Apoptosis and Immune System - URA 1961 CNRS  


  HEADSUSIN, Santos A. Dr. / susin@pasteur.fr
  MEMBERSSUSIN, Santos A. DR2 CNRS, ARTUS, Cédric Post-doc, BARBIER, Sandrine PhD student
BOUHARROUR, Aïda PhD student, BOUJRAD, Hanan PhD student, ROBERT, Nadine Staff technician
AYTAC, Marie-Dominique Part time secretary


  Annual Report

Programmed cell death (PCD) is essential for the development and maintenance of cell homeostasis. Aberrations in apoptosis signaling pathways result in a variety of pathological conditions and are common in cancer cells. In fact, cellular changes leading to inhibition of apoptosis play an essential role in tumor development. The elucidation of the apoptotic pathways is thus an important area of study that may provide insight into the causes of drug resistance and facilitate the development of novel anticancer therapies. 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 or necrosis-like PCD. Our data demonstrate that CD47-mediated PCD proceeds via the induction of atypically regulated mitochondrial alterations that are independent from some of the major apoptotic effectors, such as Bax, Bak, Bim and the caspases. Indeed, our results are the first published incidence of massive mitochondrial alterations induced without the involvement of caspases, the Bcl-2 family of proteins, or the release of apoptogenic proteins from mitochondria.

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. Employing a large panel of gene knockout cells, we identify two essential molecular links between PARP and AIF: calpains and Bax (see figure below).

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

Asi.jpg

Schematic model for MNNG-induced death. MNNG-induced DNA damage leads through PARP-1 to calpain activation. Calpain in turn activates Bax, resulting in its translocation from cytosol to mitochondria, where it facilitates the release of tAIF from the mitochondrial intermembrane space to the cytosol. Activated calpain also regulates AIF release by cleaving the membrane-anchored AIF to the soluble form tAIF. Once liberated in the cytosol, tAIF translocates to the nucleus where it generates 3'-OH DNA breaks and chromatin condensation.



  Publications

1.- Moubarak RS, Yuste VJ, Greer PA, Menissier-de Murcia J, and Susin SA. 2007. Sequential Activation of PARP-1, Calpains, and Bax is Essential in AIF-Mediated Programmed Necrosis. Molecular and Cellular Biology, vol. 27, pp. 4844-4862. PMID: 17470554

2.- Bras M, Yuste VJ, Roué G, Barbier S, Sancho P, Virely C, Rubio M, Baudet S, Esquerda JE, Merle-Béral H, Sarfati M, and Susin SA. 2007. Drp1 Mediates Caspase-Independent Type III Cell Death in Normal and Leukemic Cells. Molecular and Cellular Biology, vol. 27, pp. 7073-7088. PMID: 17682056

3.- Delettre C, Yuste VJ, Moubarak RS, Bras M, Lesbordes-Brion, J-C, Petres S, Bellalou J, and Susin SA. 2006. AIFsh, a novel apoptosis-inducing factor (AIF) pro-apoptotic isoform with potential pathological relevance in human cancer. Journal of Biological Chemistry, vol 281, pp. 6413-6427. PMID: 16365034

4.- Delettre C, Yuste VJ, Moubarak RS, Bras M, Robert N, and Susin SA. 2006. Identification and characterization of AIFsh2 a novel mitochondrial apoptosis-inducing factor (AIF) isoform with NADH oxidase activity. Journal of Biological Chemistry, vol 281, pp. 18507-18518. PMID: 16644725

5.- Yuste VJ, Moubarak RS, Delettre C, Bras M, Sancho P, Robert N, d’Alayer J, and Susin SA. 2005. Cysteine protease inhibition prevents mitochondrial Apoptosis-Inducing Factor (AIF) release. Cell Death and Differentiation, vol 12, pp. 1445-1448. PMID: 15933737





Activity Reports 2007 - Institut Pasteur
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