Cellular and Molecular Life Sciences

, Volume 71, Issue 5, pp 745–770 | Cite as

Bacterial serine proteases secreted by the autotransporter pathway: classification, specificity, and role in virulence



Serine proteases exist in eukaryotic and prokaryotic organisms and have emerged during evolution as the most abundant and functionally diverse group. In Gram-negative bacteria, there is a growing family of high molecular weight serine proteases secreted to the external milieu by a fascinating and widely employed bacterial secretion mechanism, known as the autotransporter pathway. They were initially found in Neisseria, Shigella, and pathogenic Escherichiacoli, but have now also been identified in Citrobacterrodentium, Salmonella, and Edwardsiella species. Here, we focus on proteins belonging to the serine protease autotransporter of Enterobacteriaceae (SPATEs) family. Recent findings regarding the predilection of serine proteases to host intracellular or extracellular protein-substrates involved in numerous biological functions, such as those implicated in cytoskeleton stability, autophagy or innate and adaptive immunity, have helped provide a better understanding of SPATEs’ contributions in pathogenesis. Here, we discuss their classification, substrate specificity, and potential roles in pathogenesis.


SPATE Autotransporter Glycoprotein Immune evasion Cytotoxin 



Adhesin involved in diffuse adherence-like


Adherent-invasive E. coli


Avian pathogenic E. coli


Diffuse-adhering E. coli


Enteroaggregative E. coli


Enterohemorrhagic E. coli


Enteroinvasive E. coli


Enteropathogenic E. coli


Enterotoxigenic E. coli


Extra-intestinal E. coli


Hemolytic uremic syndrome


Rabbit pathogenic E. coli


Serine protease autotransporters from Enterobacteriaceae


Shiga-toxin secreting E. coli


Trimeric autotransporters


Two-partner secretion system


Uropathogenic E. coli


  1. 1.
    Pallen MJ, Chaudhuri RR, Henderson IR (2003) Genomic analysis of secretion systems. Curr Opin Microbiol 6(5):519–527PubMedGoogle Scholar
  2. 2.
    Henderson IR, Navarro-Garcia F, Nataro JP (1998) The great escape: structure and function of the autotransporter proteins. Trends Microbiol 6(9):370–378PubMedGoogle Scholar
  3. 3.
    Jacob-Dubuisson F, Locht C, Antoine R (2001) Two-partner secretion in Gram-negative bacteria: a thrifty, specific pathway for large virulence proteins. Mol Microbiol 40(2):306–313PubMedGoogle Scholar
  4. 4.
    Linke D et al (2006) Trimeric autotransporter adhesins: variable structure, common function. Trends Microbiol 14(6):264–270PubMedGoogle Scholar
  5. 5.
    Salacha R et al (2010) The Pseudomonas aeruginosa patatin-like protein PlpD is the archetype of a novel Type V secretion system. Environ Microbiol 12(6):1498–1512PubMedGoogle Scholar
  6. 6.
    Oberhettinger P et al (2012) Intimin and invasin export their C-terminus to the bacterial cell surface using an inverse mechanism compared to classical autotransport. PLoS ONE 7(10):e47069PubMedCentralPubMedGoogle Scholar
  7. 7.
    Kaper JB, Nataro JP, Mobley HL (2004) Pathogenic Escherichia coli. Nat Rev Microbiol 2(2):123–140PubMedGoogle Scholar
  8. 8.
    Yen YT et al (2008) Common themes and variations in serine protease autotransporters. Trends Microbiol 16(8):370–379PubMedGoogle Scholar
  9. 9.
    Desvaux M et al (2009) Secretion and subcellular localizations of bacterial proteins: a semantic awareness issue. Trends Microbiol 17(4):139–145PubMedGoogle Scholar
  10. 10.
    Henderson IR, Cappello R, Nataro JP (2000) Autotransporter proteins, evolution and redefining protein secretion: response. Trends Microbiol 8(12):534–535PubMedGoogle Scholar
  11. 11.
    Henderson IR et al (2000) Renaming protein secretion in the gram-negative bacteria. Trends Microbiol 8(8):352Google Scholar
  12. 12.
    Selkrig J et al (2012) Discovery of an archetypal protein transport system in bacterial outer membranes. Nat Struct Mol Biol 19(5):506–510PubMedGoogle Scholar
  13. 13.
    Jong WS et al (2010) YidC is involved in the biogenesis of the secreted autotransporter hemoglobin protease. J Biol Chem 285(51):39682–39690PubMedGoogle Scholar
  14. 14.
    Ruiz-Perez F et al (2009) Roles of periplasmic chaperone proteins in the biogenesis of serine protease autotransporters of Enterobacteriaceae. J Bacteriol 191(21):6571–6583PubMedCentralPubMedGoogle Scholar
  15. 15.
    Ruiz-Perez F, Henderson IR, Nataro JP (2010) Interaction of FkpA, a peptidyl-prolyl cis/trans isomerase with EspP autotransporter protein. Gut Microbes 1(5):339–344PubMedGoogle Scholar
