Manipulation of host vesicular trafficking and innate immune defence by Legionella Dot/Icm effectors

Cellular Microbiology

Volumn 13, Issue 12, 2011, Pages 1870-1880

  Ge, Jianning ^a   Shao, Feng ^a  

^a NATIONAL INSTITUTE OF BIOLOGICAL SCIENCES   (China)

Author keywords

[No Author keywords available]

Indexed keywords

ANKYRIN; IMMUNOGLOBULIN ENHANCER BINDING PROTEIN; VESICULAR TRANSPORT PROTEIN;

APOPTOSIS; BACTERIAL SECRETION SYSTEM; CELL MATURATION; CELL MIGRATION; CELL VACUOLE; EFFECTOR CELL; ENDOCYTOSIS; HUMAN; INNATE IMMUNITY; LEGIONELLA PNEUMOPHILA; LYSOSOME; MOLECULAR MECHANICS; NONHUMAN; PATHOGENESIS; PRIORITY JOURNAL; SHORT SURVEY; SIGNAL TRANSDUCTION; VIRUS ENTRY; VIRUS REPLICATION;

ANKYRIN REPEAT; BACTERIAL PROTEINS; BACTERIAL SECRETION SYSTEMS; CELL MEMBRANE; GTP PHOSPHOHYDROLASES; HOST-PATHOGEN INTERACTIONS; IMMUNITY, INNATE; LEGIONELLA; LEGIONNAIRES' DISEASE; MOLECULAR CHAPERONES; PROTEIN TRANSPORT; SIGNAL TRANSDUCTION; VACUOLES;

BACTERIA (MICROORGANISMS); LEGIONELLA; LEGIONELLA PNEUMOPHILA;

EID: 81355138899     PISSN: 14625814     EISSN: 14625822     Source Type: Journal    
DOI: 10.1111/j.1462-5822.2011.01710.x     Document Type: Short Survey

References (95)

