The Pseudomonas aeruginosa Exoenzyme Y: A Promiscuous Nucleotidyl Cyclase Edema Factor and Virulence Determinant.
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.
Department of Physiology and Cell Biology, University of South Alabama, Mobile, AL, 36688, USA.|The Center for Lung Biology, University of South Alabama, Mobile, AL, 36688, USA.
K Adam
KA
Morrow
Department of Microbiology and Molecular Genetics, Medical College of Wisconsin, Milwaukee, WI, 53226, USA.|Center for Infectious Disease Research, Medical College of Wisconsin, Milwaukee, WI, 53226, USA.
Dara W
DW
Frank
The Center for Lung Biology, University of South Alabama, Mobile, AL, 36688, USA.|Department of Biochemistry and Molecular Biology, University of South Alabama, Mobile, AL, 36688, USA.
Ron
R
Balczon
Department of Physiology and Cell Biology, University of South Alabama, Mobile, AL, 36688, USA. tstevens@southalabama.edu.|The Center for Lung Biology, University of South Alabama, Mobile, AL, 36688, USA. tstevens@southalabama.edu.|Department of Medicine, University of South Alabama, Mobile, AL, 36688, USA. tstevens@southalabama.edu.
Troy
T
Stevens
D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D001426:Bacterial Proteins / Q000378:metabolism*; D002199:Capillary Permeability; D003599:Cytoskeleton / Q000201:enzymology / Q000382:microbiology; D042783:Endothelial Cells / Q000201:enzymology / Q000382:microbiology; D005964:Glucosyltransferases / Q000378:metabolism*; D006162:Guanylate Cyclase / Q000378:metabolism; D054884:Host-Pathogen Interactions; D006801:Humans; D010766:Phosphorylation; D011552:Pseudomonas Infections / Q000201:enzymology*; D011550:Pseudomonas aeruginosa / Q000201:enzymology* / Q000472:pathogenicity; D015290:Second Messenger Systems; D014774:Virulence; D016875:tau Proteins / Q000378:metabolism
D001426:Bacterial Proteins; C054369:MAPT protein, human; D016875:tau Proteins; C111504:ExoY protein, bacteria; D005964:Glucosyltransferases; C579271:ADCY10 protein, human; D000262:Adenylyl Cyclases; D006162:Guanylate Cyclase
Nucleotidyl cyclase; P. aeruginosa virulence; Permeability; Tau toxicity; cAMP compartmentalization