  16. 16.
    Purdy GE, Fisher CR, Payne SM (2007) IcsA surface presentation in Shigella flexneri requires the periplasmic chaperones DegP, Skp, and SurA. J Bacteriol 189(15):5566–5573PubMedCentralPubMedGoogle Scholar
  17. 17.
    Ieva R, Bernstein HD (2009) Interaction of an autotransporter passenger domain with BamA during its translocation across the bacterial outer membrane. Proc Natl Acad Sci USA 106(45):19120–19125PubMedGoogle Scholar
  18. 18.
    Sauri A et al (2009) The Bam (Omp85) complex is involved in secretion of the autotransporter haemoglobin protease. Microbiology 155(Pt 12):3982–3991PubMedGoogle Scholar
  19. 19.
    Ieva R et al (2011) Sequential and spatially restricted interactions of assembly factors with an autotransporter beta domain. Proc Natl Acad Sci USA 108(31):E383–E391PubMedGoogle Scholar
  20. 20.
    Jain S, Goldberg MB (2007) Requirement for YaeT in the outer membrane assembly of autotransporter proteins. J Bacteriol 189(14):5393–5398PubMedCentralPubMedGoogle Scholar
  21. 21.
    Rossiter AE et al (2011) The essential beta-barrel assembly machinery complex components BamD and BamA are required for autotransporter biogenesis. J Bacteriol 193(16):4250–4253PubMedCentralPubMedGoogle Scholar
  22. 22.
    Pohlner J et al (1987) Gene structure and extracellular secretion of Neisseria gonorrhoeae IgA protease. Nature 325(6103):458–462PubMedGoogle Scholar
  23. 23.
    Klauser T et al (1993) Characterization of the Neisseria Iga beta-core. The essential unit for outer membrane targeting and extracellular protein secretion. J Mol Biol 234(3):579–593PubMedGoogle Scholar
  24. 24.
    Bernstein HD (2007) Are bacterial ‘autotransporters’ really transporters? Trends Microbiol 15(10):441–447PubMedGoogle Scholar
  25. 25.
    Jacob-Dubuisson F, Fernandez R, Coutte L (2004) Protein secretion through autotransporter and two-partner pathways. Biochim Biophys Acta 1694(1–3):235–257PubMedGoogle Scholar
  26. 26.
    Dautin N, Bernstein HD (2007) Protein secretion in gram-negative bacteria via the autotransporter pathway. Annu Rev Microbiol 61:89–112PubMedGoogle Scholar
  27. 27.
    Leyton DL, Rossiter AE, Henderson IR (2012) From self sufficiency to dependence: mechanisms and factors important for autotransporter biogenesis. Nat Rev Microbiol 10(3):213–225PubMedGoogle Scholar
  28. 28.
    Leo JC, Grin I, Linke D (2012) Type V secretion: mechanism(s) of autotransport through the bacterial outer membrane. Philos Trans R Soc Lond B 367(1592):1088–1101Google Scholar
  29. 29.
    Sijbrandi R et al (2003) Signal recognition particle (SRP)-mediated targeting and Sec-dependent translocation of an extracellular Escherichia coli protein. J Biol Chem 278(7):4654–4659PubMedGoogle Scholar
  30. 30.
    Szabady RL et al (2005) An unusual signal peptide facilitates late steps in the biogenesis of a bacterial autotransporter. Proc Natl Acad Sci USA 102(1):221–226PubMedGoogle Scholar
  31. 31.
    Junker M, Besingi RN, Clark PL (2009) Vectorial transport and folding of an autotransporter virulence protein during outer membrane secretion. Mol Microbiol 71(5):1323–1332PubMedGoogle Scholar
  32. 32.
    Peterson JH et al (2010) Secretion of a bacterial virulence factor is driven by the folding of a C-terminal segment. Proc Natl Acad Sci USA 107(41):17739–17744PubMedGoogle Scholar
  33. 33.
    Renn JP et al (2012) ATP-independent control of autotransporter virulence protein transport via the folding properties of the secreted protein. Chem Biol 19(2):287–296PubMedCentralPubMedGoogle Scholar
  34. 34.
    Junker M et al (2006) Pertactin beta-helix folding mechanism suggests common themes for the secretion and folding of autotransporter proteins. Proc Natl Acad Sci USA 103(13):4918–4923PubMedGoogle Scholar
  35. 35.
    Page MJ, Di Cera E (2008) Serine peptidases: classification, structure and function. Cell Mol Life Sci 65(7–8):1220–1236PubMedGoogle Scholar
  36. 36.
    Rawlings ND, Barrett AJ, Bateman A (2012) MEROPS: the database of proteolytic enzymes, their substrates and inhibitors. Nucleic Acids Res 40(Database issue):D343–D350Google Scholar
  37. 37.
    Rawlings ND, Barrett AJ, Bateman A (2010) MEROPS: the peptidase database. Nucleic Acids Res 38:D227–233Google Scholar
  38. 38.
    Dautin N (2010) Serine protease autotransporters of Enterobacteriaceae (SPATEs): biogenesis and function. Toxins (Basel) 2(6):1179–1206Google Scholar
  39. 39.
