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Type VII Secretion: A Highly Versatile Secretion System

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  • Authors: Louis S. Ates1, Edith N. G. Houben2, Wilbert Bitter3
  • Editor: Indira T. Kudva5
  • VIEW AFFILIATIONS HIDE AFFILIATIONS
    Affiliations: 1: Department of Medical Microbiology and Infection Control, VU University Medical Center, Amsterdam, The Netherlands; 2: Section Molecular Microbiology, Amsterdam Institute of Molecules, Medicine and Systems, Vrije Universiteit Amsterdam, 1081 BT Amsterdam, The Netherlands; 3: Department of Medical Microbiology and Infection Control, VU University Medical Center, Amsterdam, The Netherlands; 4: Section Molecular Microbiology, Amsterdam Institute of Molecules, Medicine and Systems, Vrije Universiteit Amsterdam, 1081 BT Amsterdam, The Netherlands; 5: National Animal Disease Center, Agricultural Research Service, U.S. Department of Agriculture, Ames, IA
  • Source: microbiolspec February 2016 vol. 4 no. 1 doi:10.1128/microbiolspec.VMBF-0011-2015
  • Received 13 January 2015 Accepted 24 August 2015 Published 26 February 2016
  • Wilbert Bitter, W.Bitter@Vumc.nl
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  • Abstract:

    Type VII secretion (T7S) systems of mycobacteria secrete substrates over the unusual diderm cell envelope. Furthermore, T7S gene clusters are present throughout the phylum , and functional T7S-like systems have been identified in . Most of the T7S substrates can be divided into two families: the Esx proteins, which are found in both and , and the PE and PPE proteins, which are more mycobacterium-specific. Members of both families have been shown to be secreted as folded heterodimers, suggesting that this is a conserved feature of T7S substrates. Most knowledge of the mechanism of T7S and the roles of T7S systems in virulence comes from studies of pathogenic mycobacteria. These bacteria can contain up to five T7S systems, called ESX-1 to ESX-5, each having its own role in bacterial physiology and virulence.

    In this article, we discuss the general composition of T7S systems and the role of the individual components in secretion. These conserved components include two membrane proteins with (predicted) enzymatic activities: a predicted ATPase (EccC), likely to be required for energy provision of T7S, and a subtilisin-like protease (MycP) involved in processing of specific substrates. Additionally, we describe the role of a conserved intracellular chaperone in T7S substrate recognition, based on recently published crystal structures and molecular analysis. Finally, we discuss system-specific features of the different T7S systems in mycobacteria and their role in pathogenesis and provide an overview of the role of T7S in virulence of other pathogenic bacteria.

  • Citation: Ates L, Houben E, Bitter W. 2016. Type VII Secretion: A Highly Versatile Secretion System. Microbiol Spectrum 4(1):VMBF-0011-2015. doi:10.1128/microbiolspec.VMBF-0011-2015.

