Bacterial effector protein

Bacterial effectors are proteins secreted by pathogenic bacteria into the cells of their host, usually using a type 3 secretion system (TTSS/T3SS) or a type 4 secretion system (TFSS/T4SS). Some bacteria inject only a few effectors into their host’s cells while others may inject dozens or even hundreds. Effector proteins may have many different activities, but usually help the pathogen to invade host tissue, suppress its immune system, or otherwise help the pathogen to survive.[1] Effector proteins are usually critical for virulence. For instance, in the causative agent of plague (Yersinia pestis), the loss of the T3SS is sufficient to render the bacteria completely avirulent, even when they are directly introduced into the bloodstream.[2] Gram negative microbes are also suspected to deploy bacterial outer membrane vesicles to translocate effector proteins and virulence factors via a novel membrane vesicle trafficking secretory pathway, in order to modify their environment or attack/invade target cells, for example, at the host-pathogen interface.

Diversity of bacterial effectors

Many pathogenic bacteria are known to have secreted effectors but for most species the exact number is unknown. Once a pathogen genome has been sequenced, effectors can be predicted based on protein sequence similarity, but such predictions are not always precise. More importantly, it is difficult to prove experimentally that a predicted effector is actually secreted into a host cell because the amount of each effector protein is tiny. For instance, Tobe et al. (2006) predicted more than 60 effectors for pathogenic E. coli but could only show for 39 that they are secreted into human Caco-2 cells. Finally, even within the same bacterial species, different strains often have different repertoires of effectors. For instance, the plant pathogen Pseudomonas syringae has 14 effectors in one strain, but more than 150 have been found in multiple different strains.

Species number of effectors reference
Chlamydia (multiple species)16+[3]
E. coli EHEC (O157:H7)40-60[4]
E. coli (EPEC)>20[5]
Legionella pneumophila>330 (T4SS)[6][7][8]
Pseudomonas aeruginosa4[9]
Pseudomonas syringae14 (>150 in multiple strains)[10]
Salmonella enterica60+[11]
Yersinia (multiple species)14[12]

Mechanism of action

Given the diversity of effectors, they affect a wide variety of intracellular processes. The T3SS effectors of pathogenic E. coli, Shigella, Salmonella, and Yersinia regulate actin dynamics to facilitate their own attachment or invasion, subvert endocytic trafficking, block phagocytosis, modulate apoptotic pathways, and manipulate innate immunity as well as host responses.[13]

Phagocytosis. Phagocytes are immune cells that can recognize and "eat" bacteria. Phagocytes recognize bacteria directly [e.g., through the so-called scavenger receptor A which recognizes bacterial lipopolysaccharide (LPS) [14]] or indirectly through antibodies (IgG) and complement proteins (C3bi) which coat the bacteria and are recognized by the Fcγ receptors and integrinαmβ2 (complement receptor 3). For instance, intracellular Salmonella and Shigella escape phagocytic killing through manipulation of endolysosomal trafficking (see there). Yersinia predominantly survives extracellularly using the translocation of effectors to inhibit cytoskeletal rearrangements and thus phagocytosis. EPEC/EHEC inhibit both transcytosis through M cells and internalization by phagocytes.[15][16] Yersinia inhibits phagocytosis through the concerted actions of several effector proteins, including YopE which acts as a RhoGAP[17] and inhibits Rac-dependent actin polymerization.

Endocytic trafficking. Several bacteria, including Salmonella and Shigella, enter the cell and survive intracellularly by manipulating the endocytic pathway. Once internalized by host cells Salmonella subverts the endolysosome trafficking pathway to create a Salmonella-containing vacuole (SCV), which is essential for its intracellular survival. As the SCVs mature they travel to the microtubule organizing center (MTOC), a perinuclear region adjacent to the Golgi, where they produce Salmonella induced filaments (Sifs) dependent on the T3SS effectors SseF and SseG.[18] By contrast, internalized Shigella avoids the endolysosome system by rapidly lysing its vacuole through the action of the T3SS effectors IpaB and C although the details of this process are poorly understood.[19]

Secretory pathway. Some pathogens, such as EPEC/EHEC disrupt the secretory pathway.[20][21] For instance, their effector EspG can reduce the secretion of interleukin-8 (IL-8),[22] and thus affect the immune system (immunomodulation).[18] EspG functions as a Rab GTPase-activating protein (Rab-GAP),[22] trapping Rab-GTPases in their inactive GDP bound form, and reducing ER–Golgi transport (of IL-8 and other proteins).