    Leyton DL et al (2007) Contribution of a novel gene, rpeA, encoding a putative autotransporter adhesin to intestinal colonization by rabbit-specific enteropathogenic Escherichia coli. Infect Immun 75(9):4664–4669PubMedCentralPubMedGoogle Scholar
  40. 40.
    Dautin N et al (2007) Cleavage of a bacterial autotransporter by an evolutionarily convergent autocatalytic mechanism. EMBO J 26(7):1942–1952PubMedGoogle Scholar
  41. 41.
    Barnard TJ et al (2012) Molecular basis for the activation of a catalytic asparagine residue in a self-cleaving bacterial autotransporter. J Mol Biol 415(1):128–142PubMedCentralPubMedGoogle Scholar
  42. 42.
    Tajima N et al (2010) A novel intein-like autoproteolytic mechanism in autotransporter proteins. J Mol Biol 402(4):645–656PubMedGoogle Scholar
  43. 43.
    Otto BR et al (2005) Crystal structure of hemoglobin protease, a heme binding autotransporter protein from pathogenic Escherichia coli. J Biol Chem 280(17):17339–17345PubMedGoogle Scholar
  44. 44.
    Emsley P et al (1996) Structure of Bordetella pertussis virulence factor P.69 pertactin. Nature 381(6577):90–92PubMedGoogle Scholar
  45. 45.
    Johnson TA et al (2009) Active-site gating regulates substrate selectivity in a chymotrypsin-like serine protease the structure of Haemophilus influenzae immunoglobulin A1 protease. J Mol Biol 389(3):559–574PubMedCentralPubMedGoogle Scholar
  46. 46.
    Meng G et al (2011) Crystal structure of the Haemophilus influenzae Hap adhesin reveals an intercellular oligomerization mechanism for bacterial aggregation. EMBO J 30(18):3864–3874PubMedGoogle Scholar
  47. 47.
    Gangwer KA et al (2007) Crystal structure of the Helicobacter pylori vacuolating toxin p55 domain. Proc Natl Acad Sci USA 104(41):16293–16298PubMedGoogle Scholar
  48. 48.
    van den Berg B (2010) Crystal structure of a full-length autotransporter. J Mol Biol 396(3):627–633PubMedGoogle Scholar
  49. 49.
    Celik N et al (2012) A bioinformatic strategy for the detection, classification and analysis of bacterial autotransporters. PLoS ONE 7(8):e43245PubMedCentralPubMedGoogle Scholar
  50. 50.
    Oliver DC et al (2003) A conserved region within the Bordetella pertussis autotransporter BrkA is necessary for folding of its passenger domain. Mol Microbiol 47(5):1367–1383PubMedGoogle Scholar
  51. 51.
    Xicohtencatl-Cortes J et al (2010) Bacterial macroscopic rope-like fibers with cytopathic and adhesive properties. J Biol Chem 285(42):32336–32342PubMedGoogle Scholar
  52. 52.
    Klemm P, Vejborg RM, Sherlock O (2006) Self-associating autotransporters, SAATs: functional and structural similarities. Int J Med Microbiol 296(4–5):187–195PubMedGoogle Scholar
  53. 53.
    Nishimura K et al (2010) Role of domains within the autotransporter Hbp/Tsh. Acta Crystallogr D Biol Crystallogr 66(Pt 12):1295–1300PubMedGoogle Scholar
  54. 54.
    Khan S et al (2011) Crystal structure of the passenger domain of the Escherichia coli autotransporter EspP. J Mol Biol 413(5):985–1000PubMedCentralPubMedGoogle Scholar
  55. 55.
    Leyton DL et al (2011) Size and conformation limits to secretion of disulfide-bonded loops in autotransporter proteins. J Biol Chem 286(49):42283–42291PubMedGoogle Scholar
  56. 56.
    Dutta PR et al (2002) Functional comparison of serine protease autotransporters of enterobacteriaceae. Infect Immun 70(12):7105–7113PubMedCentralPubMedGoogle Scholar
  57. 57.
    Hart E et al (2008) RegA, an AraC-like protein, is a global transcriptional regulator that controls virulence gene expression in Citrobacter rodentium. Infect Immun 76(11):5247–5256PubMedCentralPubMedGoogle Scholar
  58. 58.
    Cheney CP et al (1980) Species specificity of in vitro Escherichia coli adherence to host intestinal cell membranes and its correlation with in vivo colonization and infectivity. Infect Immun 28(3):1019–1027PubMedCentralPubMedGoogle Scholar
  59. 59.
    Tan C et al (2011) Genome sequence of a porcine extraintestinal pathogenic Escherichia coli strain. J Bacteriol 193(18):5038PubMedCentralPubMedGoogle Scholar
  60. 60.
    Arnold K et al (2006) The SWISS-MODEL workspace: a web-based environment for protein structure homology modelling. Bioinformatics 22(2):195–201PubMedGoogle Scholar
  61. 61.
    Ruiz-Perez F et al (2011) Serine protease autotransporters from Shigella flexneri and pathogenic Escherichia coli target a broad range of leukocyte glycoproteins. Proc Natl Acad Sci USA 108(31):12881–12886PubMedGoogle Scholar
  62. 62.