References

1. Zuber B, Chami M, Houssin C, Dubochet J, Griffiths G, Daffé M. 2008. Direct visualization of the outer membrane of mycobacteria and corynebacteria in their native state. J Bacteriol 190:5672–5680. [PubMed][CrossRef]
2. Sani M, Houben ENG, Geurtsen J, Pierson J, de Punder K, van Zon M, Wever B, Piersma SR, Jiménez CR, Daffé M, Appelmelk BJ, Bitter W, van der Wel N, Peters PJ. 2010. Direct visualization by cryo-EM of the mycobacterial capsular layer: a labile structure containing ESX-1-secreted proteins. PLoS Pathog 6:e1000794. doi:10.1371/journal.ppat.1000794. [CrossRef]
3. Andersen P, Andersen AB, Sørensen AL, Nagai S. 1995. Recall of long-lived immunity to Mycobacterium tuberculosis infection in mice. J Immunol 154:3359–3372. [PubMed]
4. Bitter W, Houben ENG, Bottai D, Brodin P, Brown EJ, Cox JS, Derbyshire K, Fortune SM, Gao L-Y, Liu J, Gey van Pittius NC, Pym AS, Rubin EJ, Sherman DR, Cole ST, Brosch R. 2009. Systematic genetic nomenclature for type VII secretion systems. PLoS Pathog 5:e1000507. doi:10.1371/journal.ppat.1000507. [CrossRef]
5. Mahairas GG, Sabo PJ, Hickey MJ, Singh DC, Stover CK. 1996. Molecular analysis of genetic differences between Mycobacterium bovis BCG and virulent M. bovis. J Bacteriol 178:1274–1282. [PubMed]
6. Pym AS, Brodin P, Majlessi L, Brosch R, Demangel C, Williams A, Griffiths KE, Marchal G, Leclerc C, Cole ST. 2003. Recombinant BCG exporting ESAT-6 confers enhanced protection against tuberculosis. Nat Med 9:533–539. [PubMed][CrossRef]
7. Gey Van Pittius NC, Gamieldien J, Hide W, Brown GD, Siezen RJ, Beyers AD. 2001. The ESAT-6 gene cluster of Mycobacterium tuberculosis and other high G+C Gram-positive bacteria. Genome Biol 2:RESEARCH0044.
8. Ummels R, Abdallah AM, Kuiper V, Aâjoud A, Sparrius M, Naeem R, Spaink HP, van Soolingen D, Pain A, Bitter W. 2014. Identification of a novel conjugative plasmid in mycobacteria that requires both type IV and type VII secretion. MBio 5:e01744-14. doi:10.1128/mBio.01744-14. [PubMed][CrossRef]
9. Abdallah AM, Gey van Pittius NC, Champion PAD, Cox J, Luirink J, Vandenbroucke-Grauls CMJE, Appelmelk BJ, Bitter W. 2007. Type VII secretion: mycobacteria show the way. Nat Rev Microbiol 5:883–891. [PubMed][CrossRef]
10. Pallen MJ. 2002. The ESAT-6/WXG100 superfamily: and a new Gram-positive secretion system? Trends Microbiol 10:209–212. [PubMed][CrossRef]
11. Burts ML, Williams WA, DeBord K, Missiakas DM. 2005. EsxA and EsxB are secreted by an ESAT-6-like system that is required for the pathogenesis of Staphylococcus aureus infections. Proc Natl Acad Sci USA 102:1169–1174. [PubMed][CrossRef]
12. Huppert LA, Ramsdell TL, Chase MR, Sarracino DA, Fortune SM, Burton BM. 2014. The ESX system in Bacillus subtilis mediates protein secretion. PLoS One 9:e96267. doi:10.1371/journal.pone.0096267. [PubMed][CrossRef]
13. Daleke MH, Cascioferro A, de Punder K, Ummels R, Abdallah AM, van der Wel N, Peters PJ, Luirink J, Manganelli R, Bitter W. 2011. Conserved Pro-Glu (PE) and Pro-Pro-Glu (PPE) protein domains target LipY lipases of pathogenic mycobacteria to the cell surface via the ESX-5 pathway. J Biol Chem 286:19024–19034. [PubMed][CrossRef]
14. Abdallah AM, Verboom T, Weerdenburg EM, Gey van Pittius NC, Mahasha PW, Jiménez C, Parra M, Cadieux N, Brennan MJ, Appelmelk BJ, Bitter W. 2009. PPE and PE_PGRS proteins of Mycobacterium marinum are transported via the type VII secretion system ESX-5. Mol Microbiol 73:329–340. [PubMed][CrossRef]
15. Daleke MH, van der Woude AD, Parret AH, Ummels R, de Groot AM, Watson D, Piersma SR, Jiménez CR, Luirink J, Bitter W, Houben ENG. 2012. Specific chaperones for the type VII protein secretion pathway. J Biol Chem 287:31939–31947. [PubMed][CrossRef]
16. Ekiert DC, Cox JS. 2014. Structure of a PE-PPE-EspG complex from Mycobacterium tuberculosis reveals molecular specificity of ESX protein secretion. Proc Natl Acad Sci USA 111:14758–14763. [PubMed][CrossRef]
17. Korotkova N, Freire D, Phan TH, Ummels R, Creekmore CC, Evans TJ, Wilmanns M, Bitter W, Parret AHA, Houben ENG, Korotkov KV. 2014. Structure of the Mycobacterium tuberculosis type VII secretion system chaperone EspG5 in complex with PE25-PPE41 dimer. Mol Microbiol 94:367–382. [PubMed][CrossRef]
18. Solomonson M, Setiaputra D, Makepeace KAT, Lameignere E, Petrotchenko EV, Conrady DG, Bergeron JR, Vuckovic M, DiMaio F, Borchers CH, Yip CK, Strynadka NCJ. 2015. Structure of EspB from the ESX-1 type VII secretion system and insights into its export mechanism. Structure 23:571–583. [PubMed][CrossRef]
19. Wagner JM, Evans TJ, Korotkov KV. 2014. Crystal structure of the N-terminal domain of EccA5 ATPase from the ESX-1 secretion system of Mycobacterium tuberculosis. Proteins 82:159–163. [PubMed][CrossRef]
20. Luthra A, Mahmood A, Arora A, Ramachandran R. 2008. Characterization of Rv3868, an essential hypothetical protein of the ESX-1 secretion system in Mycobacterium tuberculosis. J Biol Chem 283:36532–36541. [PubMed][CrossRef]
21. Cerveny L, Straskova A, Dankova V, Hartlova A, Ceckova M, Staud F, Stulik J. 2013. Tetratricopeptide repeat motifs in the world of bacterial pathogens: role in virulence mechanisms. Infect Immun 81:629–635. [PubMed][CrossRef]
22. Bottai D, Di Luca M, Majlessi L, Frigui W, Simeone R, Sayes F, Bitter W, Brennan MJ, Leclerc C, Batoni G, Campa M, Brosch R, Esin S. 2012. Disruption of the ESX-5 system of Mycobacterium tuberculosis causes loss of PPE protein secretion, reduction of cell wall integrity and strong attenuation. Mol Microbiol 83:1195–1209. [PubMed][CrossRef]
23. Abdallah AM, Verboom T, Hannes F, Safi M, Strong M, Eisenberg D, Musters RJP, Vandenbroucke-Grauls CMJE, Appelmelk BJ, Luirink J, Bitter W. 2006. A specific secretion system mediates PPE41 transport in pathogenic mycobacteria. Mol Microbiol 62:667–679. [PubMed][CrossRef]
24. Gao L-Y, Guo S, McLaughlin B, Morisaki H, Engel JN, Brown EJ. 2004. A mycobacterial virulence gene cluster extending RD1 is required for cytolysis, bacterial spreading and ESAT-6 secretion. Mol Microbiol 53:1677–1693. [PubMed][CrossRef]
25. Joshi SA, Ball DA, Sun MG, Carlsson F, Watkins BY, Aggarwal N, McCracken JM, Huynh KK, Brown EJ. 2012. EccA1, a component of the Mycobacterium marinum ESX-1 protein virulence factor secretion pathway, regulates mycolic acid lipid synthesis. Chem Biol 19:372–380. [PubMed][CrossRef]
26. Sassetti CM, Boyd DH, Rubin EJ. 2003. Genes required for mycobacterial growth defined by high density mutagenesis. Mol Microbiol 48:77–84. [PubMed][CrossRef]
27. Houben ENG, Bestebroer J, Ummels R, Wilson L, Piersma SR, Jiménez CR, Ottenhoff THM, Luirink J, Bitter W. 2012. Composition of the type VII secretion system membrane complex. Mol Microbiol 86:472–484. [PubMed][CrossRef]
28. Converse SE, Cox JS. 2005. A protein secretion pathway critical for Mycobacterium tuberculosis virulence is conserved and functional in Mycobacterium smegmatis. J Bacteriol 187:1238–1245. [PubMed][CrossRef]