Apoptosis (programmed cell death). Apoptosis is usually a mechanism of defense to infection, given that apoptotic cells eventually attract immune cells to remove them and the pathogen. Many pathogenic bacteria have developed mechanisms to prevent apoptosis, not the least to maintain their host environment. For instance, the EPEC/EHEC effectors NleH and NleF block apoptosis.[23][24] Similarly, the Shigella effectors IpgD and OspG (a homolog of NleH) block apoptosis,[23][25] the former by phosphorylating and stabilizing the double minute 2 protein (MDM2) which in turn leads to a block of NF-kB-induced apoptosis.[26] Salmonella inhibits apoptosis and activates pro-survival signals, dependent on the effectors AvrA and SopB, respectively.[27]

Induction of cell death. In contrast to inhibition of apoptosis, several effectors appear to induce programmed cell death. For instance, EHEC effectors EspF, EspH, and Cif induce apoptosis.[28][29][30]

Inflammatory response. Human cells have receptors that recognize pathogen-associated molecular patterns (PAMPs). When bacteria bind to these receptors, they activate signaling cascades such as the NF-kB and MAPK pathways. This leads to expression of cytokines, immunomodulating agents, such as interleukins and interferons which regulate immune response to infection and inflammation. Several bacterial effectors affect NF-kB signaling. For instance, the EPEC/EHEC effectors NleE, NleB, NleC, NleH, and Tir are immunosuppressing effectors that target proteins in the NF-kB signaling pathway. NleC has been shown to cleave the NF-kB p65 subunit (RelA), blocking the production of IL-8 following infection.[31] NleH1, but not NleH2, blocks translocation of NF-kB into the nucleus.[32][33] The Tir effector protein inhibits cytokine production.[34][35] Similarly, YopE, YopP, and YopJ (in Yersinia enterocolitica, Yersinia pestis, and Yersinia pseudotuberculosis respectively) target the NF-kB pathway. YopE inhibits activation of NF-kB, which in part prevents the production of IL-8.[36]

