin-insensitive pathway. Infect Immun 69:5157–5161PubMedCrossRefGoogle Scholar
  44. Kobayashi K, Inohara N, Hernandez LD, Galan JE, Nunez G et al (2002) RICK/Rip2/CARDIAK mediates signalling for receptors of the innate and adaptive immune systems. Nature 416:194–199PubMedCrossRefGoogle Scholar
  45. Kobayashi KS, Chamaillard M, Ogura Y, Henegariu O, Inohara N et al (2005) Nod2-dependent regulation of innate and adaptive immunity in the intestinal tract. Science 307:731–734PubMedCrossRefGoogle Scholar
  46. Kubori T, Hyakutake A, Nagai H (2008) Legionella translocates an E3 ubiquitin ligase that has multiple U-boxes with distinct functions. Mol Microbiol 67:1307–1319PubMedCrossRefGoogle Scholar
  47. Laguna RK, Creasey EA, Li Z, Valtz N, Isberg RR (2006) A Legionella pneumophila-translocated substrate that is required for growth within macrophages and protection from host cell death. Proc Natl Acad Sci U S A 103:18745–18750PubMedCrossRefGoogle Scholar
  48. Li H, Xu H, Zhou Y, Zhang J, Long C et al (2007) The phosphothreonine lyase activity of a bacterial type III effector family. Science 315:1000–1003PubMedCrossRefGoogle Scholar
  49. Li Q, Verma IM (2002) NF-kappaB regulation in the immune system. Nat Rev Immunol 2:725–734PubMedCrossRefGoogle Scholar
  50. Li Z, Dugan AS, Bloomfield G, Skelton J, Ivens A et al (2009) The amoebal MAP kinase response to Legionella pneumophila is regulated by DupA. Cell Host Microbe 6:253–267PubMedCrossRefGoogle Scholar
  51. Loegering DJ, Lennartz MR (2011) Protein kinase C and toll-like receptor signaling. Enzyme Res 2011:537821PubMedCrossRefGoogle Scholar
  52. Losick VP, Haenssler E, Moy MY, Isberg RR (2010) LnaB: a Legionella pneumophila activator of NF-kappaB. Cell Microbiol 12:1083–1097PubMedCrossRefGoogle Scholar
  53. Losick VP, Isberg RR (2006) NF-kappaB translocation prevents host cell death after low-dose challenge by Legionella pneumophila. J Exp Med 203:2177–2189PubMedCrossRefGoogle Scholar
  54. Manning G, Plowman GD, Hunter T, Sudarsanam S (2002) Evolution of protein kinase signaling from yeast to man. Trends Biochem Sci 27:514–520PubMedCrossRefGoogle Scholar
  55. Marra A, Blander SJ, Horwitz MA, Shuman HA (1992) Identification of a Legionella pneumophila locus required for intracellular multiplication in human macrophages. Proc Natl Acad Sci U S A 89:9607–9611PubMedCrossRefGoogle Scholar
  56. Morinaga Y, Yanagihara K, Araki N, Migiyama Y, Nagaoka K et al (2012) Live Legionella pneumophila induces MUC5AC production by airway epithelial cells independently of intracellular invasion. Can J Microbiol 58:151–157PubMedCrossRefGoogle Scholar
  57. N’Guessan PD, Etouem MO, Schmeck B, Hocke AC, Scharf S et al (2007) Legionella pneumophila-induced PKCalpha-, MAPK-, and NF-kappaB-dependent COX-2 expression in human lung epithelium. Am J Physiol Lung Cell Mol Physiol 292:L267–L277PubMedCrossRefGoogle Scholar
  58. Nagai H, Kagan JC, Zhu X, Kahn RA, Roy CR (2002) A bacterial guanine nucleotide exchange factor activates ARF on Legionella phagosomes. Science 295:679–682PubMedCrossRefGoogle Scholar
  59. Natoli G (2009) Control of NF-kappaB-dependent transcriptional responses by chromatin organization. Cold Spring Harb Perspect Biol 1:a000224PubMedCrossRefGoogle Scholar
  60. Ninio S, Zuckman-Cholon DM, Cambronne ED, Roy CR (2005) The Legionella IcmS-IcmW protein complex is important for Dot/Icm-mediated protein translocation. Mol Microbiol 55:912–926PubMedCrossRefGoogle Scholar