29. Brodin P, Majlessi L, Marsollier L, de Jonge MI, Bottai D, Demangel C, Hinds J, Neyrolles O, Butcher PD, Leclerc C, Cole ST, Brosch R. 2006. Dissection of ESAT-6 system 1 of Mycobacterium tuberculosis and impact on immunogenicity and virulence. Infect Immun 74:88–98. [PubMed][CrossRef]
30. Stanley SA, Raghavan S, Hwang WW, Cox JS. 2003. Acute infection and macrophage subversion by Mycobacterium tuberculosis require a specialized secretion system. Proc Natl Acad Sci USA 100:13001–13006. [PubMed][CrossRef]
31. Siegrist MS, Steigedal M, Ahmad R, Mehra A, Dragset MS, Schuster BM, Philips JA, Carr SA, Rubin EJ. 2014. Mycobacterial Esx-3 requires multiple components for iron acquisition. MBio 5:e01073-14. doi:10.1128/mBio.01073-14. [PubMed][CrossRef]
32. Niederweis M, Danilchanka O, Huff J, Hoffmann C, Engelhardt H. 2010. Mycobacterial outer membranes: in search of proteins. Trends Microbiol 18:109–116. [PubMed][CrossRef]
33. Chandran V, Fronzes R, Duquerroy S, Cronin N, Navaza J, Waksman G. 2009. Structure of the outer membrane complex of a type IV secretion system. Nature 462:1011–1015. [PubMed][CrossRef]
34. Rosenberger T, Brülle JK, Sander P. 2013. Correction: A β-lactamase based reporter system for ESX dependent protein translocation in mycobacteria. PLoS One 8. doi:10.1371/annotation/f03f7456-0e04-4c4b-a606-51f262900e8d. [CrossRef]
35. Burton B, Dubnau D. 2010. Membrane-associated DNA transport machines. Cold Spring Harbor Perspect Biol 2:a000406. [PubMed][CrossRef]
36. Atmakuri K, Cascales E, Christie PJ. 2004. Energetic components VirD4, VirB11 and VirB4 mediate early DNA transfer reactions required for bacterial type IV secretion. Mol Microbiol 54:1199–1211. [PubMed][CrossRef]
37. Champion PAD, Stanley SA, Champion MM, Brown EJ, Cox JS. 2006. C-terminal signal sequence promotes virulence factor secretion in Mycobacterium tuberculosis. Science 313:1632–1636. [PubMed][CrossRef]
38. Ramsdell TL, Huppert LA, Sysoeva TA, Fortune SM, Burton BM. 2014. Linked domain architectures allow for specialization of function in the FtsK/SpoIIIE ATPases of ESX secretion systems. J Mol Biol 427:1119–1132. [PubMed][CrossRef]
39. Ates LS, Ummels R, Commandeur S, van der Weerd R, Sparrius M, Weerdenburg E, Alber M, Kalscheuer R, Piersma SR, Abdallah AM, Abd El Ghany M, Abdel-Haleem AM, Pain A, Jiménez CR, Bitter W, Houben ENG. 2015. Essential role of the ESX-5 secretion system in outer membrane permeability of pathogenic mycobacteria. PLOS Genet 11:e1005190. doi:10.1371/journal.pgen.1005190. [CrossRef]
40. Rosenberg OS, Dovala D, Li X, Connolly L, Bendebury A, Finer-Moore J, Holton J, Cheng Y, Stroud RM, Cox JS. 2015. Substrates control multimerization and activation of the multi-domain ATPase motor of type VII secretion. Cell 161:501–512. [PubMed][CrossRef]
41. Brown GD, Dave JA, Gey van Pittius NC, Stevens L, Ehlers MR, Beyers AD. 2000. The mycosins of Mycobacterium tuberculosis H37Rv: a family of subtilisin-like serine proteases. Gene 254:147–155. [PubMed][CrossRef]
42. Dave JA, Gey van Pittius NC, Beyers AD, Ehlers MRW, Brown GD. 2002. Mycosin-1, a subtilisin-like serine protease of Mycobacterium tuberculosis, is cell wall-associated and expressed during infection of macrophages. BMC Microbiol 2:30. [PubMed][CrossRef]
43. Ohol YM, Goetz DH, Chan K, Shiloh MU, Craik CS, Cox JS. 2010. Mycobacterium tuberculosis MycP1 protease plays a dual role in regulation of ESX-1 secretion and virulence. Cell Host Microbe 7:210–220. [PubMed][CrossRef]
44. Solomonson M, Huesgen PF, Wasney GA, Watanabe N, Gruninger RJ, Prehna G, Overall CM, Strynadka NCJ. 2013. Structure of the mycosin-1 protease from the mycobacterial ESX-1 protein type VII secretion system. J Biol Chem 288:17782–17790. [PubMed][CrossRef]
45. Wagner JM, Evans TJ, Chen J, Zhu H, Houben ENG, Bitter W, Korotkov KV. 2013. Understanding specificity of the mycosin proteases in ESX/type VII secretion by structural and functional analysis. J Struct Biol 184:115–128. [PubMed][CrossRef]
46. Shinde U, Inouye M. 1995. Folding mediated by an intramolecular chaperone: autoprocessing pathway of the precursor resolved via a substrate assisted catalysis mechanism. J Mol Biol 247:390–395. [PubMed][CrossRef]
47. Finn RD, Bateman A, Clements J, Coggill P, Eberhardt RY, Eddy SR, Heger A, Hetherington K, Holm L, Mistry J, Sonnhammer ELL, Tate J, Punta M. 2014. Pfam: the protein families database. Nucleic Acids Res 42:D222–D230. [PubMed][CrossRef]
48. Garufi G, Butler E, Missiakas D. 2008. ESAT-6-like protein secretion in Bacillus anthracis. J Bacteriol 190:7004–7011. [PubMed][CrossRef]
49. Renshaw PS, Panagiotidou P, Whelan A, Gordon SV, Hewinson RG, Williamson RA, Carr MD. 2002. Conclusive evidence that the major T-cell antigens of the Mycobacterium tuberculosis complex ESAT-6 and CFP-10 form a tight, 1:1 complex and characterization of the structural properties of ESAT-6, CFP-10, and the ESAT-6*CFP-10 complex. Implications for pathogenesis and virulence. J Biol Chem 277:21598–21603. [PubMed][CrossRef]
50. Lightbody KL, Renshaw PS, Collins ML, Wright RL, Hunt DM, Gordon SV, Hewinson RG, Buxton RS, Williamson RA, Carr MD. 2004. Characterisation of complex formation between members of the Mycobacterium tuberculosis complex CFP-10/ESAT-6 protein family: towards an understanding of the rules governing complex formation and thereby functional flexibility. FEMS Microbiol Lett 238:255–262. [PubMed]
51. Berthet FX, Rasmussen PB, Rosenkrands I, Andersen P, Gicquel B. 1998. A Mycobacterium tuberculosis operon encoding ESAT-6 and a novel low-molecular-mass culture filtrate protein (CFP-10). Microbiology 144:3195–3203. [PubMed][CrossRef]
52. Shukla A, Pallen M, Anthony M, White SA. 2010. The homodimeric GBS1074 from Streptococcus agalactiae. Acta Crystallogr Sect F Struct Biol Cryst Commun 66:1421–1425. [PubMed][CrossRef]
53. Baptista C, Barreto HC, São-José C. 2013. High levels of DegU-P activate an Esat-6-like secretion system in Bacillus subtilis. PLoS One 8:e67840. doi:10.1371/journal.pone.0067840. [PubMed][CrossRef]
54. Poulsen C, Panjikar S, Holton SJ, Wilmanns M, Song Y-H. 2014. WXG100 protein superfamily consists of three subfamilies and exhibits an α-helical C-terminal conserved residue pattern. PLoS One 9:e89313. doi:10.1371/journal.pone.0089313. [CrossRef]
55. Renshaw PS, Lightbody KL, Veverka V, Muskett FW, Kelly G, Frenkiel TA, Gordon SV, Hewinson RG, Burke B, Norman J, Williamson RA, Carr MD. 2005. Structure and function of the complex formed by the tuberculosis virulence factors CFP-10 and ESAT-6. EMBO J 24:2491–2498. [PubMed][CrossRef]
56. Ilghari D, Lightbody KL, Veverka V, Waters LC, Muskett FW, Renshaw PS, Carr MD. 2011. Solution structure of the Mycobacterium tuberculosis EsxG·EsxH complex: functional implications and comparisons with other M. tuberculosis Esx family complexes. J Biol Chem 286:29993–30002. [PubMed][CrossRef]
57. Arbing MA, Kaufmann M, Phan T, Chan S, Cascio D, Eisenberg D. 2010. The crystal structure of the Mycobacterium tuberculosis Rv3019c-Rv3020c ESX complex reveals a domain-swapped heterotetramer. Protein Sci 19:1692–1703. [PubMed][CrossRef]