Databases and online resources

See also

References

  1. ↑ Mattoo, S.; Lee, Y. M.; Dixon, J. E. (2007). "Interactions of bacterial effector proteins with host proteins". Current Opinion in Immunology 19 (4): 392–401. doi:10.1016/j.coi.2007.06.005. PMID 17662586.
  2. ↑ Viboud, G. I.; Bliska, J. B. (2005). "YERSINIAOUTER PROTEINS: Role in Modulation of Host Cell Signaling Responses and Pathogenesis". Annual Review of Microbiology 59: 69–89. doi:10.1146/annurev.micro.59.030804.121320. PMID 15847602.
  3. ↑ Betts, H. J.; Wolf, K.; Fields, K. A. (2009). "Effector protein modulation of host cells: Examples in the Chlamydia spp. arsenal". Current Opinion in Microbiology 12 (1): 81–87. doi:10.1016/j.mib.2008.11.009. PMID 19138553.
  4. ↑ Tobe, T.; Beatson, S. A.; Taniguchi, H.; Abe, H.; Bailey, C. M.; Fivian, A.; Younis, R.; Matthews, S.; Marches, O.; Frankel, G.; Hayashi, T.; Pallen, M. J. (2006). "An extensive repertoire of type III secretion effectors in Escherichia coli O157 and the role of lambdoid phages in their dissemination". Proceedings of the National Academy of Sciences 103 (40): 14941–14946. doi:10.1073/pnas.0604891103. PMC 1595455. PMID 16990433.
  5. ↑ Dean, P.; Kenny, B. (2009). "The effector repertoire of enteropathogenic E. Coli: Ganging up on the host cell". Current Opinion in Microbiology 12 (1): 101–109. doi:10.1016/j.mib.2008.11.006. PMC 2697328. PMID 19144561.
  6. ↑ Burstein, D; Zusman, T; Degtyar, E; Viner, R; Segal, G; Pupko, T (2009). "Genome-scale identification of Legionella pneumophila effectors using a machine learning approach". PLoS Pathogens 5 (7): e1000508. doi:10.1371/journal.ppat.1000508. PMC 2701608. PMID 19593377.
  7. ↑ Huang, L; Boyd, D; Amyot, W. M.; Hempstead, A. D.; Luo, Z. Q.; O'Connor, T. J.; Chen, C; Machner, M; Montminy, T; Isberg, R. R. (2011). "The E Block motif is associated with Legionella pneumophila translocated substrates". Cellular Microbiology 13 (2): 227–45. doi:10.1111/j.1462-5822.2010.01531.x. PMC 3096851. PMID 20880356.
  8. ↑ Zhu, W; Banga, S; Tan, Y; Zheng, C; Stephenson, R; Gately, J; Luo, Z. Q. (2011). "Comprehensive identification of protein substrates of the Dot/Icm type IV transporter of Legionella pneumophila". PLoS ONE 6 (3): e17638. doi:10.1371/journal.pone.0017638. PMC 3052360. PMID 21408005.
  9. ↑ Engel, J.; Balachandran, P. (2009). "Role of Pseudomonas aeruginosa type III effectors in disease". Current Opinion in Microbiology 12 (1): 61–66. doi:10.1016/j.mib.2008.12.007. PMID 19168385.
  10. ↑ Alfano, J. R.; Collmer, A. (2004). "TYPE III SECRETION SYSTEM EFFECTOR PROTEINS: Double Agents in Bacterial Disease and Plant Defense". Annual Review of Phytopathology 42: 385–414. doi:10.1146/annurev.phyto.42.040103.110731. PMID 15283671.
  11. ↑ Van Engelenburg, S. B.; Palmer, A. E. (2010). "Imaging type-III secretion reveals dynamics and spatial segregation of Salmonella effectors". Nature Methods 7 (4): 325–330. doi:10.1038/nmeth.1437. PMC 2862489. PMID 20228815.
  12. ↑ Matsumoto, H.; Young, G. M. (2009). "Translocated effectors of Yersinia". Current Opinion in Microbiology 12 (1): 94–100. doi:10.1016/j.mib.2008.12.005. PMC 2669664. PMID 19185531.
  13. ↑ Kleiner, M.; Young, J. C.; Shah, M.; Verberkmoes, N. C.; Dubilier, N. (2013). "Metaproteomics Reveals Abundant Transposase Expression in Mutualistic Endosymbionts". MBio 4 (3): e00223–e00213. doi:10.1128/mBio.00223-13. PMC 3684830. PMID 23781067.
  14. ↑ Peiser, L.; Gough, P. J.; Kodama, T.; Gordon, S. (2000). "Macrophage class a scavenger receptor-mediated phagocytosis of Escherichia coli: Role of cell heterogeneity, microbial strain, and culture conditions in vitro". Infection and immunity 68 (4): 1953–1963. doi:10.1128/IAI.68.4.1953-1963.2000. PMC 97372. PMID 10722588.
