Institut de recherche biomédicale
     

    Project 2

    •  

    Characterization of the cellular pathways controlling the survival of infected cells

     

    Principal Investigator : Cécile Arrieumerlou

    cecile.arrieumerlou@inserm.fr
    Phone : 01 40 51 64 76


    Objective


    Like other pathogens, S. flexneri actively replicates inside epithelial cells. To sustain growth, intracellular bacteria steal nutrients from infected cells and impose an important metabolic stress that reduces cellular ATP levels. In addition, infection causes DNA breaks and damages of mitochondria. Interestingly, despite an overwhelming bacterial burden, epithelial cells remain alive several hours post infection. This is explained by the ability of bacteria to manipulate host cell death/survival signals via type III secreted proteins. Among others, the IpgD effector plays a role in this process. It harbors a phosphoinositide 4-phosphatase activity generating phosphatidylinositol 5 monophosphate (PtdIns5P) and activates the pro-survival AKT pathway of infected cells by a yet uncharacterized mechanism.


    Research interests

     

    By performing LC-MS/MS-based phosphoproteomics experiments, we determined the dynamics of host phosphorylation after S. flexneri infection of epithelial cells http://www.ncbi.nlm.nih.gov/pubmed/23828894. We found that mTOR signaling is highly enriched in the phosphoproteome of infected cells, and that this pathway controls AKT activation. mTOR is a central serine/threonine protein kinase that regulates cell growth, metabolism, autophagy, the actin cytoskeleton, cell proliferation, cell survival and protein synthesis. mTOR deregulation occurs in human disease, including cancer, obesity, type 2 diabetes, and neurodegeneration. It is found as part of two different protein complexes: mTOR complex 1 (mTORC1) and complex 2 (mTORC2). While both complexes are activated during infection, we showed that AKT is activated by mTORC2. mTORC2 is generally regulated by insulin, growth factors and nutrient levels but its mechanism of activation remains largely unknown. As mTORC2 is a central player of both bacterial and viral infection and has a broad impact in health and disease in general, we are particularly interested in its mode of activation. We use an original protein delivery tool developed in the laboratory to explore the implication of the proteins PI3K, IPMK and the PI5P and PIP3 phospholipids in this process.

     

    Publications


    Schmutz C, Ahrne EL, Kasper CA, Tschon T, Sorg I, Dreier RF, Schmidt A, Arrieumerlou C. Systems-level overview of host protein phosphorylation during Shigella flexneri infection revealed by phosphoproteomics. Mol Cell Proteomics. 2013 Oct; 12(10):2952-68.

     

    Financial supports

    This project is supported by the Swiss National fund and INSERM.





    Equipes du département