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Kinase-independent synthesis of 3-phosphorylated phosphoinositides by a phosphotransferase
Nature Cell Biology ( IF 17.3 ) Pub Date : 2022-04-28 , DOI: 10.1038/s41556-022-00895-y
Glenn F W Walpole 1, 2 , Jonathan Pacheco 3 , Neha Chauhan 4 , Jonathan Clark 5 , Karen E Anderson 5 , Yazan M Abbas 6 , Danielle Brabant-Kirwan 7 , Fernando Montaño-Rendón 1, 8 , Zetao Liu 1, 2 , Hongxian Zhu 1, 9 , John H Brumell 1, 8, 9 , Alexander Deiters 10 , Len R Stephens 5 , Phillip T Hawkins 5 , Gerald R V Hammond 3 , Sergio Grinstein 1, 2, 4, 8 , Gregory D Fairn 2, 4, 8, 11
Affiliation  

Despite their low abundance, phosphoinositides play a central role in membrane traffic and signalling. PtdIns(3,4,5)P3 and PtdIns(3,4)P2 are uniquely important, as they promote cell growth, survival and migration. Pathogenic organisms have developed means to subvert phosphoinositide metabolism to promote successful infection and their survival in host organisms. We demonstrate that PtdIns(3,4)P2 is a major product generated in host cells by the effectors of the enteropathogenic bacteria Salmonella and Shigella. Pharmacological, gene silencing and heterologous expression experiments revealed that, remarkably, the biosynthesis of PtdIns(3,4)P2 occurs independently of phosphoinositide 3-kinases. Instead, we found that the Salmonella effector SopB, heretofore believed to be a phosphatase, generates PtdIns(3,4)P2 de novo via a phosphotransferase/phosphoisomerase mechanism. Recombinant SopB is capable of generating PtdIns(3,4,5)P3 and PtdIns(3,4)P2 from PtdIns(4,5)P2 in a cell-free system. Through a remarkable instance of convergent evolution, bacterial effectors acquired the ability to synthesize 3-phosphorylated phosphoinositides by an ATP- and kinase-independent mechanism, thereby subverting host signalling to gain entry and even provoke oncogenic transformation.



中文翻译:


通过磷酸转移酶不依赖于激酶合成 3-磷酸化磷酸肌醇



尽管磷酸肌醇的丰度较低,但它在膜运输和信号传导中发挥着核心作用。 PtdIns(3,4,5)P 3和 PtdIns(3,4)P 2尤为重要,因为它们促进细胞生长、存活和迁移。病原生物已开发出破坏磷酸肌醇代谢的方法,以促进成功感染及其在宿主生物中的生存。我们证明,PtdIns(3,4)P 2是肠道病原菌沙门氏菌志贺氏菌的效应子在宿主细胞中产生的主要产物。药理学、基因沉默和异源表达实验显着地表明,PtdIns(3,4)P 2的生物合成独立于磷酸肌醇3-激酶而发生。相反,我们发现沙门氏菌效应子 SopB(此前被认为是磷酸酶)通过磷酸转移酶/磷酸异构酶机制从头生成 PtdIns(3,4)P 2 。重组 SopB 能够在无细胞系统中从 PtdIns(4,5)P 2生成 PtdIns(3,4,5)P 3和 PtdIns(3,4)P 2 。通过一个显着的趋同进化实例,细菌效应子获得了通过 ATP 和激酶独立机制合成 3-磷酸化磷酸肌醇的能力,从而颠覆宿主信号传导以进入甚至引发致癌转化。

更新日期:2022-04-29
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