Abstract
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.
Original language | English |
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Pages (from-to) | 708-722 |
Number of pages | 15 |
Journal | Nature Cell Biology |
Volume | 24 |
Issue number | 5 |
DOIs | |
Publication status | Published - May 2022 |
Bibliographical note
Funding Information:We thank S. Emr (Department of Molecular Biology and Genetics, Cornell University) for sharing plasmids and yeast strains for this study. We thank K. Lau and P. Paroutis (The Imaging Facility, The Hospital for Sick Children) for technical training and discussions of analyses. Models (Figs. 1c ,2d ,3a ,3h ,8i and Extended Data Figs. 3a ,3b ,4b ,8e) were created with BioRender.com. G.F.W.W. is supported by a Vanier Canada Graduate Scholarship from the Canadian Institutes of Health Research (CIHR) and an MD/PhD Studentship from the University of Toronto. J.H.B. is supported by CIHR grant no. FDN-154329. A.D. is funded by grant no. R01GM132565 from the National Institutes of Health. G.R.V.H. is funded by grant no. 1R35GM119412-01 from the National Institutes of Health. S.G. is supported by CIHR grant no. FDN-143202, and G.D.F. is supported by CIHR project grant no. PJT165968 and the Natural Sciences and Engineering Research Council (NSERC) of Canada.
Funding Information:
We thank S. Emr (Department of Molecular Biology and Genetics, Cornell University) for sharing plasmids and yeast strains for this study. We thank K. Lau and P. Paroutis (The Imaging Facility, The Hospital for Sick Children) for technical training and discussions of analyses. Models (Figs. ,,,, and Extended Data Figs. ,,,) were created with BioRender.com . G.F.W.W. is supported by a Vanier Canada Graduate Scholarship from the Canadian Institutes of Health Research (CIHR) and an MD/PhD Studentship from the University of Toronto. J.H.B. is supported by CIHR grant no. FDN-154329. A.D. is funded by grant no. R01GM132565 from the National Institutes of Health. G.R.V.H. is funded by grant no. 1R35GM119412-01 from the National Institutes of Health. S.G. is supported by CIHR grant no. FDN-143202, and G.D.F. is supported by CIHR project grant no. PJT165968 and the Natural Sciences and Engineering Research Council (NSERC) of Canada.
Publisher Copyright:
© 2022, The Author(s), under exclusive licence to Springer Nature Limited.
ASJC Scopus Subject Areas
- Cell Biology
PubMed: MeSH publication types
- Journal Article
- Research Support, Non-U.S. Gov't
- Research Support, N.I.H., Extramural