58. Gey van Pittius NC, Sampson SL, Lee H, Kim Y, van Helden PD, Warren RM. 2006. Evolution and expansion of the Mycobacterium tuberculosis PE and PPE multigene families and their association with the duplication of the ESAT-6 (esx) gene cluster regions. BMC Evol Biol 6:95. [PubMed][CrossRef]
59. Strong M, Sawaya MR, Wang S, Phillips M, Cascio D, Eisenberg D. 2006. Toward the structural genomics of complexes: crystal structure of a PE/PPE protein complex from Mycobacterium tuberculosis. Proc Natl Acad Sci USA 103:8060–8065. [PubMed][CrossRef]
60. Daleke MH, Ummels R, Bawono P, Heringa J, Vandenbroucke-Grauls CMJE, Luirink J, Bitter W. 2012. General secretion signal for the mycobacterial type VII secretion pathway. Proc Natl Acad Sci USA 109:11342–11347. [PubMed][CrossRef]
61. Kelley LA, Sternberg MJE. 2009. Protein structure prediction on the Web: a case study using the Phyre server. Nat Protoc 4:363–371. [PubMed][CrossRef]
62. Zhang D, Iyer LM, Aravind L. 2011. A novel immunity system for bacterial nucleic acid degrading toxins and its recruitment in various eukaryotic and DNA viral systems. Nucleic Acids Res 39:4532–4552. [PubMed][CrossRef]
63. Anderson M, Aly KA, Chen Y-H, Missiakas D. 2013. Secretion of atypical protein subtrates by the ESAT-6 secretion system of Staphylococcus aureus. Mol Microbiol 90:734–743. [PubMed][CrossRef]
64. Philipp WJ, Nair S, Guglielmi G, Lagranderie M, Gicquel B, Cole ST. 1996. Physical mapping of Mycobacterium bovis BCG pasteur reveals differences from the genome map of Mycobacterium tuberculosis H37Rv and from M. bovis. Microbiology 142:3135–3145. [PubMed][CrossRef]
65. Pym AS, Brodin P, Brosch R, Huerre M, Cole ST. 2002. Loss of RD1 contributed to the attenuation of the live tuberculosis vaccines Mycobacterium bovis BCG and Mycobacterium microti. Mol Microbiol 46:709–717. [PubMed][CrossRef]
66. Hsu T, Hingley-Wilson SM, Chen B, Chen M, Dai AZ, Morin PM, Marks CB, Padiyar J, Goulding C, Gingery M, Eisenberg D, Russell RG, Derrick SC, Collins FM, Morris SL, King CH, Jacobs WR. 2003. The primary mechanism of attenuation of bacillus Calmette-Guerin is a loss of secreted lytic function required for invasion of lung interstitial tissue. Proc Natl Acad Sci USA 100:12420–12425. [PubMed][CrossRef]
67. Lewis KN, Liao R, Guinn KM, Hickey MJ, Smith S, Behr MA, Sherman DR. 2003. Deletion of RD1 from Mycobacterium tuberculosis mimics bacille Calmette-Guérin attenuation. J Infect Dis 187:117–123. [PubMed][CrossRef]
68. Fortune SM, Jaeger A, Sarracino DA, Chase MR, Sassetti CM, Sherman DR, Bloom BR, Rubin EJ. 2005. Mutually dependent secretion of proteins required for mycobacterial virulence. Proc Natl Acad Sci USA 102:10676–10681. [PubMed][CrossRef]
69. Pang X, Samten B, Cao G, Wang X, Tvinnereim AR, Chen X-L, Howard ST. 2013. MprAB regulates the espA operon in Mycobacterium tuberculosis and modulates ESX-1 function and host cytokine response. J Bacteriol 195:66–75. [PubMed][CrossRef]
70. Hunt DM, Sweeney NP, Mori L, Whalan RH, Comas I, Norman L, Cortes T, Arnvig KB, Davis EO, Stapleton MR, Green J, Buxton RS. 2012. Long-range transcriptional control of an operon necessary for virulence-critical ESX-1 secretion in Mycobacterium tuberculosis. J Bacteriol 194:2307–2320. [CrossRef]
71. Garces A, Atmakuri K, Chase MR, Woodworth JS, Krastins B, Rothchild AC, Ramsdell TL, Lopez MF, Behar SM, Sarracino DA, Fortune SM. 2010. EspA acts as a critical mediator of ESX1-dependent virulence in Mycobacterium tuberculosis by affecting bacterial cell wall integrity. PLoS Pathog 6:e1000957. doi:10.1371/journal.ppat.1000957. [CrossRef]
72. Van der Wel N, Hava D, Houben D, Fluitsma D, van Zon M, Pierson J, Brenner M, Peters PJ. 2007. M. tuberculosis and M. leprae translocate from the phagolysosome to the cytosol in myeloid cells. Cell 129:1287–1298. [PubMed][CrossRef]
73. Simeone R, Bobard A, Lippmann J, Bitter W, Majlessi L, Brosch R, Enninga J. 2012. Phagosomal rupture by Mycobacterium tuberculosis results in toxicity and host cell death. PLoS Pathog 8:e1002507. doi:10.1371/journal.ppat.1002507. [PubMed][CrossRef]
74. Houben D, Demangel C, van Ingen J, Perez J, Baldeón L, Abdallah AM, Caleechurn L, Bottai D, van Zon M, de Punder K, van der Laan T, Kant A, Bossers-de Vries R, Willemsen P, Bitter W, van Soolingen D, Brosch R, van der Wel N, Peters PJ. 2012. ESX-1-mediated translocation to the cytosol controls virulence of mycobacteria. Cell Microbiol 14:1287–1298. [PubMed][CrossRef]
75. Koo IC, Wang C, Raghavan S, Morisaki JH, Cox JS, Brown EJ. 2008. ESX-1-dependent cytolysis in lysosome secretion and inflammasome activation during mycobacterial infection. Cell Microbiol 10:1866–1878. [PubMed][CrossRef]
76. Smith J, Manoranjan J, Pan M, Bohsali A, Xu J, Liu J, McDonald KL, Szyk A, LaRonde-LeBlanc N, Gao L-Y. 2008. Evidence for pore formation in host cell membranes by ESX-1-secreted ESAT-6 and its role in Mycobacterium marinum escape from the vacuole. Infect Immun 76:5478–5487. [PubMed][CrossRef]
77. De Jonge MI, Pehau-Arnaudet G, Fretz MM, Romain F, Bottai D, Brodin P, Honoré N, Marchal G, Jiskoot W, England P, Cole ST, Brosch R. 2007. ESAT-6 from Mycobacterium tuberculosis dissociates from its putative chaperone CFP-10 under acidic conditions and exhibits membrane-lysing activity. J Bacteriol 189:6028–6034. [PubMed][CrossRef]
78. Flint JL, Kowalski JC, Karnati PK, Derbyshire KM. 2004. The RD1 virulence locus of Mycobacterium tuberculosis regulates DNA transfer in Mycobacterium smegmatis. Proc Natl Acad Sci USA 101:12598–12603. [PubMed][CrossRef]
79. Kennedy GM, Hooley GC, Champion MM, Mba Medie F, Champion PAD. 2014. A novel ESX-1 locus reveals that surface-associated ESX-1 substrates mediate virulence in Mycobacterium marinum. J Bacteriol 196:1877–1888. [PubMed][CrossRef]
80. Wirth SE, Krywy JA, Aldridge BB, Fortune SM, Fernandez-Suarez M, Gray TA, Derbyshire KM. 2012. Polar assembly and scaffolding proteins of the virulence-associated ESX-1 secretory apparatus in mycobacteria. Mol Microbiol 83:654–664. [PubMed][CrossRef]
81. Carlsson F, Joshi SA, Rangell L, Brown EJ. 2009. Polar localization of virulence-related Esx-1 secretion in mycobacteria. PLoS Pathog 5:e1000285. doi:10.1371/journal.ppat.1000285. [PubMed][CrossRef]
82. Abramovitch RB, Rohde KH, Hsu F-F, Russell DG. 2011. aprABC: a Mycobacterium tuberculosis complex-specific locus that modulates pH-driven adaptation to the macrophage phagosome. Mol Microbiol 80:678–694. [PubMed][CrossRef]
83. Tan S, Sukumar N, Abramovitch RB, Parish T, Russell DG. 2013. Mycobacterium tuberculosis responds to chloride and pH as synergistic cues to the immune status of its host cell. PLoS Pathog 9:e1003282. doi:10.1371/journal.ppat.1003282. [PubMed][CrossRef]
84. Lee JS, Krause R, Schreiber J, Mollenkopf H-J, Kowall J, Stein R, Jeon B-Y, Kwak J-Y, Song M-K, Patron JP, Jorg S, Roh K, Cho S-N, Kaufmann SHE. 2008. Mutation in the transcriptional regulator PhoP contributes to avirulence of Mycobacterium tuberculosis H37Ra strain. Cell Host Microbe 3:97–103. [PubMed][CrossRef]
85. Frigui W, Bottai D, Majlessi L, Monot M, Josselin E, Brodin P, Garnier T, Gicquel B, Martin C, Leclerc C, Cole ST, Brosch R. 2008. Control of M. tuberculosis ESAT-6 secretion and specific T cell recognition by PhoP. PLoS Pathog 4:e33. doi:10.1371/journal.ppat.0040033. [PubMed][CrossRef]