    Dutta PR, Sui BQ, Nataro JP (2003) Structure-function analysis of the enteroaggregative Escherichia coli plasmid-encoded toxin autotransporter using scanning linker mutagenesis. J Biol Chem 278(41):39912–39920PubMedGoogle Scholar
  63. 63.
    Henderson IR et al (1999) Involvement of the enteroaggregative Escherichia coli plasmid-encoded toxin in causing human intestinal damage. Infect Immun 67(10):5338–5344PubMedCentralPubMedGoogle Scholar
  64. 64.
    Al-Hasani K et al (2009) The immunogenic SigA enterotoxin of Shigella flexneri 2a binds to HEp-2 cells and induces fodrin redistribution in intoxicated epithelial cells. PLoS ONE 4(12):e8223PubMedCentralPubMedGoogle Scholar
  65. 65.
    Navarro-Garcia F et al (2004) The serine protease motif of EspC from enteropathogenic Escherichia coli produces epithelial damage by a mechanism different from that of Pet toxin from enteroaggregative E. coli. Infect Immun 72(6):3609–3621PubMedCentralPubMedGoogle Scholar
  66. 66.
    Canizalez-Roman A, Navarro-Garcia F (2003) Fodrin CaM-binding domain cleavage by Pet from enteroaggregative Escherichia coli leads to actin cytoskeletal disruption. Mol Microbiol 48(4):947–958PubMedGoogle Scholar
  67. 67.
    Maroncle NM et al (2006) Protease activity, secretion, cell entry, cytotoxicity, and cellular targets of secreted autotransporter toxin of uropathogenic Escherichia coli. Infect Immun 74(11):6124–6134PubMedCentralPubMedGoogle Scholar
  68. 68.
    Harrington SM et al (2009) The Pic protease of enteroaggregative Escherichia coli promotes intestinal colonization and growth in the presence of mucin. Infect Immun 77(6):2465–2473PubMedCentralPubMedGoogle Scholar
  69. 69.
    Henderson IR et al (1999) Characterization of pic, a secreted protease of Shigella flexneri and enteroaggregative Escherichia coli. Infect Immun 67(11):5587–5596PubMedCentralPubMedGoogle Scholar
  70. 70.
    Leyton DL et al (2003) Transfer region of pO113 from enterohemorrhagic Escherichia coli: similarity with R64 and identification of a novel plasmid-encoded autotransporter, EpeA. Infect Immun 71(11):6307–6319PubMedCentralPubMedGoogle Scholar
  71. 71.
    Boisen N et al (2009) Short report: high prevalence of serine protease autotransporter cytotoxins among strains of enteroaggregative Escherichia coli. Am J Trop Med Hyg 80(2):294–301PubMedCentralPubMedGoogle Scholar
  72. 72.
    Rasko DA et al (2011) Origins of the E. coli strain causing an outbreak of hemolytic-uremic syndrome in Germany. N Engl J Med 365(8):709–717PubMedCentralPubMedGoogle Scholar
  73. 73.
    Campanella JJ, Bitincka L, Smalley J (2003) MatGAT: an application that generates similarity/identity matrices using protein or DNA sequences. BMC Bioinf 4:29Google Scholar
  74. 74.
    Rajakumar K, Sasakawa C, Adler B (1997) Use of a novel approach, termed island probing, identifies the Shigella flexneri she pathogenicity island which encodes a homolog of the immunoglobulin A protease-like family of proteins. Infect Immun 65(11):4606–4614PubMedCentralPubMedGoogle Scholar
  75. 75.
    Parham NJ et al (2004) PicU, a second serine protease autotransporter of uropathogenic Escherichia coli. FEMS Microbiol Lett 230(1):73–83PubMedGoogle Scholar
  76. 76.
    Heimer SR et al (2004) Autotransporter genes pic and tsh are associated with Escherichia coli strains that cause acute pyelonephritis and are expressed during urinary tract infection. Infect Immun 72(1):593–597PubMedCentralPubMedGoogle Scholar
  77. 77.
    Hull RA et al (1999) Virulence properties of Escherichia coli 83972, a prototype strain associated with asymptomatic bacteriuria. Infect Immun 67(1):429–432PubMedCentralPubMedGoogle Scholar
  78. 78.
    Stathopoulos C, Provence DL, Curtiss R 3rd (1999) Characterization of the avian pathogenic Escherichia coli hemagglutinin Tsh, a member of the immunoglobulin A protease-type family of autotransporters. Infect Immun 67(2):772–781PubMedCentralPubMedGoogle Scholar
  79. 79.
    Otto BR et al (1998) Characterization of a hemoglobin protease secreted by the pathogenic Escherichia coli strain EB1. J Exp Med 188(6):1091–1103PubMedCentralPubMedGoogle Scholar
  80. 80.
    Parreira VR, Gyles CL (2003) A novel pathogenicity island integrated adjacent to the thrW tRNA gene of avian pathogenic Escherichia coli encodes a vacuolating autotransporter toxin. Infect Immun 71(9):5087–5096PubMedCentralPubMedGoogle Scholar
  81. 81.
    Parham NJ et al (2005) Distribution of the serine protease autotransporters of the Enterobacteriaceae among extraintestinal clinical isolates of Escherichia coli. J Clin Microbiol 43(8):4076–4082PubMedCentralPubMedGoogle Scholar
