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Home page > Research Groups > Solange DESAGHER - Molecular Mechanisms of Apoptosis Regulation

Solange DESAGHER - Molecular Mechanisms of Apoptosis Regulation

Apoptosis is an evolutionarily conserved form of programmed cell death that is essential for morphogenesis, tissue homeostasis and defence against auto-reactive, infected or pre-cancer cells. As a consequence, alterations in apoptotic pathways contribute to the pathology of a number of human diseases. Insufficient apoptosis is necessary for tumourigenesis and favours viral infection or autoimmunity, while increased apoptosis is evident in neurodegenerative diseases, infertility and AIDS. Our main goal is to identify novel molecular mechanisms of apoptosis regulation related to the ubiquitin-proteasome system, notably in neurons.

Much progress has been made in characterizing the signalling pathways that control the survival/death fate of neurons. Mechanisms controlling the apoptotic machinery at the mitochondria have also been extensively studied. Nonetheless, little is known regarding the molecular mechanisms linking these two control points. Identifying these links is yet of crucial importance as, in most cases, permeabilisation of the outer mitochondrial membrane is the point of no return and cell death can be only prevented by acting upstream or at the level of mitochondria. Increasing data suggest that the ubiquitin-proteasome system may constitute one of the links between signalling pathways and the mitochondrial apoptotic machinery. This system is a pivotal mechanism through which cells identify, target and degrade cellular proteins, particularly short-lived regulatory proteins and damaged or misfolded proteins. The E3 ubiquitin-ligases confer a high degree of selectivity to this process by recognizing the target proteins and by favouring the conjugation of ubiquitin to specific lysine residues of their substrates. Protein ubiquitination can have various outcomes: protein degradation by the proteasome as well as changes in protein function, localization or interaction with partners. Since the early 1990s, accumulating evidence indicate that the ubiquitin-proteasome system plays an important role in the regulation of apoptosis by controlling the level or the function of key regulatory proteins. Notably, in several neuronal types, short-term treatment with proteasome inhibitors has been shown to prevent apoptosis upstream of the mitochondrial control point. This suggests that essential anti-apoptotic proteins have to be eliminated by the proteasome for the death process to be initiated in neurons. However, only a few of these proteins have been identified so far and the specific E3 ubiquitin-ligases responsible for their degradation are mostly unknown. We have identified a novel E3 ubiquitin-ligase, Trim17, in primary cultures of mouse cerebellar granule neurons that constitute one of the best characterized in vitro models of neuronal apoptosis. We found that Trim17 is both necessary and sufficient for neuronal apoptosis. Moreover, Trim17 acts upstream of the mitochondria and its pro-apoptotic effect depends on its E3 ubiquitin-ligase activity. Our current objective is to elucidate the mechanisms of action of Trim17 by identifying its partners and substrates. We have shown that Trim17 is an E3 ubiquitin-ligase for Mcl-1, an anti-apoptotic protein of the Bcl-2 family which is essential for the survival of multiple cell lineages and contributes to the tumourigenesis and drug resistance of many human cancers. We have also characterized the functional interactions between Trim17 and the transcription factor NFATc3. Indeed, we have found that Trim17 binds preferentially to the SUMOylated forms of NFATc3 and that this interaction inhibits the activity of NFATc3 by preventing its nuclear translocation. In return, NFATc3 induces the transcription of the Trim17 gene, with the resulting feedback loop providing a fine regulation of neuronal apoptosis. Using GST pull-down experiments and a Yeast two-hybrid screen, we have identified additional partners of Trim17. We are currently characterizing the function and the regulation of these proteins. These studies should contribute to the elucidation of novel molecular pathways controlling apoptosis and to the identification of novel therapeutic targets for the treatment of human disorders such as Parkinson’s disease and cancer.

Institut de Génétique Moléculaire de Montpellier
CNRS-UMR 5535 - 1919, Route de Mende - 34293 Montpellier  Cedex 5
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