2012年5月25日，國(guó)際著名雜志Journal of Biological Chemistry上刊登了美國(guó)南亞拉巴馬大學(xué)研究人員的最新研究成果“Pseudomonas aeruginosa Exotoxin Y is a Promiscuous Cyclase that Increase Endothelial Tau Phosphorylation and Permeability”,，文章中，研究者揭示了綠膿桿菌的外毒素T（ExoY）是一種泛宿主化的環(huán)化酶,，可以增加內(nèi)皮細(xì)胞Tau蛋白的磷酸化以及細(xì)胞通透性。
綠膿桿菌的外毒素Y,，即ExoY是該菌三型分泌系統(tǒng)的一種外毒素效應(yīng)蛋白,，在臨床分離的90%綠膿桿菌菌株中都可以發(fā)現(xiàn)該毒素蛋白。
ExoY是一種可溶性的腺苷環(huán)化酶,，可以在細(xì)菌三型分泌系統(tǒng)的幫助下進(jìn)入宿主細(xì)胞,，隨后宿主細(xì)胞中發(fā)揮作用，增加細(xì)胞質(zhì)的cAMP（3’-5’環(huán)磷酸腺苷）水平,，可以介導(dǎo)內(nèi)皮細(xì)胞Tau蛋白的高度磷酸化,，損傷細(xì)胞微管和微絲的穩(wěn)定性。進(jìn)而引發(fā)內(nèi)皮細(xì)胞間隙的形成并且增加血管的通透性,。
在這篇研究報(bào)告中,，研究者Troy Stevens表示,，綠膿桿菌（P.aeruginosa）的外毒素蛋白ExoY可以增加內(nèi)皮細(xì)胞的cAMP（3’-5’環(huán)磷酸腺苷）和cGMP(3’-5’環(huán)磷酸鳥苷)水平；細(xì)胞質(zhì)中的cAMP和低水平的cGMP菌可以介導(dǎo)內(nèi)皮細(xì)胞Tau蛋白-214位絲氨酸的高度磷酸化,，而且ExoY的毒性可以導(dǎo)致不溶性Tau蛋白的胞內(nèi)積累,。同時(shí)研究者又揭示了細(xì)胞質(zhì)中的cAMP可以導(dǎo)致大量的內(nèi)皮細(xì)胞間的間隙以及增加肺部微血管內(nèi)皮細(xì)胞的通透性，因此,，高度磷酸化和不溶性的Tau蛋白成為了類似阿爾茲海默癥的神經(jīng)變性的tau樣病變的標(biāo)志,。
研究者的研究發(fā)現(xiàn)表明，綠膿桿菌的急性感染和慢性的神經(jīng)變性疾病可以共用Tau蛋白的高度磷酸化以及蛋白不溶性來作為共同的病理生理性疾病的機(jī)制,。（生物谷：T.Shen編譯）
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.