  82. 82.
    Moriel DG et al (2010) Identification of protective and broadly conserved vaccine antigens from the genome of extraintestinal pathogenic Escherichia coli. Proc Natl Acad Sci USA 107(20):9072–9077PubMedGoogle Scholar
  83. 83.
    Fookes M et al (2011) Salmonella bongori provides insights into the evolution of the Salmonellae. PLoS Pathog 7(8):e1002191PubMedCentralPubMedGoogle Scholar
  84. 84.
    Avasthi TS et al (2011) Genome of multidrug-resistant uropathogenic Escherichia coli strain NA114 from India. J Bacteriol 193(16):4272–4273PubMedCentralPubMedGoogle Scholar
  85. 85.
    Sandt CH, Hill CW (2000) Four different genes responsible for nonimmune immunoglobulin-binding activities within a single strain of Escherichia coli. Infect Immun 68(4):2205–2214PubMedCentralPubMedGoogle Scholar
  86. 86.
    Toh H et al (2010) Complete genome sequence of the wild-type commensal Escherichia coli strain SE15, belonging to phylogenetic group B2. J Bacteriol 192(4):1165–1166PubMedCentralPubMedGoogle Scholar
  87. 87.
    Patel SK et al (2004) Identification and molecular characterization of EatA, an autotransporter protein of enterotoxigenic Escherichia coli. Infect Immun 72(3):1786–1794PubMedCentralPubMedGoogle Scholar
  88. 88.
    Schmidt H et al (2001) Identification and characterization of a novel genomic island integrated at selC in locus of enterocyte effacement-negative, Shiga toxin-producing Escherichia coli. Infect Immun 69(11):6863–6873PubMedCentralPubMedGoogle Scholar
  89. 89.
    Eslava C et al (1998) Pet, an autotransporter enterotoxin from enteroaggregative Escherichia coli. Infect Immun 66(7):3155–3163PubMedCentralPubMedGoogle Scholar
  90. 90.
    Al-Hasani K et al (2000) The sigA gene which is borne on the she pathogenicity island of Shigella flexneri 2a encodes an exported cytopathic protease involved in intestinal fluid accumulation. Infect Immun 68(5):2457–2463PubMedCentralPubMedGoogle Scholar
  91. 91.
    Guyer DM et al (2000) Identification of sat, an autotransporter toxin produced by uropathogenic Escherichia coli. Mol Microbiol 38(1):53–66PubMedGoogle Scholar
  92. 92.
    Brunder W, Schmidt H, Karch H (1997) EspP, a novel extracellular serine protease of enterohaemorrhagic Escherichia coli O157:H7 cleaves human coagulation factor V. Mol Microbiol 24(4):767–778PubMedGoogle Scholar
  93. 93.
    Djafari S et al (1997) Characterization of an exported protease from Shiga toxin-producing Escherichia coli. Mol Microbiol 25(4):771–784PubMedGoogle Scholar
  94. 94.
    Navarro-Garcia F et al (1999) Cytoskeletal effects induced by pet, the serine protease enterotoxin of enteroaggregative Escherichia coli. Infect Immun 67(5):2184–2192PubMedCentralPubMedGoogle Scholar
  95. 95.
    Mellies JL et al (2001) espC pathogenicity island of enteropathogenic Escherichia coli encodes an enterotoxin. Infect Immun 69(1):315–324PubMedCentralPubMedGoogle Scholar
  96. 96.
    Clarke DJ et al (2011) Complete genome sequence of the Crohn’s disease-associated adherent-invasive Escherichia coli strain HM605. J Bacteriol 193(17):4540PubMedCentralPubMedGoogle Scholar
  97. 97.
    Yen MR et al (2002) Protein-translocating outer membrane porins of Gram-negative bacteria. Biochim Biophys Acta 1562(1–2):6–31PubMedGoogle Scholar
  98. 98.
    Chaudhuri RR et al (2010) Complete genome sequence and comparative metabolic profiling of the prototypical enteroaggregative Escherichia coli strain 042. PLoS ONE 5(1):e8801PubMedCentralPubMedGoogle Scholar
  99. 99.
    Brockmeyer J et al (2007) Subtypes of the plasmid-encoded serine protease EspP in Shiga toxin-producing Escherichia coli: distribution, secretion, and proteolytic activity. Appl Environ Microbiol 73(20):6351–6359PubMedCentralPubMedGoogle Scholar
  100. 100.
    Davis J et al (2001) Evolution of an autotransporter: domain shuffling and lateral transfer from pathogenic Haemophilus to Neisseria. J Bacteriol 183(15):4626–4635PubMedCentralPubMedGoogle Scholar
  101. 101.
    Cote JP et al (2012) Identification and mechanism of evolution of new alleles coding for the AIDA-I autotransporter of porcine pathogenic Escherichia coli. Appl Environ Microbiol 78(13):4597–4605PubMedCentralPubMedGoogle Scholar
  102. 102.
    Navarro-Garcia F, Sonnested M, Teter K (2010) Host-toxin interactions involving EspC and Pet, two serine protease autotransporters of the Enterobacteriaceae. Toxins (Basel) 2(5):1134–1147Google Scholar
  103. 103.