1. Abu Kwaik, Y. (1996) The phagosome containing Legionella pneumophila within the protozoan Hartmannella vermiformis is surrounded by the rough endoplasmic reticulum. Appl Environ Microbiol 62: 2022-2028.
2. Abu-Zant, A., Santic, M., Molmeret, M., Jones, S., Helbig, J., and Abu Kwaik, Y. (2005) Incomplete activation of macrophage apoptosis during intracellular replication of Legionella pneumophila. Infect Immun 73: 5339-5349.
3. Abu-Zant, A., Jones, S., Asare, R., Suttles, J., Price, C., Graham, J., and Kwaik, Y.A. (2007) Anti-apoptotic signalling by the Dot/Icm secretion system of L.pneumophila. Cell Microbiol 9: 246-264.
4. Al-Khodor, S., Price, C.T., Habyarimana, F., Kalia, A., and Abu Kwaik, Y. (2008) A Dot/Icm-translocated ankyrin protein of Legionella pneumophila is required for intracellular proliferation within human macrophages and protozoa. Mol Microbiol 70: 908-923.
5. Amor, J.C., Swails, J., Zhu, X., Roy, C.R., Nagai, H., Ingmundson, A., etal. (2005) The structure of RalF, an ADP-ribosylation factor guanine nucleotide exchange factor from Legionella pneumophila, reveals the presence of a cap over the active site. J Biol Chem 280: 1392-1400.
6. Banga, S., Gao, P., Shen, X., Fiscus, V., Zong, W.X., Chen, L., and Luo, Z.Q. (2007) Legionella pneumophila inhibits macrophage apoptosis by targeting pro-death members of the Bcl2 protein family. Proc Natl Acad Sci USA 104: 5121-5126.
7. Bardill, J.P., Miller, J.L., and Vogel, J.P. (2005) IcmS-dependent translocation of SdeA into macrophages by the Legionella pneumophila type IV secretion system. Mol Microbiol 56: 90-103.
8. Bartfeld, S., Engels, C., Bauer, B., Aurass, P., Flieger, A., Bruggemann, H., and Meyer, T.F. (2009) Temporal resolution of two-tracked NF-kappaB activation by Legionella pneumophila. Cell Microbiol 11: 1638-1651.
9. Belyi, Y., Niggeweg, R., Opitz, B., Vogelsgesang, M., Hippenstiel, S., Wilm, M., and Aktories, K. (2006) Legionella pneumophila glucosyltransferase inhibits host elongation factor 1A. Proc Natl Acad Sci USA 103: 16953-16958.
10. Belyi, Y., Tabakova, I., Stahl, M., and Aktories, K. (2008) Lgt: a family of cytotoxic glucosyltransferases produced by Legionella pneumophila. J Bacteriol 190: 3026-3035.
11. Berger, K.H., and Isberg, R.R. (1993) Two distinct defects in intracellular growth complemented by a single genetic locus in Legionella pneumophila. Mol Microbiol 7: 7-19.
12. Brombacher, E., Urwyler, S., Ragaz, C., Weber, S.S., Kami, K., Overduin, M., and Hilbi, H. (2009) Rab1 guanine nucleotide exchange factor SidM is a major phosphatidylinositol 4-phosphate-binding effector protein of Legionella pneumophila. J Biol Chem 284: 4846-4856.
13. Bruggemann, H., Cazalet, C., and Buchrieser, C. (2006) Adaptation of Legionella pneumophila to the host environment: role of protein secretion, effectors and eukaryotic-like proteins. Curr Opin Microbiol 9: 86-94.
14. Burstein, D., Zusman, T., Degtyar, E., Viner, R., Segal, G., and Pupko, T. (2009) Genome-scale identification of Legionella pneumophila effectors using a machine learning approach. PLoS Pathog 5: e1000508.
15. Campodonico, E.M., Chesnel, L., and Roy, C.R. (2005) A yeast genetic system for the identification and characterization of substrate proteins transferred into host cells by the Legionella pneumophila Dot/Icm system. Mol Microbiol 56: 918-933.
16. Cazalet, C., Rusniok, C., Bruggemann, H., Zidane, N., Magnier, A., Ma, L., etal. (2004) Evidence in the Legionella pneumophila genome for exploitation of host cell functions and high genome plasticity. Nat Genet 36: 1165-1173.
17. Chen, J., de Felipe, K.S., Clarke, M., Lu, H., Anderson, O.R., Segal, G., and Shuman, H.A. (2004) Legionella effectors that promote nonlytic release from protozoa. Science 303: 1358-1361.
18. Chiu, Y.H., Macmillan, J.B., and Chen, Z.J. (2009) RNA polymerase III detects cytosolic DNA and induces type I interferons through the RIG-I pathway. Cell 138: 576-591.
