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Type 6 Secretion Systems Bacterial Wars and Deadly Syringes

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Page 1: Type 6 Secretion Systems

Type 6 Secretion Systems

Bacterial Wars and Deadly Syringes

Page 2: Type 6 Secretion Systems

What exactly is a T6SS?

Syringe like structure designed to deliver effector proteins

Found in more than 25% of Gram negative bacteria

Delivers them in a cell-contact dependent manner

Used in a defensive manner against competitors

It is also able to inject effectors directly into eukaryotes during an infection

So where did it come from?

Page 3: Type 6 Secretion Systems

Structure and Phage Homology

Show structural and functional homology to the T4 Bacteriophage

Believed to actually be an inverted phage tail

Gene homology with Phage Genes Study by Leiman in 2009 found

homology between phage tail proteins and 3 T6SS components.

Study by Pell in 2009 found similariteis between the Hcp protein of T6SS and a major phage tail protein

Study by Pukatzki in 2007 showed that the VgrG are analogous to the Needle and spike complex of T4 Phage

Page 4: Type 6 Secretion Systems

Delivery of Effectors

The VgrG proteins are located at the distal end of the Hcp tube forming the spike

Following polymerisation of the outer sheath VipA/VipB proteins, the repeating Hcp proteins of the inner tube are ejected outward like a syringe

This is very similar to the mechanism employed by a phage tail

Following this extension effector proteins can be delivered to the target cell.

The exact mechanism however is still to be determined.

Page 5: Type 6 Secretion Systems

Friend or Foe?

Pseudomonas aeruginosa Tae effector proteins Tse1 and Tse3 Tse2 identified as a toxin but

mechanism remains unknown T6SS “duelling” between sister cells

Vibrio cholera effector proteins TseL, VasX and VgrG3

What are these used for? Against rivals of heterologous

bacteria Against sister cells Against eukaryotic cells during an

infection

Page 6: Type 6 Secretion Systems

Immunity to Self Harm

Immunity Determinants Some of the organisms these

have been identified in include Pseudomonas aeruginosa, Burkholderia thailandensis, Vibrio cholera and Serratia marcescens

Protects itself from self intoxication and sister cells by using immunity proteins Tsi1 and Tsi3

Genes encoding effector proteins are located close to ORFs encoding immunity proteins

Page 7: Type 6 Secretion Systems

Research and Future Implications

Pseudomonas T6SS has been shown to play a key role in chronic infections Biofilm formation Quorum Sensing Virulence

2006 Study by Mougous et al found that pulmonary secretions of cystic fibrosis patients contained Hcp1 Pseudomonas infects >80% of Cystic

Fibrosis sufferers A 2014 study by Ma et al reported on the

effctivness of Agrobacterium tumefaxciens T6SS system to kill Pseudomonas within a planta coinfection assay Possible way to turn non pathogenic

bacteria against pathogenic bacteria by using the T6SS machinery

A better understanding of T6SS could offer new antimicrobial treatments to sufferers of chronic diseases such as cystic fibrosis

Page 8: Type 6 Secretion Systems

References• Basler, M., Ho, B. T. & Mekalanos, J. J. 2013. Tit-for-tat: Type VI secretion system counterattack during bacterial cell-cell

interactions. Cell, 152, 884-894.• Basler, M. & Mekalanos, J. J. 2012. Type 6 secretion dynamics within and between bacterial cells. Science, 337, 815-815.• Basler, M., Pilhofer, M., Henderson, G. P., Jensen, G. J. & Mekalanos, J. J. 2012. Type VI secretion requires a dynamic

contractile phage tail-like structure. Nature, 483, 182-U78.• Brooks, T. M., Unterweger, D., Bachmann, V., Kostiuk, B. & Pukatzki, S. 2013. Lytic activity of the Vibrio cholerae type VI

secretion toxin VgrG-3 is inhibited by the antitoxin TsaB. Journal of Biological Chemistry, 288, 7618-7625.• Brunet, Y. R., Espinosa, L., Harchouni, S., Mignot, T. & Cascales, E. 2013. Imaging type VI secretion-mediated bacterial

killing. Cell Reports, 3, 36-41.• Dong, T. G., Ho, B. T., Yoder-Himes, D. R. & Mekalanos, J. J. 2013. Identification of T6SS-dependent effector and immunity

proteins by Tn-seq in Vibrio cholerae. Proceedings of the National Academy of Sciences of the United States of America, 110, 2623-2628.

• Filloux, A. 2013. The rise of the type VI secretion system. F1000prime reports, 5, 52-52.• Hood, R. D., Singh, P., Hsu, F., Guevener, T., Carl, M. A., Trinidad, R. R. S., Silverman, J. M., Ohlson, B. B., Hicks, K. G.,

Plemel, R. L., Li, M., Schwarz, S., Wang, W. Y., Merz, A. J., Goodlett, D. R. & Mougous, J. D. 2010. A type VI secretion system of Pseudomonas aeruginosa targets, a toxin to bacteria. Cell Host & Microbe, 7, 25-37.

• Kanamaru, S. 2009. Structural similarity of tailed phages and pathogenic bacterial secretion systems. Proceedings of the National Academy of Sciences of the United States of America, 106, 4067-4068.