    Taddei CR et al (2005) Secreted autotransporter toxin produced by a diffusely adhering Escherichia coli strain causes intestinal damage in animal model assays. FEMS Microbiol Lett 250(2):263–269PubMedGoogle Scholar
  104. 104.
    Gutierrez-Jimenez J, Arciniega I, Navarro-Garcia F (2008) The serine protease motif of Pic mediates a dose-dependent mucolytic activity after binding to sugar constituents of the mucin substrate. Microb Pathog 45(2):115–123PubMedGoogle Scholar
  105. 105.
    Khan AB et al (2009) Serine protease espP subtype alpha, but not beta or gamma, of Shiga toxin-producing Escherichia coli is associated with highly pathogenic serogroups. Int J Med Microbiol 299(4):247–254PubMedGoogle Scholar
  106. 106.
    Weiss A, Brockmeyer J (2013) Prevalence, biogenesis, and functionality of the serine protease autotransporter EspP. Toxins (Basel) 5(1):25–48Google Scholar
  107. 107.
    Tapia-Pastrana G et al (2012) VirK is a periplasmic protein required for efficient secretion of plasmid-encoded toxin from enteroaggregative Escherichia coli. Infect Immun 80(7):2276–2285PubMedCentralPubMedGoogle Scholar
  108. 108.
    Nemec KN et al (2010) A host-specific factor is necessary for efficient folding of the autotransporter plasmid-encoded toxin. Biochimie 92(2):171–177PubMedCentralPubMedGoogle Scholar
  109. 109.
    Orth D et al (2010) EspP, a serine protease of enterohemorrhagic Escherichia coli, impairs complement activation by cleaving complement factors C3/C3b and C5. Infect Immun 78(10):4294–4301PubMedCentralPubMedGoogle Scholar
  110. 110.
    van Diemen PM et al (2005) Identification of enterohemorrhagic Escherichia coli O26:H-genes required for intestinal colonization in calves. Infect Immun 73(3):1735–1743PubMedCentralPubMedGoogle Scholar
  111. 111.
    Puttamreddy S, Cornick NA, Minion FC (2010) Genome-wide transposon mutagenesis reveals a role for pO157 genes in biofilm development in Escherichia coli O157:H7 EDL933. Infect Immun 78(6):2377–2384PubMedCentralPubMedGoogle Scholar
  112. 112.
    Dziva F et al (2007) EspP, a Type V-secreted serine protease of enterohaemorrhagic Escherichia coli O157:H7, influences intestinal colonization of calves and adherence to bovine primary intestinal epithelial cells. FEMS Microbiol Lett 271(2):258–264PubMedGoogle Scholar
  113. 113.
    Sui BQ, Dutta PR, Nataro JP (2003) Intracellular expression of the plasmid-encoded toxin from enteroaggregative Escherichia coli. Infect Immun 71(9):5364–5370PubMedCentralPubMedGoogle Scholar
  114. 114.
    Villaseca JM et al (2000) Pet toxin from enteroaggregative Escherichia coli produces cellular damage associated with fodrin disruption. Infect Immun 68(10):5920–5927PubMedCentralPubMedGoogle Scholar
  115. 115.
    Cappello RE et al (2011) Effects of the plasmid-encoded toxin of enteroaggregative Escherichia coli on focal adhesion complexes. FEMS Immunol Med Microbiol 61(3):301–314PubMedCentralPubMedGoogle Scholar
  116. 116.
    Navarro-Garcia F et al (2007) Intoxication of epithelial cells by plasmid-encoded toxin requires clathrin-mediated endocytosis. Microbiology 153(Pt 9):2828–2838PubMedGoogle Scholar
  117. 117.
    Navarro-Garcia F et al (2007) Pet, a non-AB toxin, is transported and translocated into epithelial cells by a retrograde trafficking pathway. Infect Immun 75(5):2101–2109PubMedCentralPubMedGoogle Scholar
  118. 118.
    Vidal JE, Navarro-Garcia F (2008) EspC translocation into epithelial cells by enteropathogenic Escherichia coli requires a concerted participation of type V and III secretion systems. Cell Microbiol 10(10):1975–1986PubMedGoogle Scholar
  119. 119.
    Vidal JE, Navarro-Garcia F (2006) Efficient translocation of EspC into epithelial cells depends on enteropathogenic Escherichia coli and host cell contact. Infect Immun 74(4):2293–2303PubMedCentralPubMedGoogle Scholar
  120. 120.
    Drago-Serrano ME, Parra SG, Manjarrez-Hernandez HA (2006) EspC, an autotransporter protein secreted by enteropathogenic Escherichia coli (EPEC), displays protease activity on human hemoglobin. FEMS Microbiol Lett 265(1):35–40PubMedGoogle Scholar
  121. 121.
    Kenny B, Finlay BB (1995) Protein secretion by enteropathogenic Escherichia coli is essential for transducing signals to epithelial cells. Proc Natl Acad Sci USA 92(17):7991–7995PubMedGoogle Scholar
  122. 122.
    Mundy R et al (2005) Citrobacter rodentium of mice and man. Cell Microbiol 7(12):1697–1706PubMedGoogle Scholar
  123. 123.
