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Systems-level overview of host protein phosphorylation during Shigella flexneri infection revealed by phosphoproteomics


Schmutz, Christoph; Ahrne, Erik Lennart; Kasper, Christoph Alexander; Tschon, Therese; Sorg, Isabel; Dreier, Roland Felix; Schmidt, Alexander; Arrieumerlou, Cecile (2013). Systems-level overview of host protein phosphorylation during Shigella flexneri infection revealed by phosphoproteomics. Molecular & Cellular Proteomics, 12(10):2952-2968.

Abstract

The enteroinvasive bacterium Shigella flexneri invades the intestinal epithelium of humans. During infection, several injected effector proteins promote bacterial internalization, and interfere with multiple host cell responses. To obtain a systems-level overview of host signaling during infection, we analyzed the global dynamics of protein phosphorylation by LC-MS/MS and identified several hundred of proteins undergoing a phosphorylation change during the first hours of infection. Functional bioinformatic analysis revealed that they were mostly related to the cytoskeleton, transcription, signal transduction, and cell cycle. Fuzzy c-means clustering identified six temporal profiles of phosphorylation and a functional module composed of ATM-phosphorylated proteins related to genotoxic stress. Pathway enrichment analysis defined mTOR as the most overrepresented pathway. We showed that mTOR complex 1 and 2 were required for S6 kinase and AKT activation, respectively. Comparison with a published phosphoproteome of Salmonella typhimurium-infected cells revealed a large subset of co-regulated phosphoproteins. Finally, we showed that S. flexneri effector OspF affected the phosphorylation of several hundred proteins, thereby demonstrating the wide-reaching impact of a single bacterial effector on the host signaling network.

Abstract

The enteroinvasive bacterium Shigella flexneri invades the intestinal epithelium of humans. During infection, several injected effector proteins promote bacterial internalization, and interfere with multiple host cell responses. To obtain a systems-level overview of host signaling during infection, we analyzed the global dynamics of protein phosphorylation by LC-MS/MS and identified several hundred of proteins undergoing a phosphorylation change during the first hours of infection. Functional bioinformatic analysis revealed that they were mostly related to the cytoskeleton, transcription, signal transduction, and cell cycle. Fuzzy c-means clustering identified six temporal profiles of phosphorylation and a functional module composed of ATM-phosphorylated proteins related to genotoxic stress. Pathway enrichment analysis defined mTOR as the most overrepresented pathway. We showed that mTOR complex 1 and 2 were required for S6 kinase and AKT activation, respectively. Comparison with a published phosphoproteome of Salmonella typhimurium-infected cells revealed a large subset of co-regulated phosphoproteins. Finally, we showed that S. flexneri effector OspF affected the phosphorylation of several hundred proteins, thereby demonstrating the wide-reaching impact of a single bacterial effector on the host signaling network.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:Special Collections > SystemsX.ch
Special Collections > SystemsX.ch > Research, Technology and Development Projects > BattleX
Special Collections > SystemsX.ch > Research, Technology and Development Projects > InfectX
Dewey Decimal Classification:570 Life sciences; biology
Language:English
Date:2013
Deposited On:18 Sep 2013 12:43
Last Modified:06 Aug 2017 05:21
Publisher:American Society for Biochemistry and Molecular Biology
ISSN:1535-9476
Additional Information:This research was originally published in Molecular & Cellular Proteomics. Schmutz, Christoph; Ahrne, Erik Lennart; Kasper, Christoph Alexander; Tschon, Therese; Sorg, Isabel; Dreier, Roland Felix; Schmidt, Alexander; Arrieumerlou, Cecile (2013). Systems-level overview of host protein phosphorylation during Shigella flexneri infection revealed by phosphoproteomics. Molecular & Cellular Proteomics:Epub ahead of print. © the American Society for Biochemistry and Molecular Biology.
Free access at:PubMed ID. An embargo period may apply.
Publisher DOI:https://doi.org/10.1074/mcp.M113.029918
PubMed ID:23828894

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