86. Solans L, Aguiló N, Samper S, Pawlik A, Frigui W, Martín C, Brosch R, Gonzalo-Asensio J. 2014. A specific polymorphism in Mycobacterium tuberculosis H37Rv causes differential ESAT-6 expression and identifies WhiB6 as a novel ESX-1 component. Infect Immun 82:3446–3456. [PubMed][CrossRef]
87. Raghavan S, Manzanillo P, Chan K, Dovey C, Cox JS. 2008. Secreted transcription factor controls Mycobacterium tuberculosis virulence. Nature 454:717–721. [PubMed][CrossRef]
88. Blasco B, Chen JM, Hartkoorn R, Sala C, Uplekar S, Rougemont J, Pojer F, Cole ST. 2012. Virulence regulator EspR of Mycobacterium tuberculosis is a nucleoid-associated protein. PLoS Pathog 8:e1002621. doi:10.1371/journal.ppat.1002621. [PubMed][CrossRef]
89. Rosenberg OS, Dovey C, Tempesta M, Robbins RA, Finer-Moore JS, Stroud RM, Cox JS. 2011. EspR, a key regulator of Mycobacterium tuberculosis virulence, adopts a unique dimeric structure among helix-turn-helix proteins. Proc Natl Acad Sci USA 108:13450–13455. [PubMed][CrossRef]
90. Gordon BRG, Li Y, Wang L, Sintsova A, van Bakel H, Tian S, Navarre WW, Xia B, Liu J. 2010. Lsr2 is a nucleoid-associated protein that targets AT-rich sequences and virulence genes in Mycobacterium tuberculosis. Proc Natl Acad Sci USA 107:5154–5159. [PubMed][CrossRef]
91. Gonzalo-Asensio J, Malaga W, Pawlik A, Astarie-Dequeker C, Passemar C, Moreau F, Laval F, Daffé M, Martin C, Brosch R, Guilhot C. 2014. Evolutionary history of tuberculosis shaped by conserved mutations in the PhoPR virulence regulator. Proc Natl Acad Sci USA 111:11491–11496. [PubMed][CrossRef]
92. Derbyshire KM, Gray TA. 2014. Distributive conjugal transfer: new insights into horizontal gene transfer and genetic exchange in mycobacteria. Microbiol Spectrum 2(1). doi:10.1128/microbiolspec.MGM2-0022-2013. [CrossRef]
93. Coros A, Callahan B, Battaglioli E, Derbyshire KM. 2008. The specialized secretory apparatus ESX-1 is essential for DNA transfer in Mycobacterium smegmatis. Mol Microbiol 69:794–808. [PubMed]
94. Gray TA, Krywy JA, Harold J, Palumbo MJ, Derbyshire KM. 2013. Distributive conjugal transfer in mycobacteria generates progeny with meiotic-like genome-wide mosaicism, allowing mapping of a mating identity locus. PLoS Biol 11:e1001602. doi:10.1371/journal.pbio.1001602. [CrossRef]
95. Gutierrez MC, Brisse S, Brosch R, Fabre M, Omaïs B, Marmiesse M, Supply P, Vincent V. 2005. Ancient origin and gene mosaicism of the progenitor of Mycobacterium tuberculosis. PLoS Pathog 1:e5. doi:10.1371/journal.ppat.0010005. [CrossRef]
96. Griffin JE, Gawronski JD, Dejesus MA, Ioerger TR, Akerley BJ, Sassetti CM. 2011. High-resolution phenotypic profiling defines genes essential for mycobacterial growth and cholesterol catabolism. PLoS Pathog 7:e1002251. doi:10.1371/journal.ppat.1002251. [CrossRef]
97. Rodriguez GM, Voskuil MI, Gold B, Schoolnik GK, Smith I. 2002. ideR, an essential gene in Mycobacterium tuberculosis: role of IdeR in iron-dependent gene expression, iron metabolism, and oxidative stress response. Infect Immun 70:3371–3381. [PubMed][CrossRef]
98. Maciag A, Dainese E, Rodriguez GM, Milano A, Provvedi R, Pasca MR, Smith I, Palù G, Riccardi G, Manganelli R. 2007. Global analysis of the Mycobacterium tuberculosis Zur (FurB) regulon. J Bacteriol 189:730–740. [PubMed][CrossRef]
99. Siegrist MS, Unnikrishnan M, McConnell MJ, Borowsky M, Cheng T-Y, Siddiqi N, Fortune SM, Moody DB, Rubin EJ. 2009. Mycobacterial Esx-3 is required for mycobactin-mediated iron acquisition. Proc Natl Acad Sci USA 106:18792–18797. [PubMed][CrossRef]
100. Serafini A, Boldrin F, Palù G, Manganelli R. 2009. Characterization of a Mycobacterium tuberculosis ESX-3 conditional mutant: essentiality and rescue by iron and zinc. J Bacteriol 191:6340–6344. [PubMed][CrossRef]
101. Cole ST, Brosch R, Parkhill J, Garnier T, Churcher C, Harris D, Gordon SV, Eiglmeier K, Gas S, Barry CE, Tekaia F, Badcock K, Basham D, Brown D, Chillingworth T, Connor R, Davies R, Devlin K, Feltwell T, Gentles S, Hamlin N, Holroyd S, Hornsby T, Jagels K, Krogh A, McLean J, Moule S, Murphy L, Oliver K, Osborne J, Quail MA, Rajandream MA, Rogers J, Rutter S, Seeger K, Skelton J, Squares R, Squares S, Sulston JE, Taylor K, Whitehead S, Barrell BG. 1998. Deciphering the biology of Mycobacterium tuberculosis from the complete genome sequence. Nature 393:537–544. [PubMed][CrossRef]
102. Mishra KC, de Chastellier C, Narayana Y, Bifani P, Brown AK, Besra GS, Katoch VM, Joshi B, Balaji KN, Kremer L. 2008. Functional role of the PE domain and immunogenicity of the Mycobacterium tuberculosis triacylglycerol hydrolase LipY. Infect Immun 76:127–140. [PubMed][CrossRef]
103. Sampson SL. 2011. Mycobacterial PE/PPE proteins at the host-pathogen interface. Clin Dev Immunol 2011:497203. [PubMed][CrossRef]
104. Di Luca M, Bottai D, Batoni G, Orgeur M, Aulicino A, Counoupas C, Campa M, Brosch R, Esin S. 2012. The ESX-5 associated eccB-EccC locus is essential for Mycobacterium tuberculosis viability. PLoS One 7:e52059. doi:10.1371/journal.pone.0052059. [CrossRef]
105. Lamrabet O, Ghigo E, Mège J-L, Lepidi H, Nappez C, Raoult D, Drancourt M. 2014. MspA-Mycobacterium tuberculosis-transformant with reduced virulence: the “unbirthday paradigm.” Microb Pathog 76:10–18. [PubMed][CrossRef]
106. Abdallah AM, Bestebroer J, Savage NDL, de Punder K, van Zon M, Wilson L, Korbee CJ, van der Sar AM, Ottenhoff THM, van der Wel NN, Bitter W, Peters PJ. 2011. Mycobacterial secretion systems ESX-1 and ESX-5 play distinct roles in host cell death and inflammasome activation. J Immunol 187:4744–4753. [PubMed][CrossRef]
107. Weerdenburg EM, Abdallah AM, Mitra S, de Punder K, van der Wel NN, Bird S, Appelmelk BJ, Bitter W, van der Sar AM. 2012. ESX-5-deficient Mycobacterium marinum is hypervirulent in adult zebrafish. Cell Microbiol 14:728–739. [PubMed][CrossRef]
108. Daniel J, Maamar H, Deb C, Sirakova TD, Kolattukudy PE. 2011. Mycobacterium tuberculosis uses host triacylglycerol to accumulate lipid droplets and acquires a dormancy-like phenotype in lipid-loaded macrophages. PLoS Pathog 7:e1002093. doi:10.1371/journal.ppat.1002093. [PubMed][CrossRef]
109. Deb C, Daniel J, Sirakova TD, Abomoelak B, Dubey VS, Kolattukudy PE. 2006. A novel lipase belonging to the hormone-sensitive lipase family induced under starvation to utilize stored triacylglycerol in Mycobacterium tuberculosis. J Biol Chem 281:3866–3875. [PubMed][CrossRef]
110. Singh VK, Srivastava V, Singh V, Rastogi N, Roy R, Shaw AK, Dwivedi AK, Srivastava R, Srivastava BS. 2011. Overexpression of Rv3097c in Mycobacterium bovis BCG abolished the efficacy of BCG vaccine to protect against Mycobacterium tuberculosis infection in mice. Vaccine 29:4754–4760. [PubMed][CrossRef]
111. Singh VK, Srivastava M, Dasgupta A, Singh MP, Srivastava R, Srivastava BS. 2014. Increased virulence of Mycobacterium tuberculosis H37Rv overexpressing LipY in a murine model. Tuberculosis (Edinb) 94:252–261. [PubMed][CrossRef]