19. Clemens, D.L., Lee, B.Y., and Horwitz, M.A. (2000) Deviant expression of Rab5 on phagosomes containing the intracellular pathogens Mycobacterium tuberculosis and Legionella pneumophila is associated with altered phagosomal fate. Infect Immun 68: 2671-2684.
20. Conover, G.M., Derre, I., Vogel, J.P., and Isberg, R.R. (2003) The Legionella pneumophila LidA protein: a translocated substrate of the Dot/Icm system associated with maintenance of bacterial integrity. Mol Microbiol 48: 305-321.
21. Degtyar, E., Zusman, T., Ehrlich, M., and Segal, G. (2009) A Legionella effector acquired from protozoa is involved in sphingolipids metabolism and is targeted to the host cell mitochondria. Cell Microbiol 11: 1219-1235.
22. Derre, I., and Isberg, R.R. (2004) Legionella pneumophila replication vacuole formation involves rapid recruitment of proteins of the early secretory system. Infect Immun 72: 3048-3053.
23. Derre, I., and Isberg, R.R. (2005) LidA, a translocated substrate of the Legionella pneumophila type IV secretion system, interferes with the early secretory pathway. Infect Immun 73: 4370-4380.
24. Dorer, M.S., Kirton, D., Bader, J.S., and Isberg, R.R. (2006) RNA interference analysis of Legionella in Drosophila cells: exploitation of early secretory apparatus dynamics. PLoS Pathog 2: e34.
25. Ensminger, A.W., and Isberg, R.R. (2010) E3 ubiquitin ligase activity and targeting of BAT3 by multiple Legionella pneumophila translocated substrates. Infect Immun 78: 3905-3919.
26. de Felipe, K.S., Pampou, S., Jovanovic, O.S., Pericone, C.D., Ye, S.F., Kalachikov, S., and Shuman, H.A. (2005) Evidence for acquisition of Legionella type IV secretion substrates via interdomain horizontal gene transfer. J Bacteriol 187: 7716-7726.
27. de Felipe, K.S., Glover, R.T., Charpentier, X., Anderson, O.R., Reyes, M., Pericone, C.D., and Shuman, H.A. (2008) Legionella eukaryotic-like type IV substrates interfere with organelle trafficking. PLoS Pathog 4: e1000117.
28. Fontana, M.F., Banga, S., Barry, K.C., Shen, X., Tan, Y., Luo, Z.Q., and Vance, R.E. (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: e1001289.
29. Fraser, D.W., Tsai, T.R., Orenstein, W., Parkin, W.E., Beecham, H.J., Sharrar, R.G., etal. (1977) Legionnaires' disease: description of an epidemic of pneumonia. N Engl J Med 297: 1189-1197.
30. Ge, J., Xu, H., Li, T., Zhou, Y., Zhang, Z., Li, S., etal. (2009) A Legionella type IV effector activates the NF-kappaB pathway by phosphorylating the IkappaB family of inhibitors. Proc Natl Acad Sci USA 106: 13725-13730.
31. Habyarimana, F., Al-Khodor, S., Kalia, A., Graham, J.E., Price, C.T., Garcia, M.T., and Kwaik, Y.A. (2008) Role for the Ankyrin eukaryotic-like genes of Legionella pneumophila in parasitism of protozoan hosts and human macrophages. Environ Microbiol 10: 1460-1474.
32. Habyarimana, F., Price, C.T., Santic, M., Al-Khodor, S., and Kwaik, Y.A. (2010) Molecular characterization of the Dot/Icm-translocated AnkH and AnkJ eukaryotic-like effectors of Legionella pneumophila. Infect Immun 78: 1123-1134.
33. Hayashi, T., Nakamichi, M., Naitou, H., Ohashi, N., Imai, Y., and Miyake, M. (2010) Proteomic analysis of growth phase-dependent expression of Legionella pneumophila proteins which involves regulation of bacterial virulence traits. PLoS ONE 5: e11718.
34. Heidtman, M., Chen, E.J., Moy, M.Y., and Isberg, R.R. (2009) Large-scale identification of Legionella pneumophila Dot/Icm substrates that modulate host cell vesicle trafficking pathways. Cell Microbiol 11: 230-248.
35. Hervet, E., Charpentier, X., Vianney, A., Lazzaroni, J.C., Gilbert, C., Atlan, D., and Doublet, P. (2011) The protein kinase LegK2 is a T4SS effector involved in endoplasmic reticulum recruitment and intracellular replication of Legionella pneumophila. Infect Immun 79: 1936-1950.
36. Horwitz, M.A. (1983a) Formation of a novel phagosome by the Legionnaires' disease bacterium (Legionella pneumophila) in human monocytes. J Exp Med 158: 1319-1331.
