Apoptosis and Immune System - CNRS URA1961  

  HEADDr SUSIN, Santos A. / susin@pasteur.fr
  MEMBERSDr ARTUS Cédric / BARBIER Sandrine / BRAS Marlène / MOUBARAK Rana / BOUJRAD Hanan

  Annual Report

Programmed cell death (PCD) is essential for the development and maintenance of immune cell homeostasis. Aberrations in apoptosis signaling pathways result in a variety of pathological conditions and are common in cancer cells. In mammalian cells, the onset of apoptosis correlates with the activation of a family of cystein proteases called caspases. However, new evidence indicates that T and B cell elimination does not depend only on caspases. Alternative caspase-independent models have therefore been proposed.

The Apoptosis and Immune System team is devoted to performing an exhaustive work characterizing both the principal agents involved and the pathways implicated in caspase-independent cell death. Our research work has developed in two main directions:

Aim 1.- A first aspect, mainly performed in normal and leukemic primary B-cells, reports the cellular and biochemical mechanisms regulating the least understood form of caspase-independent cell death: type III PCD. As a model of study we are interested in the knowledge of the molecular basis regulating CD47 mediated PCD in B-chronic lymphocytic leukemia (CLL). Our study performed in B-cells from 30 CLL patients demonstrates that, even in CLL apoptotic resistant cells, it is possible to bring on PCD through the induction of this type III PCD.

Aim 2.- A second part of our work addressed molecular and mechanistic questions related to the function of the mitochondrial protein AIF, a bifunctional NADH oxidase involved in mitochondrial respiration and caspase-independent apoptosis. Our research project on AIF leads to the understanding of the molecular mechanisms regulating its mitochondrial release and to the characterization of two new AIF isoforms (AIFsh and AIFsh2). More recently, we integrated our results into a caspase-independent cell death pathway controlled by AIF: alkylating DNA-damage mediated death. This work confirms that, similarly to apoptosis, caspase-independent AIF-mediated death is a highly regulated form of PCD.

The understanding of caspase-independent mechanisms in normal and pathological regulation of apoptosis should provide conceptual progress for therapeutic interventions in deficient or excessive PCD. Combination of caspase-directed and alternative therapies based on caspase-independent death effectors offers a more efficient therapeutic approach to circumvent the commonly observed cell death resistance of transformed cells. Additionally, the unraveling of the mechanisms governing alternative caspase-independent cell death pathways will lead to a better comprehension of immune cell homeostasis, our long term goal.

Keywords: Apoptosis, Apoptosis Inducing Factor (AIF), Cancer, B-chronic lymphocytic leukemia, Caspase-independent cell death


Figure: Représentation schématique de la structure du gène AIF et des isoformes protéiques qui en résultent. Organisation du gène AIF et des différents transcripts AIF, AIF-exB, AIFsh, AIFsh2 et AIFsh3 (ligne grise). Les codons d’initiation (ATG) et de fin de transcription (TGA/TAA) sont indiqués, les produits protéiques attendus sont représentés à droite. Les nombres désignent les exons dans la structure du gène d’AIF et les acides aminés dans la protéine. Les séquences MLS (séquence de localisation mitochondriale), Pyr-redox, NLS (séquence de localisation nucléaire) et C-terminale sont représentées.

Figure Schematic representation of the AIF gene structure, and resulting protein isoforms. Genomic organization of AIF and resulting AIF, AIF-exB, AIFsh, AIFsh2, and AIFsh3 mRNA transcripts (grey line). Translation start (ATG) and stop (TGA/TAA) codons are indicated, and the predicted protein product is shown to the right. Numbers in AIF designate exons and, in predicted proteins, aminoacids. MLS (mitochondrial localization sequence), Pyr-Redox, NLS (nuclear localization sequence) and C-terminal domains are indicated.


Publications 2006 of the unit on Pasteur's references database

Activity Reports 2006 - Institut Pasteur
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