Pseudomonas aeruginosaExoY, a cyclic GMP- and cyclic UMP-generating nucleotidyl cyclase

Seifert, Roland; Hartwig, Christina; Wolter, Sabine; Reinecke, Daniel; Burhenne, Heike; Kaever, Volkhard; Munder, Antje; Tümmler, Burkhard; Schwede, Frank; Grundmann, Manuel; Kostenis, Evi; Frank, Dara W.; Beckert, Ulrike

doi:10.1186/2050-6511-14-s1-o36

Cited by 3 publications

(3 citation statements)

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“…Our previous studies addressed ExoY's mechanism of action in the endothelium and the pulmonary microvasculature (5,41,55). Our laboratory and others have determined that ExoY is a purine and pyrimidine cyclase that synthesizes cytosolic cAMP, cGMP, and cUMP (39,41,59,72). The cAMP signal, in particular, results in endothelial cell tau hyperphosphorylation and insolubility, which result in dissociation of tau from microtubules, leading to their breakdown (5,46,55).…”

Section: Discussionmentioning

confidence: 99%

“…These cellular effects depend on the ability of ExoY to generate intracellular cyclic nucleotides, including cAMP, cGMP, and cUMP (41,59,72). While we know that the ExoY-dependent production of cAMP best correlates with cell rounding (41,46,55) and that activation of other soluble adenylyl cyclases mimics these cellular effects (46,54), the physiological function(s) of cGMP and cUMP remain(s) poorly understood.…”

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confidence: 99%

“…Among these effector proteins, ExoU and ExoY have recently garnered considerable attention, because ExoU is a phospholipase that is highly cytotoxic (71) and because ExoY is a soluble purine and pyrimidine cyclase (41,59,72) that is found in ϳ90% of P. aeruginosa isolates (17). P. aeruginosa gains access to pulmonary endothelium through the general circulation or following disruption of the alveolar epithelium.…”

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confidence: 99%

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Pseudomonas aeruginosa exoenzymes U and Y induce a transmissible endothelial proteinopathy

Morrow

Ochoa

Balczon

et al. 2016

American Journal of Physiology-Lung Cellular and Molecular Phys

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We tested the hypothesis that Pseudomonas aeruginosa type 3 secretion system effectors exoenzymes Y and U (ExoY and ExoU) induce release of a highmolecular-weight endothelial tau, causing transmissible cell injury characteristic of an infectious proteinopathy. Both the bacterial delivery of ExoY and ExoU and the conditional expression of an activity-attenuated ExoU induced time-dependent pulmonary microvascular endothelial cell gap formation that was paralleled by the loss of intracellular tau and the concomitant appearance of high-molecular-weight extracellular tau. Transfer of the highmolecular-weight tau in filtered supernatant to naïve endothelial cells resulted in intracellular accumulation of tau clusters, which was accompanied by cell injury, interendothelial gap formation, decreased endothelial network stability in Matrigel, and increased lung permeability. Tau oligomer monoclonal antibodies captured monomeric tau from filtered supernatant but did not retrieve higher-molecular-weight endothelial tau and did not rescue the injurious effects of tau. Enrichment and transfer of high-molecularweight tau to naïve cells was sufficient to cause injury. Thus we provide the first evidence for a pathophysiological stimulus that induces release and transmissibility of high-molecular-weight endothelial tau characteristic of an endothelial proteinopathy.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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Pseudomonas aeruginosa exoenzymes U and Y induce a transmissible endothelial proteinopathy

Morrow

Ochoa

Balczon

et al. 2016

American Journal of Physiology-Lung Cellular and Molecular Phys

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Regulation of HCN Ion Channels by Non-canonical Cyclic Nucleotides

VanSchouwen

Melacini

2016

Non-Canonical Cyclic Nucleotides

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The hyperpolarization-activated cyclic-nucleotide-modulated (HCN) proteins are cAMP-regulated ion channels that play a key role in nerve impulse transmission and heart rate modulation in neuronal and cardiac cells, respectively. Although they are regulated primarily by cAMP, other cyclic nucleotides such as cGMP, cCMP, and cUMP serve as partial agonists for the HCN2 and HCN4 isoforms. By competing with cAMP for binding, these non-canonical ligands alter ion channel gating, and in turn, modulate the cAMP-dependent activation profiles. The partial activation of non-canonical cyclic nucleotides can be rationalized by either a partial reversal of a two-state inactive/active conformational equilibrium, or by sampling of a third conformational state with partial activity. Furthermore, different mechanisms and degrees of activation have been observed upon binding of non-canonical cyclic nucleotides to HCN2 versus HCN4, suggesting that these ligands control HCN ion channels in an isoform-specific manner. While more work remains to be done to achieve a complete understanding of ion channel modulation by non-canonical cyclic nucleotides, it is already clear that such knowledge will ultimately prove invaluable in achieving a more complete understanding of ion channel signaling in vivo, as well as in the development of therapeutics designed to selectively modulate ion channel gating.

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The Pseudomonas aeruginosa exoenzyme Y impairs endothelial cell proliferation and vascular repair following lung injury

Stevens

Ochoa

Morrow

et al. 2014

American Journal of Physiology-Lung Cellular and Molecular Phys

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Exoenzyme Y (ExoY) is a Pseudomonas aeruginosa toxin that is introduced into host cells through the type 3 secretion system (T3SS). Once inside the host cell cytoplasm, ExoY generates cyclic nucleotides that cause tau phosphorylation and microtubule breakdown. Microtubule breakdown causes interendothelial cell gap formation and tissue edema. Although ExoY transiently induces interendothelial cell gap formation, it remains unclear whether ExoY prevents repair of the endothelial cell barrier. Here, we test the hypothesis that ExoY intoxication impairs recovery of the endothelial cell barrier following gap formation, decreasing migration, proliferation, and lung repair. Pulmonary microvascular endothelial cells (PMVECs) were infected with P. aeruginosa strains for 6 h, including one possessing an active ExoY (PA103 exoUexoT::Tc pUCPexoY; ExoY(+)), one with an inactive ExoY (PA103ΔexoUexoT::Tc pUCPexoY(K81M); ExoY(K81M)), and one that lacks PcrV required for a functional T3SS (ΔPcrV). ExoY(+) induced interendothelial cell gaps, whereas ExoY(K81M) and ΔPcrV did not promote gap formation. Following gap formation, bacteria were removed and endothelial cell repair was examined. PMVECs were unable to repair gaps even 3-5 days after infection. Serum-stimulated growth was greatly diminished following ExoY intoxication. Intratracheal inoculation of ExoY(+) and ExoY(K81M) caused severe pneumonia and acute lung injury. However, whereas the pulmonary endothelial cell barrier was functionally improved 1 wk following ExoY(K81M) infection, pulmonary endothelium was unable to restrict the hyperpermeability response to elevated hydrostatic pressure following ExoY(+) infection. In conclusion, ExoY is an edema factor that chronically impairs endothelial cell barrier integrity following lung injury.

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Pseudomonas aeruginosaExoY, a cyclic GMP- and cyclic UMP-generating nucleotidyl cyclase

Cited by 3 publications

References 5 publications

Pseudomonas aeruginosa exoenzymes U and Y induce a transmissible endothelial proteinopathy

Pseudomonas aeruginosa exoenzymes U and Y induce a transmissible endothelial proteinopathy

Regulation of HCN Ion Channels by Non-canonical Cyclic Nucleotides

The Pseudomonas aeruginosa exoenzyme Y impairs endothelial cell proliferation and vascular repair following lung injury

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