37. Horwitz, M.A. (1983b) The Legionnaires' disease bacterium (Legionella pneumophila) inhibits phagosome-lysosome fusion in human monocytes. J Exp Med 158: 2108-2126.
38. Horwitz, M.A. (1987) Characterization of avirulent mutant Legionella pneumophila that survive but do not multiply within human monocytes. J Exp Med 166: 1310-1328.
39. Horwitz, M.A., and Maxfield, F.R. (1984) Legionella pneumophila inhibits acidification of its phagosome in human monocytes. J Cell Biol 99: 1936-1943.
40. Horwitz, M.A., and Silverstein, S.C. (1980) Legionnaires' disease bacterium (Legionella pneumophila) multiples intracellularly in human monocytes. J Clin Invest 66: 441-450.
41. Huang, L., Boyd, D., Amyot, W.M., Hempstead, A.D., Luo, Z.Q., O'Connor, T.J., etal. (2011) The E Block motif is associated with Legionella pneumophila translocated substrates. Cell Microbiol 13: 227-245.
42. Ingmundson, A., Delprato, A., Lambright, D.G., and Roy, C.R. (2007) Legionella pneumophila proteins that regulate Rab1 membrane cycling. Nature 450: 365-369.
43. Ivanov, S.S., Charron, G., Hang, H.C., and Roy, C.R. (2010) Lipidation by the host prenyltransferase machinery facilitates membrane localization of Legionella pneumophila effector proteins. J Biol Chem 285: 34686-34698.
44. Kagan, J.C., and Roy, C.R. (2002) Legionella phagosomes intercept vesicular traffic from endoplasmic reticulum exit sites. Nat Cell Biol 4: 945-954.
45. Kagan, J.C., Stein, M.P., Pypaert, M., and Roy, C.R. (2004) Legionella subvert the functions of Rab1 and Sec22b to create a replicative organelle. J Exp Med 199: 1201-1211.
46. Komano, T., Yoshida, T., Narahara, K., and Furuya, N. (2000) The transfer region of IncI1 plasmid R64: similarities between R64 tra and legionella icm/dot genes. Mol Microbiol 35: 1348-1359.
47. Laguna, R.K., Creasey, E.A., Li, Z., Valtz, N., and Isberg, R.R. (2006) A Legionella pneumophila-translocated substrate that is required for growth within macrophages and protection from host cell death. Proc Natl Acad Sci USA 103: 18745-18750.
48. Lang, C., and Flieger, A. (2011) Characterisation of Legionella pneumophila phospholipases and their impact on host cells. Eur J Cell Biol 90: 903-912.
49. Liu, Y., and Luo, Z.Q. (2007) The Legionella pneumophila effector SidJ is required for efficient recruitment of endoplasmic reticulum proteins to the bacterial phagosome. Infect Immun 75: 592-603.
50. Lomma, M., Dervins-Ravault, D., Rolando, M., Nora, T., Newton, H.J., Sansom, F.M., etal. (2010) The Legionella pneumophila F-box protein Lpp2082 (AnkB) modulates ubiquitination of the host protein parvin B and promotes intracellular replication. Cell Microbiol 12: 1272-1291.
51. Losick, V.P., and Isberg, R.R. (2006) NF-kappaB translocation prevents host cell death after low-dose challenge by Legionella pneumophila. J Exp Med 203: 2177-2189.
52. Losick, V.P., Haenssler, E., Moy, M.Y., and Isberg, R.R. (2010) LnaB: a Legionella pneumophila activator of NF-kappaB. Cell Microbiol 12: 1083-1097.
53. Luo, Z.Q., and Isberg, R.R. (2004) Multiple substrates of the Legionella pneumophila Dot/Icm system identified by interbacterial protein transfer. Proc Natl Acad Sci USA 101: 841-846.
54. Machner, M.P., and Isberg, R.R. (2006) Targeting of host Rab GTPase function by the intravacuolar pathogen Legionella pneumophila. Dev Cell 11: 47-56.
55. Machner, M.P., and Isberg, R.R. (2007) A bifunctional bacterial protein links GDI displacement to Rab1 activation. Science 318: 974-977.
56. Marra, A., Blander, S.J., Horwitz, M.A., and Shuman, H.A. (1992) Identification of a Legionella pneumophila locus required for intracellular multiplication in human macrophages. Proc Natl Acad Sci USA 89: 9607-9611.
57. Monroe, K.M., McWhirter, S.M., and Vance, R.E. (2009) Identification of host cytosolic sensors and bacterial factors regulating the type I interferon response to Legionella pneumophila. PLoS Pathog 5: e1000665.