    Al-Hasani K et al (2001) Genetic organization of the she pathogenicity island in Shigella flexneri 2a. Microb Pathog 30(1):1–8PubMedGoogle Scholar
  124. 124.
    Kotloff KL et al (1999) Global burden of Shigella infections: implications for vaccine development and implementation of control strategies. Bull World Health Organ 77(8):651–666PubMedCentralPubMedGoogle Scholar
  125. 125.
    Levine MM et al (2007) Clinical trials of Shigella vaccines: two steps forward and one step back on a long, hard road. Nat Rev Microbiol 5(7):540–553PubMedCentralPubMedGoogle Scholar
  126. 126.
    Ashida H et al (2011) Shigella are versatile mucosal pathogens that circumvent the host innate immune system. Curr Opin Immunol 23(4):448–455PubMedGoogle Scholar
  127. 127.
    Niyogi SK, Vargas M, Vila J (2004) Prevalence of the sat, set and sen genes among diverse serotypes of Shigella flexneri strains isolated from patients with acute diarrhoea. Clin Microbiol Infect 10(6):574–576PubMedGoogle Scholar
  128. 128.
    Wei J et al (2003) Complete genome sequence and comparative genomics of Shigella flexneri serotype 2a strain 2457T. Infect Immun 71(5):2775–2786PubMedCentralPubMedGoogle Scholar
  129. 129.
    Yang F et al (2005) Genome dynamics and diversity of Shigella species, the etiologic agents of bacillary dysentery. Nucleic Acids Res 33(19):6445–6458PubMedCentralPubMedGoogle Scholar
  130. 130.
    Guyer DM et al (2002) Sat, the secreted autotransporter toxin of uropathogenic Escherichia coli, is a vacuolating cytotoxin for bladder and kidney epithelial cells. Infect Immun 70(8):4539–4546PubMedCentralPubMedGoogle Scholar
  131. 131.
    Guignot J et al (2007) The secreted autotransporter toxin, Sat, functions as a virulence factor in Afa/Dr diffusely adhering Escherichia coli by promoting lesions in tight junction of polarized epithelial cells. Cell Microbiol 9(1):204–221PubMedGoogle Scholar
  132. 132.
    Lievin-Le Moal V et al (2011) Secreted autotransporter toxin (Sat) triggers autophagy in epithelial cells that relies on cell detachment. Cell Microbiol 13(7):992–1013PubMedGoogle Scholar
  133. 133.
    Yang Z, Klionsky DJ (2010) Mammalian autophagy: core molecular machinery and signaling regulation. Curr Opin Cell Biol 22(2):124–131PubMedCentralPubMedGoogle Scholar
  134. 134.
    Kostakioti M, Stathopoulos C (2004) Functional analysis of the Tsh autotransporter from an avian pathogenic Escherichia coli strain. Infect Immun 72(10):5548–5554PubMedCentralPubMedGoogle Scholar
  135. 135.
    Provence DL, Curtiss R 3rd (1994) Isolation and characterization of a gene involved in hemagglutination by an avian pathogenic Escherichia coli strain. Infect Immun 62(4):1369–1380PubMedCentralPubMedGoogle Scholar
  136. 136.
    Benjelloun-Touimi Z et al (1998) SepA, the 110 kDa protein secreted by Shigella flexneri: two-domain structure and proteolytic activity. Microbiology 144(Pt 7):1815–1822PubMedGoogle Scholar
  137. 137.
    Otto BR et al (2002) Escherichia coli hemoglobin protease autotransporter contributes to synergistic abscess formation and heme-dependent growth of Bacteroides fragilis. Infect Immun 70(1):5–10PubMedCentralPubMedGoogle Scholar
  138. 138.
    Dozois CM et al (2000) Relationship between the Tsh autotransporter and pathogenicity of avian Escherichia coli and localization and analysis of the Tsh genetic region. Infect Immun 68(7):4145–4154PubMedCentralPubMedGoogle Scholar
  139. 139.
    Restieri C et al (2007) Autotransporter-encoding sequences are phylogenetically distributed among Escherichia coli clinical isolates and reference strains. Appl Environ Microbiol 73(5):1553–1562PubMedCentralPubMedGoogle Scholar
  140. 140.
    Gomis SM et al (2001) Phenotypic and genotypic characterization of virulence factors of Escherichia coli isolated from broiler chickens with simultaneous occurrence of cellulitis and other colibacillosis lesions. Can J Vet Res 65(1):1–6PubMedCentralPubMedGoogle Scholar
  141. 141.
    Navarro-Garcia F et al (2010) Pic, an autotransporter protein secreted by different pathogens in the Enterobacteriaceae family, is a potent mucus secretagogue. Infect Immun 78(10):4101–4109PubMedCentralPubMedGoogle Scholar
  142. 142.
    Freeman GJ et al (2010) TIM genes: a family of cell surface phosphatidylserine receptors that regulate innate and adaptive immunity. Immunol Rev 235(1):172–189PubMedCentralPubMedGoogle Scholar
  143. 143.
    Carlow DA et al (2009) PSGL-1 function in immunity and steady state homeostasis. Immunol Rev 230(1):75–96PubMedGoogle Scholar