112. Espitia C, Laclette JP, Mondragón-Palomino M, Amador A, Campuzano J, Martens A, Singh M, Cicero R, Zhang Y, Moreno C. 1999. The PE-PGRS glycine-rich proteins of Mycobacterium tuberculosis: a new family of fibronectin-binding proteins? Microbiology 145:3487–3495. [PubMed][CrossRef]
113. Campuzano J, Aguilar D, Arriaga K, León JC, Salas-Rangel LP, González-y-Merchand J, Hernández-Pando R, Espitia C. 2007. The PGRS domain of Mycobacterium tuberculosis PE_PGRS Rv1759c antigen is an efficient subunit vaccine to prevent reactivation in a murine model of chronic tuberculosis. Vaccine 25:3722–3729. [PubMed][CrossRef]
114. Koh KW, Lehming N, Seah GT. 2009. Degradation-resistant protein domains limit host cell processing and immune detection of mycobacteria. Mol Immunol 46:1312–1318. [PubMed][CrossRef]
115. Brennan MJ, Delogu G. 2002. The PE multigene family: a “molecular mantra” for mycobacteria. Trends Microbiol 10:246–249. [PubMed][CrossRef]
116. Levitskaya J, Coram M, Levitsky V, Imreh S, Steigerwald-Mullen PM, Klein G, Kurilla MG, Masucci MG. 1995. Inhibition of antigen processing by the internal repeat region of the Epstein-Barr virus nuclear antigen-1. Nature 375:685–688. [PubMed][CrossRef]
117. Tellam J, Smith C, Rist M, Webb N, Cooper L, Vuocolo T, Connolly G, Tscharke DC, Devoy MP, Khanna R. 2008. Regulation of protein translation through mRNA structure influences MHC class I loading and T cell recognition. Proc Natl Acad Sci USA 105:9319–9324. [PubMed][CrossRef]
118. Tellam JT, Lekieffre L, Zhong J, Lynn DJ, Khanna R. 2012. Messenger RNA sequence rather than protein sequence determines the level of self-synthesis and antigen presentation of the EBV-encoded antigen, EBNA1. PLoS Pathog 8:e1003112. doi:10.1371/journal.ppat.1003112. [PubMed][CrossRef]
119. Banu S, Honoré N, Saint-Joanis B, Philpott D, Prévost M-C, Cole ST. 2002. Are the PE-PGRS proteins of Mycobacterium tuberculosis variable surface antigens? Mol Microbiol 44:9–19. [PubMed][CrossRef]
120. Vordermeier HM, Hewinson RG, Wilkinson RJ, Wilkinson KA, Gideon HP, Young DB, Sampson SL. 2012. Conserved immune recognition hierarchy of mycobacterial PE/PPE proteins during infection in natural hosts. PLoS One 7:e40890. doi:10.1371/journal.pone.0040890. [CrossRef]
121. Copin R, Coscollá M, Seiffert SN, Bothamley G, Sutherland J, Mbayo G, Gagneux S, Ernst JD. 2014. Sequence diversity in the pe_pgrs genes of Mycobacterium tuberculosis is independent of human T cell recognition. MBio 5:e00960-13. doi:10.1128/mBio.00960-13. [PubMed][CrossRef]
122. McEvoy CRE, Cloete R, Müller B, Schürch AC, van Helden PD, Gagneux S, Warren RM, Gey van Pittius NC. 2012. Comparative analysis of Mycobacterium tuberculosis pe and ppe genes reveals high sequence variation and an apparent absence of selective constraints. PLoS One 7:e30593. doi:10.1371/journal.pone.0030593. [CrossRef]
123. Talarico S, Cave MD, Foxman B, Marrs CF, Zhang L, Bates JH, Yang Z. 2007. Association of Mycobacterium tuberculosis PE PGRS33 polymorphism with clinical and epidemiological characteristics. Tuberculosis (Edinb) 87:338–346. [PubMed][CrossRef]
124. Cascioferro A, Daleke MH, Ventura M, Donà V, Delogu G, Palù G, Bitter W, Manganelli R. 2011. Functional dissection of the PE domain responsible for translocation of PE_PGRS33 across the mycobacterial cell wall. PLoS One 6:e27713. doi:10.1371/journal.pone.0027713. [PubMed][CrossRef]
125. Delogu G, Pusceddu C, Bua A, Fadda G, Brennan MJ, Zanetti S. 2004. Rv1818c-encoded PE_PGRS protein of Mycobacterium tuberculosis is surface exposed and influences bacterial cell structure. Mol Microbiol 52:725–733. [PubMed][CrossRef]
126. Cadieux N, Parra M, Cohen H, Maric D, Morris SL, Brennan MJ. 2011. Induction of cell death after localization to the host cell mitochondria by the Mycobacterium tuberculosis PE_PGRS33 protein. Microbiology 157:793–804. [PubMed][CrossRef]
127. Basu S, Pathak SK, Banerjee A, Pathak S, Bhattacharyya A, Yang Z, Talarico S, Kundu M, Basu J. 2007. Execution of macrophage apoptosis by PE_PGRS33 of Mycobacterium tuberculosis is mediated by Toll-like receptor 2-dependent release of tumor necrosis factor-alpha. J Biol Chem 282:1039–1050. [PubMed][CrossRef]
128. Houben ENG, Korotkov KV, Bitter W. 2013. Take five: type VII secretion systems of mycobacteria. Biochim Biophys Acta 1843:1707–1716. [PubMed][CrossRef]
129. Akpe San Roman S, Facey PD, Fernandez-Martinez L, Rodriguez C, Vallin C, Del Sol R, Dyson P. 2010. A heterodimer of EsxA and EsxB is involved in sporulation and is secreted by a type VII secretion system in Streptomyces coelicolor. Microbiology 156:1719–1729. [PubMed][CrossRef]
130. Fyans JK, Bignell D, Loria R, Toth I, Palmer T. 2013. The ESX/type VII secretion system modulates development, but not virulence, of the plant pathogen Streptomyces scabies. Mol Plant Pathol 14:119–130. [PubMed][CrossRef]
131. São-José C, Baptista C, Santos MA. 2004. Bacillus subtilis operon encoding a membrane receptor for bacteriophage SPP1. J Bacteriol 186:8337–8346. [PubMed][CrossRef]
132. Van den Ent F, Löwe J. 2005. Crystal structure of the ubiquitin-like protein YukD from Bacillus subtilis. FEBS Lett 579:3837–3841. [PubMed][CrossRef]
133. Burts ML, DeDent AC, Missiakas DM. 2008. EsaC substrate for the ESAT-6 secretion pathway and its role in persistent infections of Staphylococcus aureus. Mol Microbiol 69:736–746. [PubMed][CrossRef]
134. Anderson M, Chen Y-H, Butler EK, Missiakas DM. 2011. EsaD, a secretion factor for the Ess pathway in Staphylococcus aureus. J Bacteriol 193:1583–1589. [PubMed][CrossRef]
135. Kneuper H, Cao ZP, Twomey KB, Zoltner M, Jäger F, Cargill JS, Chalmers J, van der Kooi-Pol MM, van Dijl JM, Ryan RP, Hunter WN, Palmer T. 2014. Heterogeneity in ess transcriptional organization and variable contribution of the Ess/type VII protein secretion system to virulence across closely related Staphylocccus aureus strains. Mol Microbiol 93:928–943. [PubMed][CrossRef]
136. Schulthess B, Bloes DA, Berger-Bächi B. 2012. Opposing roles of σB and σB-controlled SpoVG in the global regulation of esxA in Staphylococcus aureus. BMC Microbiol 12:17. [PubMed][CrossRef]
137. Korea CG, Balsamo G, Pezzicoli A, Merakou C, Tavarini S, Bagnoli F, Serruto D, Unnikrishnan M. 2014. Staphylococcal Esx proteins modulate apoptosis and release of intracellular Staphylococcus aureus during infection in epithelial cells. Infect Immun 82:4144–4153. [PubMed][CrossRef]
138. Rybniker J, Chen JM, Sala C, Hartkoorn RC, Vocat A, Benjak A, Boy-Röttger S, Zhang M, Székely R, Greff Z, Orfi L, Szabadkai I, Pató J, Kéri G, Cole ST. 2014. Anticytolytic screen identifies inhibitors of mycobacterial virulence protein secretion. Cell Host Microbe 16:538–548. [PubMed][CrossRef]
139. Sundaramoorthy R, Fyfe PK, Hunter WN. 2008. Structure of Staphylococcus aureus EsxA suggests a contribution to virulence by action as a transport chaperone and/or adaptor protein. J Mol Biol 383:603–614. [PubMed][CrossRef]
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/content/journal/microbiolspec/10.1128/microbiolspec.VMBF-0011-2015
2016-02-26
2017-07-27