58. Mukherjee, S., Liu, X., Arasaki, K., McDonough, J., Galan, J.E., and Roy, C.R. (2011) Modulation of Rab GTPase function by a protein phosphocholine transferase. Nature 477: 103-106.
59. Muller, M.P., Peters, H., Blumer, J., Blankenfeldt, W., Goody, R.S., and Itzen, A. (2010) The Legionella effector protein DrrA AMPylates the membrane traffic regulator Rab1b. Science 329: 946-949.
60. Murata, T., Delprato, A., Ingmundson, A., Toomre, D.K., Lambright, D.G., and Roy, C.R. (2006) The Legionella pneumophila effector protein DrrA is a Rab1 guanine nucleotide-exchange factor. Nat Cell Biol 8: 971-977.
61. Nagai, H., Kagan, J.C., Zhu, X., Kahn, R.A., and Roy, C.R. (2002) A bacterial guanine nucleotide exchange factor activates ARF on Legionella phagosomes. Science 295: 679-682.
62. Nash, T.W., Libby, D.M., and Horwitz, M.A. (1984) Interaction between the legionnaires' disease bacterium (Legionella pneumophila) and human alveolar macrophages. Influence of antibody, lymphokines, and hydrocortisone. J Clin Invest 74: 771-782.
63. Neunuebel, M.R., Chen, Y., Gaspar, A.H., Backlund, P.S., Jr, Yergey, A., and Machner, M.P. (2011) De-AMPylation of the small GTPase Rab1 by the pathogen Legionella pneumophila. Science 333: 453-456.
64. Ninio, S., Celli, J., and Roy, C.R. (2009) A Legionella pneumophila effector protein encoded in a region of genomic plasticity binds to Dot/Icm-modified vacuoles. PLoS Pathog 5: e1000278.
65. Opitz, B., Vinzing, M., van Laak, V., Schmeck, B., Heine, G., Gunther, S., etal. (2006) Legionella pneumophila induces IFNbeta in lung epithelial cells via IPS-1 and IRF3, which also control bacterial replication. J Biol Chem 281: 36173-36179.
66. Pan, X., Luhrmann, A., Satoh, A., Laskowski-Arce, M.A., and Roy, C.R. (2008) Ankyrin repeat proteins comprise a diverse family of bacterial type IV effectors. Science 320: 1651-1654.
67. Petroski, M.D., and Deshaies, R.J. (2005) Function and regulation of cullin-RING ubiquitin ligases. Nat Rev Mol Cell Biol 6: 9-20.
68. Plumlee, C.R., Lee, C., Beg, A.A., Decker, T., Shuman, H.A., and Schindler, C. (2009) Interferons direct an effective innate response to Legionella pneumophila infection. J Biol Chem 284: 30058-30066.
69. Price, C.T., Al-Khodor, S., Al-Quadan, T., Santic, M., Habyarimana, F., Kalia, A., and Kwaik, Y.A. (2009) Molecular mimicry by an F-box effector of Legionella pneumophila hijacks a conserved polyubiquitination machinery within macrophages and protozoa. PLoS Pathog 5: e1000704.
70. Price, C.T., Al-Khodor, S., Al-Quadan, T., and Abu Kwaik, Y. (2010) Indispensable role for the eukaryotic-like ankyrin domains of the ankyrin B effector of Legionella pneumophila within macrophages and amoebae. Infect Immun 78: 2079-2088.
71. Ragaz, C., Pietsch, H., Urwyler, S., Tiaden, A., Weber, S.S., and Hilbi, H. (2008) The Legionella pneumophila phosphatidylinositol-4 phosphate-binding type IV substrate SidC recruits endoplasmic reticulum vesicles to a replication-permissive vacuole. Cell Microbiol 10: 2416-2433.
72. Rigden, D.J. (2011) Identification and modelling of a PPM protein phosphatase fold in the Legionella pneumophila deAMPylase SidD. FEBS Lett 585: 2749-2754.
73. Robinson, C.G., and Roy, C.R. (2006) Attachment and fusion of endoplasmic reticulum with vacuoles containing Legionella pneumophila. Cell Microbiol 8: 793-805.
74. Roy, C.R., and Mukherjee, S. (2009) Bacterial FIC Proteins AMP Up Infection. Sci Signal 2: pe14.
75. Roy, C.R., Berger, K.H., and Isberg, R.R. (1998) Legionella pneumophila DotA protein is required for early phagosome trafficking decisions that occur within minutes of bacterial uptake. Mol Microbiol 28: 663-674.
76. Schoebel, S., Oesterlin, L.K., Blankenfeldt, W., Goody, R.S., and Itzen, A. (2009) RabGDI displacement by DrrA from Legionella is a consequence of its guanine nucleotide exchange activity. Mol Cell 36: 1060-1072.