  61. O’Connor TJ, Boyd D, Dorer MS, Isberg RR (2012) Aggravating genetic interactions allow a solution to redundancy in a bacterial pathogen. Science 338:1440–1444PubMedCrossRefGoogle Scholar
  62. Ogura Y, Inohara N, Benito A, Chen FF, Yamaoka S et al (2001) Nod2, a Nod1/Apaf-1 family member that is restricted to monocytes and activates NF-kappaB. J Biol Chem 276:4812–4818PubMedCrossRefGoogle Scholar
  63. Patterson KI, Brummer T, O’Brien PM, Daly RJ (2009) Dual-specificity phosphatases: critical regulators with diverse cellular targets. Biochem J 418:475–489PubMedGoogle Scholar
  64. Ray LB, Sturgill TW (1988) Insulin-stimulated microtubule-associated protein kinase is phosphorylated on tyrosine and threonine in vivo. Proc Natl Acad Sci U S A 85:3753–3757PubMedCrossRefGoogle Scholar
  65. Retzlaff C, Yamamoto Y, Okubo S, Hoffman PS, Friedman H et al (1996) Legionella pneumophila heat-shock protein-induced increase of interleukin-1 beta mRNA involves protein kinase C signalling in macrophages. Immunology 89:281–288PubMedCrossRefGoogle Scholar
  66. Scharf S, Hippenstiel S, Flieger A, Suttorp N, N’Guessan PD (2010) Induction of human beta-defensin-2 in pulmonary epithelial cells by Legionella pneumophila: involvement of TLR2 and TLR5, p38 MAPK, JNK, NF-kappaB, and AP-1. Am J Physiol Lung Cell Mol Physiol 298:L687–L695PubMedCrossRefGoogle Scholar
  67. Segall JE, Kuspa A, Shaulsky G, Ecke M, Maeda M et al (1995) A MAP kinase necessary for receptor-mediated activation of adenylyl cyclase in Dictyostelium. J Cell Biol 128:405–413PubMedCrossRefGoogle Scholar
  68. Shin S, Case CL, Archer KA, Nogueira CV, Kobayashi KS et al (2008) Type IV secretion-dependent activation of host MAP kinases induces an increased proinflammatory cytokine response to Legionella pneumophila. PLoS Pathog 4:e1000220PubMedCrossRefGoogle Scholar
  69. St-Denis A, Caouras V, Gervais F, Descoteaux A (1999) Role of protein kinase C-alpha in the control of infection by intracellular pathogens in macrophages. J Immunol 163:5505–5511PubMedGoogle Scholar
  70. Susa M, Marre R (1999) Legionella pneumophila invasion of MRC-5 cells induces tyrosine protein phosphorylation. Infect Immun 67:4490–4498PubMedGoogle Scholar
  71. Swantek JL, Tsen MF, Cobb MH, Thomas JA (2000) IL-1 receptor-associated kinase modulates host responsiveness to endotoxin. J Immunol 164:4301–4306PubMedGoogle Scholar
  72. Tachado SD, Samrakandi MM, Cirillo JD (2008) Non-opsonic phagocytosis of Legionella pneumophila by macrophages is mediated by phosphatidylinositol 3-kinase. PLoS ONE 3:e3324PubMedCrossRefGoogle Scholar
  73. Takamatsu R, Takeshima E, Ishikawa C, Yamamoto K, Teruya H et al (2010) Inhibition of Akt/GSK3beta signalling pathway by Legionella pneumophila is involved in induction of T-cell apoptosis. Biochem J 427:57–67PubMedCrossRefGoogle Scholar
  74. Tan SL, Parker PJ (2003) Emerging and diverse roles of protein kinase C in immune cell signalling. Biochem J 376:545–552PubMedCrossRefGoogle Scholar
  75. Trosky JE, Mukherjee S, Burdette DL, Roberts M, McCarter L et al (2004) Inhibition of MAPK signaling pathways by VopA from Vibrio parahaemolyticus. J Biol Chem 279:51953–51957PubMedCrossRefGoogle Scholar
  76. Ubersax JA, Ferrell JE Jr (2007) Mechanisms of specificity in protein phosphorylation. Nat Rev Mol Cell Biol 8:530–541PubMedCrossRefGoogle Scholar