  15. ↑ Martinez-Argudo, I.; Sands, C.; Jepson, M. A. (2007). "Translocation of enteropathogenic Escherichia coli across an in vitro M cell model is regulated by its type III secretion system". Cellular Microbiology 9 (6): 1538–1546. doi:10.1111/j.1462-5822.2007.00891.x. PMID 17298392.
  16. ↑ Goosney, D. L.; Celli, J.; Kenny, B.; Finlay, B. B. (1999). "Enteropathogenic Escherichia coli inhibits phagocytosis". Infection and immunity 67 (2): 490–495. PMC 96346. PMID 9916050.
  17. ↑ Von Pawel-Rammingen, U.; Telepnev, M. V.; Schmidt, G.; Aktories, K.; Wolf-Watz, H.; Rosqvist, R. (2000). "GAP activity of the Yersinia YopE cytotoxin specifically targets the Rho pathway: A mechanism for disruption of actin microfilament structure". Molecular Microbiology 36 (3): 737–748. doi:10.1046/j.1365-2958.2000.01898.x. PMID 10844661.
  18. 1 2 Raymond, B.; Young, J. C.; Pallett, M.; Endres, R. G.; Clements, A.; Frankel, G. (2013). "Subversion of trafficking, apoptosis, and innate immunity by type III secretion system effectors". Trends in Microbiology 21 (8): 430–441. doi:10.1016/j.tim.2013.06.008. PMID 23870533.
  19. ↑ Blocker, A.; Gounon, P.; Larquet, E.; Niebuhr, K.; Cabiaux, V.; Parsot, C.; Sansonetti, P. (1999). "The tripartite type III secreton of Shigella flexneri inserts IpaB and IpaC into host membranes". The Journal of Cell Biology 147 (3): 683–693. doi:10.1083/jcb.147.3.683. PMC 2151192. PMID 10545510.
  20. ↑ Selyunin, A. S.; Sutton, S. E.; Weigele, B. A.; Reddick, L. E.; Orchard, R. C.; Bresson, S. M.; Tomchick, D. R.; Alto, N. M. (2010). "The assembly of a GTPase–kinase signalling complex by a bacterial catalytic scaffold". Nature 469 (7328): 107–111. doi:10.1038/nature09593. PMC 3675890. PMID 21170023.
  21. ↑ Clements, A.; Smollett, K.; Lee, S. F.; Hartland, E. L.; Lowe, M.; Frankel, G. (2011). "EspG of enteropathogenic and enterohemorrhagic E. Coli binds the Golgi matrix protein GM130 and disrupts the Golgi structure and function". Cellular Microbiology 13 (9): 1429–1439. doi:10.1111/j.1462-5822.2011.01631.x. PMID 21740499.
  22. 1 2 Dong, N.; Zhu, Y.; Lu, Q.; Hu, L.; Zheng, Y.; Shao, F. (2012). "Structurally Distinct Bacterial TBC-like GAPs Link Arf GTPase to Rab1 Inactivation to Counteract Host Defenses". Cell 150 (5): 1029–1041. doi:10.1016/j.cell.2012.06.050. PMID 22939626.
  23. 1 2 Hemrajani, C.; Berger, C. N.; Robinson, K. S.; Marches, O.; Mousnier, A.; Frankel, G. (2010). "NleH effectors interact with Bax inhibitor-1 to block apoptosis during enteropathogenic Escherichia coli infection". Proceedings of the National Academy of Sciences 107 (7): 3129–3134. doi:10.1073/pnas.0911609106. PMC 2840288. PMID 20133763.
  24. ↑ Blasche, S.; Mörtl, M.; Steuber, H.; Siszler, G.; Nisa, S.; Schwarz, F.; Lavrik, I.; Gronewold, T. M. A.; Maskos, K.; Donnenberg, M. S.; Ullmann, D.; Uetz, P.; Kögl, M. (2013). Bergmann, Andreas, ed. "The E. Coli Effector Protein NleF is a Caspase Inhibitor". PLoS ONE 8 (3): e58937. doi:10.1371/journal.pone.0058937. PMC 3597564. PMID 23516580.
  25. ↑ Clark, C. S.; Maurelli, A. T. (2007). "Shigella flexneri Inhibits Staurosporine-Induced Apoptosis in Epithelial Cells". Infection and Immunity 75 (5): 2531–2539. doi:10.1128/IAI.01866-06. PMC 1865761. PMID 17339354.
  26. ↑ Bergounioux, J.; Elisee, R.; Prunier, A. L.; Donnadieu, F. O.; Sperandio, B.; Sansonetti, P.; Arbibe, L. (2012). "Calpain Activation by the Shigella flexneri Effector VirA Regulates Key Steps in the Formation and Life of the Bacterium's Epithelial Niche". Cell Host & Microbe 11 (3): 240–252. doi:10.1016/j.chom.2012.01.013. PMID 22423964.
