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The Pseudomonas aeruginosa Exoenzyme Y: A Promiscuous Nucleotidyl Cyclase Edema Factor and Virulence Determinant

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Non-canonical Cyclic Nucleotides

Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 238))

Abstract

Exoenzyme Y (ExoY) was identified as a component of the Pseudomonas aeruginosa type 3 secretion system secretome in 1998. It is a common contributor to the arsenal of type 3 secretion system effectors, as it is present in approximately 90% of Pseudomonas isolates. ExoY has adenylyl cyclase activity that is dependent upon its association with a host cell cofactor. However, recent evidence indicates that ExoY is not just an adenylyl cyclase; rather, it is a promiscuous cyclase capable of generating purine and pyrimidine cyclic nucleotide monophosphates. ExoY’s enzymatic activity causes a characteristic rounding of mammalian cells, due to microtubule breakdown. In endothelium, this cell rounding disrupts cell-to-cell junctions, leading to loss of barrier integrity and an increase in tissue edema. Microtubule breakdown seems to depend upon tau phosphorylation, where the elevation of cyclic nucleotide monophosphates activates protein kinases A and G and causes phosphorylation of endothelial microtubule associated protein tau. Phosphorylation is a stimulus for tau release from microtubules, leading to microtubule instability. Phosphorylated tau accumulates inside endothelium as a high molecular weight, oligomeric form, and is then released from the cell. Extracellular high molecular weight tau causes a transmissible cytotoxicity that significantly hinders cellular repair following infection. Thus, ExoY may contribute to bacterial virulence in at least two ways; first, by microtubule breakdown leading to loss of endothelial cell barrier integrity, and second, by promoting release of a high molecular weight tau cytotoxin that impairs cellular recovery following infection.

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Acknowledgments

This work is supported by National Institutes of Health grants HL60024 (T. Stevens) and HL66299 (T. Stevens, R. Balczon, and D. W. Frank), and an American Heart Association postdoctoral fellowship 14POST18080004 (K. A. Morrow).

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Authors and Affiliations

  1. Department of Physiology and Cell Biology, University of South Alabama, Mobile, AL, 36688, USA

    K. Adam Morrow & Troy Stevens

  2. The Center for Lung Biology, University of South Alabama, Mobile, AL, 36688, USA

    K. Adam Morrow, Ron Balczon & Troy Stevens

  3. Department of Microbiology and Molecular Genetics, Medical College of Wisconsin, Milwaukee, WI, 53226, USA

    Dara W. Frank

  4. Center for Infectious Disease Research, Medical College of Wisconsin, Milwaukee, WI, 53226, USA

    Dara W. Frank

  5. Department of Biochemistry and Molecular Biology, University of South Alabama, Mobile, AL, 36688, USA

    Ron Balczon

  6. Department of Medicine, University of South Alabama, Mobile, AL, 36688, USA

    Troy Stevens

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Correspondence to Troy Stevens .

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  1. Medical School of Hannover Insitute of Pharmakology, Hannover, Niedersachsen, Germany

    Roland Seifert

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Morrow, K.A., Frank, D.W., Balczon, R., Stevens, T. (2016). The Pseudomonas aeruginosa Exoenzyme Y: A Promiscuous Nucleotidyl Cyclase Edema Factor and Virulence Determinant. In: Seifert, R. (eds) Non-canonical Cyclic Nucleotides. Handbook of Experimental Pharmacology, vol 238. Springer, Cham. https://doi.org/10.1007/164_2016_5003

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