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

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.

Structure–Function Relationships Underlying the Capacity of Bordetella Adenylate Cyclase Toxin to Disarm Host Phagocytes

“…The AC domain of CyaA belongs to the class II of adenylyl cyclase enzymes [EC 4.6.1.1] that convert ATP to cAMP, a “second messenger” and key intracellular signaling molecule [ 40 ]. The AC of CyaA of Bordetellae [ 5 , 8 ], the edema factor (EF) of Bacillus anthracis [ 41 , 42 ] and the ExoY effector of Pseudomonas aeruginosa [ 43 , 44 ] play an important role in virulence of these pathogenic bacteria. These AC enzymes exhibit a very low catalytic activity inside bacterial cytosol and are only activated upon delivery into cytosol of host eukaryotic cells, where ExoY is activated by filamentous actin [ 45 ], while the EF and the AC domain of CyaA are activated upon binding of eukaryotic CaM in a 1:1 stoichiometry [ 22 , 41 , 46 ].…”

ExoY, an actin-activated nucleotidyl cyclase toxin from P. aeruginosa: A minireview

“…Very recently, two groups independently demonstrated that ExoY activity can also lead to the inhibition of the host immune responses by suppressing the activation of TAK1 and decreasing the production of IL-1β (He et al, 2017;Jeon et al, 2017). The contribution of ExoY to P. aeruginosa virulence during acute and/or chronic infections were recently reviewed by T. Stevens and colleagues (Morrow et al, 2017). This mini-review summarizes some recent biochemical studies on ExoY and its regulation by actin.…”

Exoenzyme Y Contributes to End-Organ Dysfunction Caused by Pseudomonas aeruginosa Pneumonia in Critically Ill Patients: An Exploratory Study

“…ExoY is present in~90% of P. aeruginosa bacteria [12]. It was first described as a soluble adenylyl cyclase, generating cAMP within the cytosolic compartment.…”