Cell signaling and activation - CNRS URA 2582 – Interactions et dynamique cellulaires  

  HEADProf ISRAËL Alain / aisrael@pasteur.fr
  MEMBERSAUTRUSSEAU Elodie / AYTAC Marie-Dominique / Dr BROU Christel / CHASTAGNER Patricia / CORTE-REAL FILIPE Josina / Dr GARCIA Alphonse / Dr GUPTA-ROSSI Neetu / HEUSS Sara/ KACHANER David/ Dr LAPLANTINE Emmanuel / Dr LOGEAT Frédérique / MESSALI Nassima/ MORETTI Julien / MOURGUIN-NAGUIN Stéphanie / ORTICA Sara /PUCA Loredana/ TARANTINO Nadine/ Dr WEIL Robert
Dr DAVID-WATINE Brigitte, Dr GARCIA Alphonse

  Annual Report

SMAC (Signalisation moléculaire et activation cellulaire) is involved in the study of three signaling pathways, NF-κB, NRP/optineurin and Notch, using essentially biochemical, genetic and cell biology approaches. Recently we have focused our interest on the multiple types of ubiquitination events involved in the regulation of two of these signaling cascades. NF-κB activation represents a general stress response pathway, involved among others in the immune, inflammatory and anti-apoptotic responses. NF-κB activity is controlled by cytoplasmic retention through inhibitory molecules, which are degraded in response to multiple signals. In addition a complex network of ubiquitinated molécules and ubiquitin receptors controls the threshold and intensity of the NF-kB response. We have demonstrated that the protein NEMO, the core élément of the NF-kB cascade, is able to recognize K63-linked and linear ubiquitin chains using different combinations of ubiquitin binding domains.

Another project involves the functional characterization of the protein NRP/optineurin, which shows very strong homologies with NEMO, but is associated with the Golgi apparatus and seems to be involved in a different type of signaling activity. We have demonstrated that NRP is a new component of the innate antiviral response, and that its activity is regulated during the cell cycle.

The third signaling cascade we study centers around the Notch family of receptors, which play an important role in a large variety of developmental events. Signaling through Notch requires a series of proteolytic events which lead to the nuclear translocation of the intracellular part of the receptor, which behaves as a transcriptional co-activator. We have pursued 2 directions of research: i) we have identified a new deubiquitinase involved in trafficking of the activated Notch receptor ; ii) we have demonstrated that the intracellular region of the Notch ligands regulates their trafficking and signaling activity.

The Phosphatases E3 group (A Garcia) studies the apoptotic signals elicited by the interaction between the phosphatase PP2A1 and the HIV1 protein Vpr. A short domain called DPT-Vpr1 able to bind PP2A1 has been identified in Vpr. Current experiments indicate that the DPT-Vpr1 peptide is able to penetrate cells and induce apoptosis.

The E3 group of B David-Watine studies the protein Tpr, which is associated with the nuclear pore, and whose siRNA-mediated depletion has consequences on the functional organisation of the nuclear pore, on cell proliferation and on the basal level of protein sumoylation. The role of Tpr in the induction of senescence in tumor cells is currently studied in collaboration with Dr Kim from Institut Pasteur Korea.

Keywords: Signal transduction, NF-kappaB, optineurin, Notch, trafficking, ubiquitination


CHASTAGNIER, P., ISRAEL, A. and BROU, C. 2006. Itch/AIP4 mediates Deltex degradation through the formation of K29-linked polyubiquitin chains. EMBO Reports, 7, 1147-1153

LOBRY, C., LOPEZ, T., ISRAEL, A. and WEIL, R. 2007. Negative feed back loop in T-cell activation through IκB kinase-induced phosphorylation and degradation of Bcl10. Proc Natl Acad Sci USA, 2007, 104, 908-913

HEUSS, S., NDIAYE-LOBRY, D., SIX, E., ISRAEL, A. & LOGEAT, F. 2008. The intracellular region of Notch ligands Dll1 and Dll3 regulates their trafficking and signaling activity. Proc Natl Acad Sci USA, 2008, 105, 11212-11217

CHASTAGNER, P., ISRAEL, A. & BROU, C. 2008. AIP4/Itch regulates Notch receptor degradation in the absence of ligand. PloS One, 16;3(7), e2735.

JOURNO, C., FILIPE, J., ABOUT, F., SEBASTIEN A. CHEVALIER, SA., BRADY, JN., PHILIPPE V., AFONSO, PV., FLYNN, D., TANGY, F., ISRAEL, A., VIDALAIN, PO., MAHIEUX, R. AND WEIL, R. NRP/Optineurin cooperates with TAX1BP1 to potentiate the activation of NF-κB by Human T-Lymphotropic Virus Type 1 Tax protein. PLoS Pathogens, 2009, 5(7):e1000521

LAPLANTINE E, FONTAN E, CHIARAVALLI J, LOPEZ T, LAKISIC G, VERON M, AGOU F, ISRAEL A. NEMO specifically recognizes K63-linked polyubiquitin chains through a new bipartite ubiquitin-binding domain. EMBO J., 2009, 28, 2885-2895.

Activity Reports 2009 - Institut Pasteur
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