  77. Vardarova K, Scharf S, Lang F, Schmeck B, Opitz B et al (2009) PKC(alpha) and PKC(epsilon) differentially regulate Legionella pneumophila-induced GM-CSF. Eur Respir J 34:1171–1179PubMedCrossRefGoogle Scholar
  78. Venkataraman C, Gao LY, Bondada S, Kwaik YA (1998) Identification of putative cytoskeletal protein homologues in the protozoan host Hartmannella vermiformis as substrates for induced tyrosine phosphatase activity upon attachment to the Legionnaires’ disease bacterium, Legionella pneumophila. J Exp Med 188:505–514PubMedCrossRefGoogle Scholar
  79. Venkataraman C, Haack BJ, Bondada S, Abu Kwaik Y (1997) Identification of a Gal/GalNAc lectin in the protozoan Hartmannella vermiformis as a potential receptor for attachment and invasion by the Legionnaires’ disease bacterium. J Exp Med 186:537–547PubMedCrossRefGoogle Scholar
  80. Venkataraman C, Kwaik YA (2000) Signal transduction in the protozoan host Hartmannella vermiformis upon attachment to Legionella pneumophila. Microbes Infect 2:867–875PubMedCrossRefGoogle Scholar
  81. Ventura C, Maioli M (2001) Protein kinase C control of gene expression. Crit Rev Eukaryot Gene Expr 11:243–267PubMedCrossRefGoogle Scholar
  82. Verstrepen L, Bekaert T, Chau TL, Tavernier J, Chariot A et al (2008) TLR-4, IL-1R and TNF-R signaling to NF-kappaB: variations on a common theme. Cell Mol Life Sci 65:2964–2978PubMedCrossRefGoogle Scholar
  83. Vitale G, Pellizzari R, Recchi C, Napolitani G, Mock M et al (1998) Anthrax lethal factor cleaves the N-terminus of MAPKKs and induces tyrosine/threonine phosphorylation of MAPKs in cultured macrophages. Biochem Biophys Res Commun 248:706–711PubMedCrossRefGoogle Scholar
  84. Weinstein SL, Sanghera JS, Lemke K, DeFranco AL, Pelech SL (1992) Bacterial lipopolysaccharide induces tyrosine phosphorylation and activation of mitogen-activated protein kinases in macrophages. J Biol Chem 267:14955–14962PubMedGoogle Scholar
  85. Welsh CT, Summersgill JT, Miller RD (2004) Increases in c-Jun N-terminal kinase/stress-activated protein kinase and p38 activity in monocyte-derived macrophages following the uptake of Legionella pneumophila. Infect Immun 72:1512–1518PubMedCrossRefGoogle Scholar
  86. Xiao H, Liu M (2012) Atypical protein kinase C in cell motility. Cell Mol Life Sci doi: 10.1007/s00018-012-1192-1
  87. Zhang ZY, Zhou B, Xie L (2002) Modulation of protein kinase signaling by protein phosphatases and inhibitors. Pharmacol Ther 93:307–317PubMedCrossRefGoogle Scholar
  88. Zhu JW, Brdicka T, Katsumoto TR, Lin J, Weiss A (2008) Structurally distinct phosphatases CD45 and CD148 both regulate B cell and macrophage immunoreceptor signaling. Immunity 28:183–196PubMedCrossRefGoogle Scholar
  89. Zhu W, Banga S, Tan Y, Zheng C, Stephenson R et al (2011) Comprehensive identification of protein substrates of the Dot/Icm type IV transporter of Legionella pneumophila. PLoS ONE 6:e17638PubMedCrossRefGoogle Scholar
  90. Zuckman DM, Hung JB, Roy CR (1999) Pore-forming activity is not sufficient for Legionella pneumophila phagosome trafficking and intracellular growth. Mol Microbiol 32:990–1001PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  1. 1.Howard Hughes Medical InstituteTufts University School of MedicineBostonUSA
  2. 2.Department of Molecular Biology and MicrobiologyTufts University School of MedicineBostonUSA
  3. 3.Graduate Program in Molecular Microbiology, Sackler School of Graduate Biomedical ScienceTufts University School of MedicineBostonUSA

Personalised recommendations