77. Schoebel, S., Blankenfeldt, W., Goody, R.S., and Itzen, A. (2010) High-affinity binding of phosphatidylinositol 4-phosphate by Legionella pneumophila DrrA. EMBO Rep 11: 598-604.
78. Segal, G., Purcell, M., and Shuman, H.A. (1998) Host cell killing and bacterial conjugation require overlapping sets of genes within a 22-kb region of the Legionella pneumophila genome. Proc Natl Acad Sci USA 95: 1669-1674.
79. Shen, X., Banga, S., Liu, Y., Xu, L., Gao, P., Shamovsky, I., etal. (2009) Targeting eEF1A by a Legionella pneumophila effector leads to inhibition of protein synthesis and induction of host stress response. Cell Microbiol 11: 911-926.
80. Shin, S., Case, C.L., Archer, K.A., Nogueira, C.V., Kobayashi, K.S., Flavell, R.A., etal. (2008) Type IV secretion-dependent activation of host MAP kinases induces an increased proinflammatory cytokine response to Legionella pneumophila. PLoS Pathog 4: e1000220.
81. Shohdy, N., Efe, J.A., Emr, S.D., and Shuman, H.A. (2005) Pathogen effector protein screening in yeast identifies Legionella factors that interfere with membrane trafficking. Proc Natl Acad Sci USA 102: 4866-4871.
82. Stetson, D.B., and Medzhitov, R. (2006) Recognition of cytosolic DNA activates an IRF3-dependent innate immune response. Immunity 24: 93-103.
83. Suh, H.Y., Lee, D.W., Lee, K.H., Ku, B., Choi, S.J., Woo, J.S., etal. (2010) Structural insights into the dual nucleotide exchange and GDI displacement activity of SidM/DrrA. EMBO J 29: 496-504.
84. Swanson, M.S., and Isberg, R.R. (1995) Association of Legionella pneumophila with the macrophage endoplasmic reticulum. Infect Immun 63: 3609-3620.
85. Tan, Y., and Luo, Z.Q. (2011) Legionella pneumophila SidD is a deAMPylase that modifies Rab1. Nature 475: 506-509.
86. Tilney, L.G., Harb, O.S., Connelly, P.S., Robinson, C.G., and Roy, C.R. (2001) How the parasitic bacterium Legionella pneumophila modifies its phagosome and transforms it into rough ER: implications for conversion of plasma membrane to the ER membrane. J Cell Sci 114: 4637-4650.
87. VanRheenen, S.M., Luo, Z.Q., O'Connor, T., and Isberg, R.R. (2006) Members of a Legionella pneumophila family of proteins with ExoU (phospholipase A) active sites are translocated to target cells. Infect Immun 74: 3597-3606.
88. Vogel, J.P., Andrews, H.L., Wong, S.K., and Isberg, R.R. (1998) Conjugative transfer by the virulence system of Legionella pneumophila. Science 279: 873-876.
89. Worby, C.A., Mattoo, S., Kruger, R.P., Corbeil, L.B., Koller, A., Mendez, J.C., etal. (2009) The fic domain: regulation of cell signaling by adenylylation. Mol Cell 34: 93-103.
90. Xu, L., Shen, X., Bryan, A., Banga, S., Swanson, M.S., and Luo, Z.Q. (2010) Inhibition of host vacuolar H+-ATPase activity by a Legionella pneumophila effector. PLoS Pathog 6: e1000822.
91. Yarbrough, M.L., Li, Y., Kinch, L.N., Grishin, N.V., Ball, H.L., and Orth, K. (2009) AMPylation of Rho GTPases by Vibrio VopS disrupts effector binding and downstream signaling. Science 323: 269-272.
92. Zhu, W., Banga, S., Tan, Y., Zheng, C., Stephenson, R., Gately, J., and Luo, Z.Q. (2011) Comprehensive Identification of Protein Substrates of the Dot/Icm Type IV Transporter of Legionella pneumophila. PLoS ONE 6: e17638.
93. Zhu, Y., Hu, L., Zhou, Y., Yao, Q., Liu, L., and Shao, F. (2010) Structural mechanism of host Rab1 activation by the bifunctional Legionella type IV effector SidM/DrrA. Proc Natl Acad Sci USA 107: 4699-4704.
94. Zusman, T., Aloni, G., Halperin, E., Kotzer, H., Degtyar, E., Feldman, M., and Segal, G. (2007) The response regulator PmrA is a major regulator of the icm/dot type IV secretion system in Legionella pneumophila and Coxiella burnetii. Mol Microbiol 63: 1508-1523.
95. Zusman, T., Degtyar, E., and Segal, G. (2008) Identification of a hypervariable region containing new Legionella pneumophila Icm/Dot translocated substrates by using the conserved icmQ regulatory signature. Infect Immun 76: 4581-4591.