Abstract:

Type VII secretion (T7S) systems of mycobacteria secrete substrates over the unusual diderm cell envelope. Furthermore, T7S gene clusters are present throughout the phylum , and functional T7S-like systems have been identified in . Most of the T7S substrates can be divided into two families: the Esx proteins, which are found in both and , and the PE and PPE proteins, which are more mycobacterium-specific. Members of both families have been shown to be secreted as folded heterodimers, suggesting that this is a conserved feature of T7S substrates. Most knowledge of the mechanism of T7S and the roles of T7S systems in virulence comes from studies of pathogenic mycobacteria. These bacteria can contain up to five T7S systems, called ESX-1 to ESX-5, each having its own role in bacterial physiology and virulence.

In this article, we discuss the general composition of T7S systems and the role of the individual components in secretion. These conserved components include two membrane proteins with (predicted) enzymatic activities: a predicted ATPase (EccC), likely to be required for energy provision of T7S, and a subtilisin-like protease (MycP) involved in processing of specific substrates. Additionally, we describe the role of a conserved intracellular chaperone in T7S substrate recognition, based on recently published crystal structures and molecular analysis. Finally, we discuss system-specific features of the different T7S systems in mycobacteria and their role in pathogenesis and provide an overview of the role of T7S in virulence of other pathogenic bacteria.

