Article

Caspase Cleavage Product Of BAP31 Induces Mitochondrial Fission Through Endoplasmic Reticulum Calcium Signals, Enhancing Cytochrome C Release To The Cytosol.

Department of Biochemistry, McGill University, Montreal, Quebec, Canada H3G 1Y6.
The Journal of Cell Biology (Impact Factor: 9.69). 04/2003; 160(7):1115-27. DOI: 10.1083/jcb.200212059
Source: PubMed

ABSTRACT Stimulation of cell surface death receptors activates caspase-8, which targets a limited number of substrates including BAP31, an integral membrane protein of the endoplasmic reticulum (ER). Recently, we reported that a caspase-resistant BAP31 mutant inhibited several features of Fas-induced apoptosis, including the release of cytochrome c (cyt.c) from mitochondria (Nguyen, M., D.G. Breckenridge, A. Ducret, and G.C. Shore. 2000. Mol. Cell. Biol. 20:6731-6740), implicating ER-mitochondria crosstalk in this pathway. Here, we report that the p20 caspase cleavage fragment of BAP31 can direct pro-apoptotic signals between the ER and mitochondria. Adenoviral expression of p20 caused an early release of Ca2+ from the ER, concomitant uptake of Ca2+ into mitochondria, and mitochondrial recruitment of Drp1, a dynamin-related protein that mediates scission of the outer mitochondrial membrane, resulting in dramatic fragmentation and fission of the mitochondrial network. Inhibition of Drp1 or ER-mitochondrial Ca2+ signaling prevented p20-induced fission of mitochondria. p20 strongly sensitized mitochondria to caspase-8-induced cyt.c release, whereas prolonged expression of p20 on its own ultimately induced caspase activation and apoptosis through the mitochondrial apoptosome stress pathway. Therefore, caspase-8 cleavage of BAP31 at the ER stimulates Ca2+-dependent mitochondrial fission, enhancing the release of cyt.c in response to this initiator caspase.

Download full-text

Full-text

Available from: Richard Marcellus, Feb 23, 2015
0 Followers
 · 
103 Views
  • Source
    • "Mitochondrial hyper-fission is a conserved hallmark of the stress response in higher eukaryotes [32] [33] [34] as well as yeast [35] [36] [37] (see [38] for review). In many examples, mitochondrial fission is an early event in the PCD pathway [39] [40]. Thus, the resistance to ROS-induced programmed cell death (PCD) exhibited by cyclin C null cells [6] [7] is likely due to a defect in the extensive mitochondrial fragmentation associated with cellular damage. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Mtl1 is a member of a cell wall sensor family that monitors cell wall integrity in budding yeast. In response to cell wall stress, Mtl1 activates the cell wall integrity (CWI) MAP kinase pathway which transmits this signal to the nucleus to effect changes in gene expression. One target of the CWI MAP kinase is cyclin C, a negative regulator of stress response genes. CWI activation results in cyclin C relocalization from the nucleus to the cytoplasm where it stimulates programmed cell death (PCD) before it is destroyed. This report demonstrates that under low oxidative stress conditions, a combination of membrane sensors, Mtl1 and either Wsc1 or Mid2, are required jointly to transmit the oxidative stress signal to initiate cyclin C destruction. However, when exposed to elevated oxidative stress, additional pathways independent of these three sensor proteins are activated to destroy cyclin C. In addition, N-glycosylation is important for Mtl1 function as mutating the receptor residue (Asn42) or an enzyme required for synthesis of N-acetylglucosamine (Gfa1) reduces sensor activity. Finally, combining gfa1-1 with the cyclin C null allele induces a severe synthetic growth defect. This surprising result reveals a previously unknown genetic interaction between cyclin C and plasma membrane integrity.
    Oxidative Medicine and Cellular Longevity 10/2013; 2013:320823. DOI:10.1155/2013/320823 · 3.36 Impact Factor
  • Source
    • "Indeed, the p20Bap31 fragment not only causes a release of Ca 2þ from the ER but also induces an early fragmentation of the mitochondrial reticular network in different cell lines incubated with thapsigargin (Breckenridge et al., 2003) or staurosporin (Frank et al., 2001). Moreover, fragmentation of mitochondria in response to ER stress was demonstrated to be dependent on the recruitment of Drp1, the dynamin-related protein that mediates fission of the OMM (Breckenridge et al., 2003). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Over the past years, knowledge and evidence about the existence of crosstalks between cellular organelles and their potential effects on survival or cell death have been constantly growing. More recently, evidence accumulated showing an intimate relationship between endoplasmic reticulum and mitochondria. These close contacts not only establish extensive physical links allowing exchange of lipids and calcium but they can also coordinate pathways involved in cell life and death. It is now obvious that ER dysfunction/stress and Unfolded Protein Response (UPR) as well as mitochondria play major roles in apoptosis. However, while the effects of major ER stress on cell death have been largely studied and reviewed, it becomes more and more evident that cells might regularly deal with sublethal ER stress, a condition that does not necessarily lead to cell death but might affect the function/activity of other organelles such as mitochondria. In this review, we will particularly focus on these new, interesting and intriguing metabolic and morphological events that occur during the early adaptative phase of the ER stress, before the onset of cell death, and that remain largely unknown. Relevance and implication of these mitochondrial changes in response to ER stress conditions for human diseases such as type II diabetes and Alzheimer's disease will also be considered. J. Cell. Physiol. © 2013 Wiley Periodicals, Inc.
    Journal of Cellular Physiology 09/2013; 228(9). DOI:10.1002/jcp.24360 · 3.87 Impact Factor
  • Source
    • "This induced proximity then activates the procaspase by dimerization of the zymogen followed by proteolytic cleavage [34] [35]. The procaspase-8L isoform, which is caspase-8/a with an N-terminal extension of 59 amino acids, has been shown to be widely expressed, albeit at lower levels than the caspase-8/a and b isoforms [33]. Interestingly, procas- pase-8L is not believed to interact with the DISC and is instead thought to localize with the endoplasmic reticulum and to be involved in initiation of the apoptotic signal induced by the adenovirus E1A [33]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The third edition of the Handbook of Proteolytic Enzymes aims to be a comprehensive reference work for the enzymes that cleave proteins and peptides, and contains over 800 chapters. Each chapter is organized into sections describing the name and history, activity and specificity, structural chemistry, preparation, biological aspects, and distinguishing features for a specific peptidase. The subject of chapter 507 is Caspase-8 and Caspase-10.
    Handbook of Proteolytic Enzymes, Third edited by Neil D Rawling, Guy S Salvesen, 01/2013: chapter Chapter 507 – Caspase-8 and Caspase-10: pages 2248–2252; Elsevier Ltd.., ISBN: 978-0-12-382219-2