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  Director : Alain ISRAEL (aisrael@pasteur.fr)


  abstract

 

The laboratory is interested in the analysis of two signaling pathways which are characterized by inducible cytoplasmic proteolytic events that result in nuclear translocation of transcription factors. One of the projects deals with the rel/NF- kB proteins, normally retained in the cytoplasm by a family of inhibitors which are inducibly degraded by the ubiquitin-proteasome pathway following a large number of stimuli. We have identified the first human genetic disease caused by a defective NF-kB pathway. A second project concerns the Notch receptor, which signals through a series of three proteolytic steps followed by the nuclear transport of its intracellular region : we have identified a mechanism controlling this activity through degradation of the nuclear form of this receptor.



  report

cale

Genetic and biochemical analysis of the NF-kB signaling cascade (G. Courtois, R. Weil, K. Schwamborn, L. Arbibe, C. Bessia)

In collaboration with an international consortium we have shown that the human genetic disease called Incontinentia pigmenti (IP) is due to mutations in the gene encoding NEMO, leading to a complete inactivation of the NF-kB pathway (NEMO is the structural/regulatory subunit of the IKK kinase complex which is central to this signaling cascade). In collaboration with the group of JL Casanova, we have shown that NEMO mutations that do not completely abolish NF-kB activity result in a series of specific symptoms that include defects in innate immunity and a syndrom called EDA (anhidrotic ectodermal dysplasia). In collaboration with K Rajewsky we have also characterized NEMO KO mice, which represent a good animal model for IP. We have also characterized a molecule which is very similar to NEMO, which is associated with kinases in a cytoplasmic high molecular weight complex, but which is not involved in the NF-kB pathway.

Analysis of NF-kB activity in vivo (S. Mémet, A. Lilienbaum, V. Fridmacher, B. Goudeau)

Following inactivation of the gene encoding the IkBe inhibitor and the demonstration that this molecule plays a specific role in the differentiation of one T-cell precursor species and in the transcriptional control of specific immunoglobulin and cytokine sub-types, we have constructed mice where the genes encoding two inhibitors, IkBe and IkBa, have been inactivated. The phenotype of these double KO mice is more severe than that of each individual KO : they die shortly after birth and display an increased NF-kB binding activity, correlated with an overexpression of some NF-kB target genes. Analysis of IkBa/IkBe-deficient lymphoid cells at E18.5 showed an impaired B cell production, arrested at the pre-B to B cell transition, due to massive apoptosis of B cell progenitors. An unexpected role of IkBe in the homing/migration of T and B lymphocytes in secondary lymphoid organs was also revealed. These results emphasize the pivotal role of NF-kB in the homeostasis and survival of lymphocytes and suggest that its reduction or rise leads to a similar dysfunction.

On the other hand an approach aimed at expressing an inhibitor of NF-kB in a tissue-specific manner has been undertaken. Particular emphasis has been put on the brain, where the analysis of reporter lacZ mice had demonstrated an important NF-kB activity. In line with this project, the response to NF-kB activating signals is currently being studied in primary cultures of neurons.

The Notch signaling pathway (F. Logeat, C. Brou, N. Gupta, E. Six, O. LeBail)

We have proposed a model according to which the activation of the Notch cascade requires a series of 3 proteolytic steps. The first step is due to furin and is required for cell surface expression of a functional receptor. A second step is required for signaling and takes place in the extracellular region of the receptor, close to the transmembrane region. The enzyme involved has been identified as being a membrane metalloprotease called TACE, originally described as responsible for the shedding of TNF. The final step is due to an activity called g-secretase, and results in the liberation and nuclear translocation of the intracellular region of the receptor, which behaves as a transcriptional co-activator. We have recently shown that the activity of this molecule is controled by the ubiquitin-proteasome pathway : following phosphorylation by a nuclear kinase, it is recognized by an E3 ubiquitin-ligase called SEL-10, therefore leading to its degradation by the proteasome.



  publications

puce Publications of the unit on Pasteur's references database


  personnel

  Office staff Researchers Scientific trainees Other personnel
 

Marie-Dominique AYTAC – INSTITUT PASTEUR

BROU Christel – INSTITUT PASTEUR – cbrou@pasteur.fr

COURTOIS Gilles – INSERM – gmcourt@pasteur.fr

LOGEAT Frédérique – CNRS – flogeat@pasteur.fr

MEMET Sylvie – INSERM

WEIL Robert – CNRS – rweil@pasteur.fr

ARBIBE Laurence - postdoc – arbibe@pasteur.fr

GUPTA Neetu – postdoc – ngupta@pasteur.fr

SCHWAMBORN Klaus – postdoc – klaus@pasteur.fr

SIX Emmanuelle – PhD Student – esix@pasteur.fr

LE BAIL Odile (engineer) – INSTITUT PASTEUR – olebail@pasteur.fr

BESSIA Christine (technician) – INSTITUT PASTEUR – cbessia@pasteur.fr

MOURGUIN-NAGUIN Stéphanie – INSTITUT PASTEUR


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