  27. ↑ Knodler, L. A.; Finlay, B. B.; Steele-Mortimer, O. (2004). "The Salmonella Effector Protein SopB Protects Epithelial Cells from Apoptosis by Sustained Activation of Akt". Journal of Biological Chemistry 280 (10): 9058–9064. doi:10.1074/jbc.M412588200. PMID 15642738.
  28. ↑ Nougayrede, J. P.; Donnenberg, M. S. (2004). "Enteropathogenic Escherichia coli EspF is targeted to mitochondria and is required to initiate the mitochondrial death pathway". Cellular Microbiology 6 (11): 1097–1111. doi:10.1111/j.1462-5822.2004.00421.x. PMID 15469437.
  29. ↑ Samba-Louaka, A.; Nougayrède, J. -P.; Watrin, C.; Oswald, E.; Taieb, F. (2009). "The Enteropathogenic Escherichia coli Effector Cif Induces Delayed Apoptosis in Epithelial Cells". Infection and Immunity 77 (12): 5471–5477. doi:10.1128/IAI.00860-09. PMC 2786488. PMID 19786559.
  30. ↑ Wong, A. R. C.; Clements, A.; Raymond, B.; Crepin, V. F.; Frankel, G. (2012). "The Interplay between the Escherichia coli Rho Guanine Nucleotide Exchange Factor Effectors and the Mammalian RhoGEF Inhibitor EspH". MBio 3 (1): e00250–e00211. doi:10.1128/mBio.00250-11. PMC 3374388. PMID 22251971.
  31. ↑ Yen, H.; Ooka, T.; Iguchi, A.; Hayashi, T.; Sugimoto, N.; Tobe, T. (2010). Van Nhieu, Guy Tran, ed. "NleC, a Type III Secretion Protease, Compromises NF-κB Activation by Targeting p65/RelA". PLoS Pathogens 6 (12): e1001231. doi:10.1371/journal.ppat.1001231. PMC 3002990. PMID 21187904.
  32. ↑ Pham, T. H.; Gao, X.; Tsai, K.; Olsen, R.; Wan, F.; Hardwidge, P. R. (2012). "Functional Differences and Interactions between the Escherichia coli Type III Secretion System Effectors NleH1 and NleH2". Infection and Immunity 80 (6): 2133–2140. doi:10.1128/IAI.06358-11. PMC 3370600. PMID 22451523.
  33. ↑ Gao, X.; Wan, F.; Mateo, K.; Callegari, E.; Wang, D.; Deng, W.; Puente, J.; Li, F.; Chaussee, M. S.; Finlay, B. B.; Lenardo, M. J.; Hardwidge, P. R. (2009). Valdivia, Raphael H, ed. "Bacterial Effector Binding to Ribosomal Protein S3 Subverts NF-κB Function". PLoS Pathogens 5 (12): e1000708. doi:10.1371/journal.ppat.1000708. PMC 2791202. PMID 20041225.
  34. ↑ Ruchaud-Sparagano, M. H. L. N.; Mühlen, S.; Dean, P.; Kenny, B. (2011). Monack, Denise M, ed. "The Enteropathogenic E. Coli (EPEC) Tir Effector Inhibits NF-κB Activity by Targeting TNFα Receptor-Associated Factors". PLoS Pathogens 7 (12): e1002414. doi:10.1371/journal.ppat.1002414. PMC 3228809. PMID 22144899.
  35. ↑ Yan, D.; Wang, X.; Luo, L.; Cao, X.; Ge, B. (2012). "Inhibition of TLR signaling by a bacterial protein containing immunoreceptor tyrosine-based inhibitory motifs". Nature Immunology 13 (11): 1063–1071. doi:10.1038/ni.2417. PMID 23001144.
  36. ↑ Viboud, G. I.; Mejía, E; Bliska, J. B. (2006). "Comparison of YopE and YopT activities in counteracting host signalling responses to Yersinia pseudotuberculosis infection". Cellular Microbiology 8 (9): 1504–15. doi:10.1111/j.1462-5822.2006.00729.x. PMID 16922868.
  37. ↑ Jehl, M. -A.; Arnold, R.; Rattei, T. (2010). "Effective--a database of predicted secreted bacterial proteins". Nucleic Acids Research 39 (Database issue): D591–D595. doi:10.1093/nar/gkq1154. PMC 3013723. PMID 21071416.
  38. ↑ Wang, Y.; Huang, H.; Sun, M. A.; Zhang, Q.; Guo, D. (2012). "T3DB: An integrated database for bacterial type III secretion system". BMC Bioinformatics 13: 66. doi:10.1186/1471-2105-13-66. PMC 3424820. PMID 22545727.
  39. ↑ Dong,X., Lu,X. and Zhang,Z. BEAN 2.0: an integrated web resource for the identification and functional analysis of type III secreted effectors. Database (2015) Vol. 2015: article ID bav064; doi:10.1093/database/bav064
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