2012年5月25日，国际著名杂志Journal of Biological Chemistry上刊登了美国南亚拉巴马大学研究人员的最新研究成果“Pseudomonas aeruginosa Exotoxin Y is a Promiscuous Cyclase that Increase Endothelial Tau Phosphorylation and Permeability”，文章中，研究者揭示了绿脓杆菌的外毒素T（ExoY）是一种泛宿主化的环化酶，可以增加内皮细胞Tau蛋白的磷酸化以及细胞通透性。
绿脓杆菌的外毒素Y，即ExoY是该菌三型分泌系统的一种外毒素效应蛋白，在临床分离的90%绿脓杆菌菌株中都可以发现该毒素蛋白。
ExoY是一种可溶性的腺苷环化酶，可以在细菌三型分泌系统的帮助下进入宿主细胞，随后宿主细胞中发挥作用，增加细胞质的cAMP（3’-5’环磷酸腺苷）水平，可以介导内皮细胞Tau蛋白的高度磷酸化，损伤细胞微管和微丝的稳定性。进而引发内皮细胞间隙的形成并且增加血管的通透性。
在这篇研究报告中，研究者Troy Stevens表示，绿脓杆菌（P.aeruginosa）的外毒素蛋白ExoY可以增加内皮细胞的cAMP（3’-5’环磷酸腺苷）和cGMP(3’-5’环磷酸鸟苷)水平；细胞质中的cAMP和低水平的cGMP菌可以介导内皮细胞Tau蛋白-214位丝氨酸的高度磷酸化，而且ExoY的毒性可以导致不溶性Tau蛋白的胞内积累。同时研究者又揭示了细胞质中的cAMP可以导致大量的内皮细胞间的间隙以及增加肺部微血管内皮细胞的通透性，因此，高度磷酸化和不溶性的Tau蛋白成为了类似阿尔兹海默症的神经变性的tau样病变的标志。
研究者的研究发现表明，绿脓杆菌的急性感染和慢性的神经变性疾病可以共用Tau蛋白的高度磷酸化以及蛋白不溶性来作为共同的病理生理性疾病的机制。（生物谷：T.Shen编译）
doi:10.1074/jbc.M111.301440
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Pseudomonas aeruginosa exotoxin Y is a promiscuous cyclase that increases endothelial Tau phosphorylation and permeability
Cristhiaan D. Ochoa, Mikhail Alexeyev, Viktoriya Pastukh, Ron Balczon and Troy Stevens*
Exotoxin Y (ExoY) is a type III secretion system effector found in ~ 90% of the P. aeruginosa isolates. Although it is known that ExoY causes inter-endothelial gaps and vascular leak, the mechanisms by which this occurs are poorly understood. Using both a bacterial-delivered and a codon-optimized conditionally expressed ExoY, we report that this toxin is a dual soluble adenylyl and guanylyl cyclase that results in intracellular cAMP and cGMP accumulation. The enzymatic activity of ExoY caused endothelial Tau serine 214 phosphorylation, accumulation of insoluble Tau, inter-endothelial cell gap formation and increased macromolecular permeability. To dissect whether the cAMP or cGMP signal was responsible for Tau phosphorylation and barrier disruption, pulmonary microvascular endothelial cells were engineered for the conditional expression of either wild type guanylyl cyclase that synthesizes cGMP, or a mutated guanylyl cyclase that synthesizes cAMP. Sodium nitroprusside stimulation of the cGMP generating cyclase resulted in transient Tau serine 214 phosphorylation and gap formation, whereas stimulation of the cAMP generating cyclase induced a robust increase in Tau serine 214 phosphorylation, gap formation, and macromolecular permeability. These results indicate that the cAMP signal is the dominant stimulus for Tau phosphorylation. Hence, ExoY is a promiscuous cyclase and edema factor that uses cAMP, and to some extent cGMP, to induce the hyperphosphorylation and insolubility of endothelial Tau. Since hyperphosphorylated and insoluble Tau are hallmarks in neurodegenerative tauopathies like Alzheimer′s disease, P. aeruginosa infections acutely cause a pathophysiological sequela only previously recognized in chronic neurodegenerative brain disease.