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Figures

Image of FIGURE 1
FIGURE 1

Genetic loci of different T7S (and T7S-like) systems. Depicted are the T7S loci, , , and of H37Rv ( 101 ), as well the T7S-like systems of (strain USA300, annotation based on Anderson et al. [ 63 ]) and subsp. (strain 168, annotation based on Huppert et al. [ 12 ]). Color coding represents conserved T7S membrane components (dark blue), (putative) substrates of the systems (green), cytosolic chaperones (yellow), and -specific T7S-like membrane components (light blue).

Source: microbiolspec February 2016 vol. 4 no. 1 doi:10.1128/microbiolspec.VMBF-0011-2015
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Image of FIGURE 2
FIGURE 2

Model for T7S in mycobacteria. The conserved membrane components (blue) form a complex in which the EccC homolog is the ATPase possibly providing energy for the secretion process. The mycosin (MycP) is not part of the core complex but is essential for successful secretion. The T7S substrates (green) are secreted dependently on the conserved signals YxxxD/E and WxG (red). Secretion of PE-PPE dimers is dependent on the cytosolic chaperones EspG and EccA (yellow). While EspG binds to the substrate pair in the cytosol, EccA might be involved in releasing this chaperone from the PE-PPE dimer upon contact with the membrane complex. In contrast, Esx proteins are not recognized by EspG, and their dependence on the cytosolic chaperones might be indirect due to interdependence of Esx and PE-PPE for secretion. The EspB monomer has a similar fold to PE-PPE dimers and contains the putative secretion signal. Upon translocation, EspB is processed and forms a heptamer with a barrel-like structure. Whether PE-PPE dimers adopt a similar quaternary structure is yet unknown. Secreted substrates can localize to the culture supernatant or remain attached in the capsular layer. Whether the secretion process is a one- or two-step process is not known, so a putative outer membrane component (gray) is indicated by a question mark.

Source: microbiolspec February 2016 vol. 4 no. 1 doi:10.1128/microbiolspec.VMBF-0011-2015
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Image of FIGURE 3
FIGURE 3

Crystal structures of T7S substrates. Structure of the heterodimer EsxB (dark blue) and EsxA (light blue) of (3FAV). The two proteins form a four-helix bundle. The Tyr of the YxxxD motif and the Gly and Trp residues of the WxG motif that are postulated to together constitute the T7S signal are shown in red ( 54 ). The EsxA protein of forms a homodimer that results in two putative secretion signals (VxxxD) on each end of the four-helix bundle (red) (2VRZ) ( 139 ). Crystal structure of PE25 (light blue) and PPE41 (dark blue) of in complex with the chaperone EspG (yellow). EspG interacts with the PPE protein through hydrophobic interactions but not directly with the PE protein. The WxG motif on the PPE and the YxxxE motif on the PE protein together form a putative T7S signal (red residues) (4KXR) ( 17 ). Crystal structure of monomeric EspB visualizing an extended secretion signal that includes the YxxxD/E and WxG motif (red residues) (3J83) ( 18 ).

Source: microbiolspec February 2016 vol. 4 no. 1 doi:10.1128/microbiolspec.VMBF-0011-2015
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Image of FIGURE 4
FIGURE 4

Crystal structures of EccC of . C-terminal domains of EccC containing all three NBDs () or containing only NBD2 and NBD3 and with a bound secretion signal of EsxB () are shown as described by Rosenberg et al. ( 40 ). The secretion signal (in green) is bound to a hydrophobic pocket of NBD3. While NBD2 and NBD3 have a bound ATP molecule (red), NBD1 has a sulfate ion at the ATP binding site instead (in orange). NBD1 activity is inhibited by a linker domain of NBD2. This inhibition can be alleviated by changing arginine 543 (the orange residue) to an alanine.

Source: microbiolspec February 2016 vol. 4 no. 1 doi:10.1128/microbiolspec.VMBF-0011-2015
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