  144. 144.
    Naor D, Sionov RV, Ish-Shalom D (1997) CD44: structure, function, and association with the malignant process. Adv Cancer Res 71:241–319PubMedGoogle Scholar
  145. 145.
    Fukuda M, Tsuboi S (1999) Mucin-type O-glycans and leukosialin. Biochim Biophys Acta 1455(2–3):205–217PubMedGoogle Scholar
  146. 146.
    Rosenstein Y, Santana A, Pedraza-Alva G (1999) CD43, a molecule with multiple functions. Immunol Res 20(2):89–99PubMedGoogle Scholar
  147. 147.
    Chen SC et al (2004) Cross-linking of P-selectin glycoprotein ligand-1 induces death of activated T cells. Blood 104(10):3233–3242PubMedGoogle Scholar
  148. 148.
    Artus C et al (2006) CD44 ligation induces caspase-independent cell death via a novel calpain/AIF pathway in human erythroleukemia cells. Oncogene 25(42):5741–5751PubMedGoogle Scholar
  149. 149.
    Bazil V et al (1995) Apoptosis of human hematopoietic progenitor cells induced by crosslinking of surface CD43, the major sialoglycoprotein of leukocytes. Blood 86(2):502–511PubMedGoogle Scholar
  150. 150.
    Klaus SJ, Sidorenko SP, Clark EA (1996) CD45 ligation induces programmed cell death in T and B lymphocytes. J Immunol 156(8):2743–2753PubMedGoogle Scholar
  151. 151.
    Kum WW et al (2010) Impaired innate immune response and enhanced pathology during Citrobacter rodentium infection in mice lacking functional P-selectin. Cell Microbiol 12(9):1250–1271PubMedGoogle Scholar
  152. 152.
    Grassl GA et al (2010) CD34 mediates intestinal inflammation in Salmonella-infected mice. Cell Microbiol 12(11):1562–1575PubMedGoogle Scholar
  153. 153.
    Niess JH et al (2005) CX3CR1-mediated dendritic cell access to the intestinal lumen and bacterial clearance. Science 307(5707):254–258PubMedGoogle Scholar
  154. 154.
    Kum WW et al (2009) Lack of functional P-selectin ligand exacerbates Salmonella serovar typhimurium infection. J Immunol 182(10):6550–6561PubMedGoogle Scholar
  155. 155.
    Medina-Contreras O et al (2011) CX3CR1 regulates intestinal macrophage homeostasis, bacterial translocation, and colitogenic Th17 responses in mice. J Clin Invest 121(12):4787–4795PubMedCentralPubMedGoogle Scholar
  156. 156.
    Nataro JP (2011) Outbreak of hemolytic-uremic syndrome linked to Shiga toxin-producing enteroaggregative Escherichia coli O104:H4. Pediatr Res 70(3):221PubMedGoogle Scholar
  157. 157.
    Benjelloun-Touimi Z, Sansonetti PJ, Parsot C (1995) SepA, the major extracellular protein of Shigella flexneri: autonomous secretion and involvement in tissue invasion. Mol Microbiol 17(1):123–135PubMedGoogle Scholar
  158. 158.
    Boisen N et al (2012) Genomic characterization of enteroaggregative Escherichia coli from children in Mali. J Infect Dis 205(3):431–444PubMedGoogle Scholar
  159. 159.
    Coron E et al (2009) Characterisation of early mucosal and neuronal lesions following Shigella flexneri infection in human colon. PLoS ONE 4(3):e4713PubMedCentralPubMedGoogle Scholar
  160. 160.
    Roy K et al (2011) Adhesin degradation accelerates delivery of heat-labile toxin by enterotoxigenic Escherichia coli. J Biol Chem 286(34):29771–29779PubMedGoogle Scholar
  161. 161.
    O’Ryan M, Prado V, Pickering LK (2005) A millennium update on pediatric diarrheal illness in the developing world. Semin Pediatr Infect Dis 16(2):125–136PubMedGoogle Scholar
  162. 162.
    Kiefer F, et al (2009) The SWISS-MODEL Repository and associated resources. Nucleic Acids Res 37:D387–392Google Scholar
  163. 163.
    Petersen TN et al (2011) SignalP 4.0: discriminating signal peptides from transmembrane regions. Nat Methods 8(10):785–786PubMedGoogle Scholar
  164. 164.
    Sievers F et al (2011) Fast, scalable generation of high-quality protein multiple sequence alignments using Clustal Omega. Mol Syst Biol 7:539PubMedCentralPubMedGoogle Scholar
  165. 165.
    Dereeper A, et al (2008) Phylogeny.fr: robust phylogenetic analysis for the non-specialist. Nucleic Acids Res 36:W465–W469Google Scholar
  166. 166.
    Guindon S et al (2010) New algorithms and methods to estimate maximum-likelihood phylogenies: assessing the performance of PhyML 3.0. Syst Biol 59(3):307–321PubMedGoogle Scholar
  167. 167.
    Chevenet F et al (2006) TreeDyn: towards dynamic graphics and annotations for analyses of trees. BMC Bioinf 7:439Google Scholar

Copyright information

© Springer Basel 2013

Authors and Affiliations

  1. 1.Department of Pediatrics, School of MedicineUniversity of VirginiaCharlottesvilleUSA

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