|Biology of Cell Interactions - CNRS URA 2582|
|HEAD||Pr. DAUTRY-VARSAT Alice / firstname.lastname@example.org|
|MEMBERS||Gaëlle Boncompain / Annick Dujeancourt / Rita Furtado /Alexandre Grassart / Pr Paul Lazarow /Marie Lemesle / Valérie Malardé / Dr Meghan Pennini / Stéphanie Perrinet / Dr Nathalie Sauvonnet / Dr Agathe Subtil
The research of this unit focuses on (i) the mechanisms of entry, signaling and the intracellular fate of receptors (ii) the mechanisms of entry and development of the intracellular bacterium, Chlamydia.
Receptor dynamics and intracellular traffic
Membrane receptors bind their ligands, are endocytosed, and sorted towards degradation or recycling. Endocytosis modulates the expression of membrane components and their signaling activity.
Receptor-mediated endocytosis through clathrin-coated pits has been by far the most thoroughly investigated. However, other internalization pathways exist, and we have shown that two members of the type I cytokine receptor family, the interleukin-2 receptor (IL-2R) β and the common cytokine receptor γc, are internalized by a clathrin-independent pathway. We are investigating the molecular machinery underlying this process. Recent results show that the GTPases RhoA, Rac1 and dynamin are required for this pathway, as well as partners of these factors, the kinases Pak1, Pak2 and cortactin, thereby providing cross-talk between endocytosis, signal transduction and the actin network.
Regulation of IL-2R sorting and intracellular fate
Ubiquitination has been shown to be important for receptor internalization, sorting, and degredation. We have demonstrated that cytokine receptors, IL-2R β and γc are ubiquitinated, and their cell surface expression is regulated by a ubiquitination/de-ubiquitination machinery, namely by the couple of enzymes c-Cbl/DUB2. In addition, the ubiquitin-ligase NEDD4 associates constiutively with γc and participates to the regulation of its half-life. Ectodomain shedding can also contribute to receptor turn over. We have shown that IL-2Rβ undergoes a proteolytic cleavage, generating an intracellular fragment that remains associated with signaling molecules.
Interactions between Chlamydia and the host
Chlamydiae species pathogenic to humans, mainly Chlamydia trachomatis and Chlamydia pneumoniae, cause a number of diseases, including trachoma, pelvic inflammatory disease and pneumonia. We analyze the mechanisms used by the bacteria to enter cells and to sustain their growth.
Identification of type III secreted proteins and functional studies
Throughout their cycle in the host cell, chlamydiae remain in a membrane-bound compartment called an inclusion. Both the bacteria and the host cell contribute to the lipid and protein composition of the inclusion membrane. We have shown that chlamydiae use a type III secretion mechanism to deliver proteins into this membrane and into the cell cytosol. We have identified about thirty proteins that are secreted by this mechanism. These proteins are very likely to be important in Chlamydia pathogenicity and most of our research is dedicated to understanding their function during infection. Some recent work has focused on the interactions between bacterial proteins anchored in the inclusion membrane and host proteins specialized in membrane compartment recognition and fusion, the SNARE proteins. We have shown that some inclusion proteins possess SNARE domains that interact with SNARE proteins of the host, recruiting several intracellular compartments to the inclusion membrane. This study demonstrates for the first time mimicry of the SNARE domain by a bacterium.
Keywords: endocytosis, membrane receptor, Chlamydia, intracellular pathogen
Sauvonnet, N., A. Dujeancourt, and A. Dautry-Varsat. 2005. Cortactin and dynamin are required for the clathrin-independent endocytosis of gc cytokine receptor. J. Cell Biol. 168:155-163.
Wyplosz, B., G. Montalescot, A. Subtil, A. Dujeancourt, M.-L. Tanguy, R. Choussat, L. Capron, and A. Dautry-Varsat. 2006. Correlation between Chlamydia pneumoniae detection from coronary angioplasty balloons and atherosclerosis severity. J.A.C.C. 47:1229-1231.
Derré, I. , Pypaert , M. , Dautry-Varsat, A. and H.Agaisse. 2007. RNAi screen in Drosophila cells reveals the involvement of the Tom complex in Chlamydia infection. PLoS Path. 3:e155.
Delevoye, C., Nilges, M., Dehoux, P., Paumet, F., Perrinet, S., Dautry-Varsat, A. and Subtil, A. 2008. SNARE Protein Mimicry by an Intracellular Bacterium. PLoS Path. 4, e1000022.
Grassart, A., Dujeancourt, A., Lazarow, P. B., Dautry-Varsat, A. and Sauvonnet, N. 2008. Clathrin-independent endocytosis used by the IL-2 receptor is regulated by Rac1, Pak1 and Pak2. EMBO Rep 9, 356-62.
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