RT Journal Article SR Electronic T1 Phosphatidylinositol 3-kinase-independent synthesis of PtdIns(3,4)P2 by a phosphotransferase JF bioRxiv FD Cold Spring Harbor Laboratory SP 2021.05.25.445663 DO 10.1101/2021.05.25.445663 A1 Glenn F. W. Walpole A1 Jonathan Pacheco A1 Neha Chauhan A1 Yazan M. Abbas A1 Fernando Montaño-Rendón A1 Zetao Liu A1 Hongxian Zhu A1 John H. Brumell A1 Alexander Deiters A1 Gerald R.V. Hammond A1 Sergio Grinstein A1 Gregory D. Fairn YR 2021 UL http://biorxiv.org/content/early/2021/05/25/2021.05.25.445663.abstract AB Despite their comparatively 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 within host organisms. We demonstrate that PtdIns(3,4)P2 is generated in host cells by 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)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 signaling to gain entry and even provoke oncogenic transformation.Competing Interest StatementThe authors have declared no competing interest.