• Kapitein, N. & Mogk, A. 2013. Deadly syringes: type VI secretion system activities in pathogenicity and interbacterial competition. Current Opinion in Microbiology, 16, 52-58.

• Leiman, P. G., Basler, M., Ramagopal, U. A., Bonanno, J. B., Sauder, J. M., Pukatzki, S., Burley, S. K., Almo, S. C. & Mekalanos, J. J. 2009. Type VI secretion apparatus and phage tail-associated protein complexes share a common evolutionary origin. Proceedings of the National Academy of Sciences of the United States of America, 106, 4154-4159.

• Li, L., Zhang, W., Liu, Q., Gao, Y., Gao, Y., Wang, Y., Wang, D. Z., Li, Z. & Wang, T. 2013. Structural insights on the bacteriolytic and self-protection mechanism of muramidase effector Tse3 in Pseudomonas aeruginosa. Journal of Biological Chemistry, 288, 30607-30613.

• Lu, D., Shang, G., Zhang, H., Yu, Q., Cong, X., Yuan, J., He, F., Zhu, C., Zhao, Y., Yin, K., Chen, Y., Hu, J., Zhang, X., Yuan, Z., Xu, S., Hu, W., Cang, H. & Gu, L. 2014. Structural insights into the T6SS effector protein Tse3 and the Tse3-Tsi3 complex from Pseudomonas aeruginosa reveal a calcium-dependent membrane-binding mechanism. Molecular Microbiology, 92, 1092-1112.

• Ma, L.-S., Hachani, A., Lin, J.-S., Filloux, A. & Lai, E.-M. 2014. Agrobacterium tumefaciens deploys a superfamily of Type VI secretion DNase effectors as weapons for interbacterial competition in planta. Cell Host & Microbe, 16, 94-104.

Page 9: Type 6 Secretion Systems

References cont..• Miyata, S. T., Kitaoka, M., Brooks, T. M., Mcauley, S. B. & Pukatzki, S. 2011. Vibrio cholerae requires the Type VI secretion

system virulence factor VasX to kill Dictyostelium discoideum. Infection and Immunity, 79, 2941-2949.• Miyata, S. T., Unterweger, D., Rudko, S. P. & Pukatzki, S. 2013. Dual expression profile of Type VI secretion system

immunity genes protects pandemic Vibrio cholerae. Plos Pathogens, 9.• Mougous, J. D., Cuff, M. E., Raunser, S., Shen, A., Zhou, M., Gifford, C. A., Goodman, A. L., Joachimiak, G., Ordonez, C. L.,

Lory, S., Walz, T., Joachimiak, A. & Mekalanos, J. J. 2006. A virulence locus of Pseudomonas aeruginosa encodes a protein secretion apparatus. Science, 312, 1526-1530.

• Pell, L. G., Kanelis, V., Donaldson, L. W., Howell, P. L. & Davidson, A. R. 2009. The phage lambda major tail protein structure reveals a common evolution for long-tailed phages and the type VI bacterial secretion system. Proceedings of the National Academy of Sciences of the United States of America, 106, 4160-4165.

• Pukatzki, S., Ma, A. T., Revel, A. T., Sturtevant, D. & Mekalanos, J. J. 2007. Type VI secretion system translocates a phage tail spike-like protein into target cells where it cross-links actin. Proceedings of the National Academy of Sciences of the United States of America, 104, 15508-15513.

• Records, A. R. 2011. The Type VI secretion system: A multipurpose delivery system with a phage-like machinery. Molecular Plant-Microbe Interactions, 24, 751-757.

• Russell, A. B., Hood, R. D., Bui, N. K., Leroux, M., Vollmer, W. & Mougous, J. D. 2011. Type VI secretion delivers bacteriolytic effectors to target cells. Nature, 475, 343-U92.

• Russell, A. B., Peterson, S. B. & Mougous, J. D. 2014. Type VI secretion system effectors: poisons with a purpose. Nature Reviews Microbiology, 12, 137-148.

• Shang, G., Liu, X., Lu, D., Zhang, J., Li, N., Zhu, C., Liu, S., Yu, Q., Zhao, Y., Zhang, H., Hu, J., Cang, H., Xu, S. & Gu, L. 2012. Structural insight into how Pseudomonas aeruginosa peptidoglycan-hydrolase Tse1 and its immunity protein Tsi1 function. Biochemical Journal, 448, 201-211.

• Unterweger, D., Miyata, S. T., Bachmann, V., Brooks, T. M., Mullins, T., Kostiuk, B., Provenzano, D. & Pukatzki, S. 2014. The Vibrio cholerae type VI secretion system employs diverse effector modules for intraspecific competition. Nature Communications, 5.

• Wootton, L. 2013. Ready, aim, fire! Nature Reviews Microbiology, 11, 224-225.• Zoued, A., Brunet, Y. R., Durand, E., Aschtgen, M.-S., Logger, L., Douzi, B., Journet, L., Cambillau, C. & Cascales, E. 2014.

Architecture and assembly of the Type VI secretion system. Biochimica Et Biophysica Acta-Molecular Cell Research, 1843, 1664-1673.