Author
L Vande Walle
Bio: L Vande Walle is an academic researcher from Ghent University. The author has contributed to research in topics: Proteases & Apoptosis. The author has an hindex of 3, co-authored 4 publications receiving 859 citations.
Topics: Proteases, Apoptosis, Acquired immune system, Autophagy, Protease
Papers
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TL;DR: Findings point to a mechanism by which casp-dependent generation of Beclin-1-C creates an amplifying loop enhancing apoptosis upon growth factor withdrawal.
Abstract: Autophagy and apoptosis are two important and interconnected stress-response mechanisms. However, the molecular interplay between these two pathways is not fully understood. To study the fate and function of autophagic proteins at the onset of apoptosis, we used a cellular model system in which autophagy precedes apoptosis. IL-3 depletion of Ba/F3 cells caused caspase (casp)-mediated cleavage of Beclin-1 and PI3KC3, two crucial components of the autophagy-inducing complex. We identified two casp cleavage sites in Beclin-1, TDVD133 and DQLD149, cleavage at which yields fragments lacking the autophagy-inducing capacity. Noteworthy, the C-terminal fragment, Beclin-1-C, localized predominantly at the mitochondria and sensitized the cells to apoptosis. Moreover, on isolated mitochondria, recombinant Beclin-1-C was able to induce the release of proapoptotic factors. These findings point to a mechanism by which casp-dependent generation of Beclin-1-C creates an amplifying loop enhancing apoptosis upon growth factor withdrawal.
609 citations
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TL;DR: The current knowledge of HtrA2/Omi biology is reviewed and the signaling pathways that underlie its mitochondrial and apoptotic functions from an evolutionary perspective are discussed.
Abstract: The HtrA family refers to a group of related oligomeric serine proteases that combine a trypsin-like protease domain with at least one PDZ interaction domain. Mammals encode four HtrA proteases, named HtrA1-4. The protease activity of the HtrA member HtrA2/Omi is required for mitochondrial homeostasis in mice and humans and inactivating mutations associated with neurodegenerative disorders such as Parkinson's disease. Moreover, HtrA2/Omi is released in the cytosol, where it contributes to apoptosis through both caspase-dependent and -independent pathways. Here, we review the current knowledge of HtrA2/Omi biology and discuss the signaling pathways that underlie its mitochondrial and apoptotic functions from an evolutionary perspective.
303 citations
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TL;DR: The data suggest that the adjuvant activity of TLR agonists in mucosal vaccination may require TLR stimulation of structural cells and harnessing the effect of adjuvants on epithelial cells can improve mucosal vaccines.
59 citations
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TL;DR: Results indicate that the acylsulfonamide analogues of the aldehyde-based inhibitor VRT-043198 might have potential as a novel type of prodrug for the latter, and inhibition of caspase 1 and 11 mediated inflammation in mouse macrophages was found to correlate with the potencies of the compounds in enzymatic assays.
Abstract: As part of an ongoing effort to discover inhibitors of caspase-1 with an optimized selectivity and biopharmaceutical profile, acylsulfonamides were explored as carboxylate isosteres for caspase inhibitors. Acylsulfonamide analogues of the clinically investigated caspase-1 inhibitor VRT-043198 and of the pan-caspase inhibitor Z-VAD-CHO were synthesized. The isostere-containing analogues with an aldehyde warhead had inhibitory potencies comparable to the carboxylate references. In addition, the conformational and tautomeric characteristics of these molecules were determined using 1H- and 13C-based NMR. The propensity of acylsulfonamides with an aldehyde warhead to occur in a ring-closed conformation at physiological pH significantly increases the sensitivity to hydrolysis of the acylsulfonamide moiety, yielding the parent carboxylate containing inhibitors. These results indicate that the acylsulfonamide analogues of the aldehyde-based inhibitor VRT-043198 might have potential as a novel type of prodrug for the latter. Finally, inhibition of caspase 1 and 11 mediated inflammation in mouse macrophages was found to correlate with the potencies of the compounds in enzymatic assays.
5 citations
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TL;DR: Autophagy is a cell biological process that is a central component of the integrated stress response and can be integrated with other cellular stress responses through parallel stimulation of autophagy and other stress responses by specific stress stimuli.
3,002 citations
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French Institute of Health and Medical Research1, University of Paris-Sud2, Institut Gustave Roussy3, University of Texas Southwestern Medical Center4, Thomas Jefferson University5, University of Massachusetts Medical School6, Roswell Park Cancer Institute7, Johns Hopkins University School of Medicine8, Penn State Milton S. Hershey Medical Center9, Goethe University Frankfurt10, St. Jude Children's Research Hospital11, University of Zurich12, University College London13, University of Adelaide14, South Australia Pathology15, Ludwig Institute for Cancer Research16, University of Graz17, Istituto Superiore di Sanità18, University of Michigan19, Northwestern University20, University of Rome Tor Vergata21, University of Cambridge22, University of Bern23, Ghent University24, Harvard University25, Karolinska Institutet26, University of Leicester27
TL;DR: A functional classification of cell death subroutines is proposed that applies to both in vitro and in vivo settings and includes extrinsic apoptosis, caspase-dependent or -independent intrinsic programmed cell death, regulated necrosis, autophagic cell death and mitotic catastrophe.
Abstract: In 2009, the Nomenclature Committee on Cell Death (NCCD) proposed a set of recommendations for the definition of distinct cell death morphologies and for the appropriate use of cell death-related terminology, including 'apoptosis', 'necrosis' and 'mitotic catastrophe'. In view of the substantial progress in the biochemical and genetic exploration of cell death, time has come to switch from morphological to molecular definitions of cell death modalities. Here we propose a functional classification of cell death subroutines that applies to both in vitro and in vivo settings and includes extrinsic apoptosis, caspase-dependent or -independent intrinsic apoptosis, regulated necrosis, autophagic cell death and mitotic catastrophe. Moreover, we discuss the utility of expressions indicating additional cell death modalities. On the basis of the new, revised NCCD classification, cell death subroutines are defined by a series of precise, measurable biochemical features.
2,238 citations
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TL;DR: Recent findings on the roles of MAPK signaling pathways in human disorders, focusing on cancer and neurodegenerative diseases including AD, PD, and ALS are summarized.
1,929 citations
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TL;DR: The dialogue between autophagy and cell death pathways influences the normal clearance of dying cells, as well as immune recognition of dead cell antigens, and the disruption of the relationship between autphagy and apoptosis has important pathophysiological consequences.
Abstract: Autophagy and apoptosis control the turnover of organelles and proteins within cells, and of cells within organisms, respectively, and many stress pathways sequentially elicit autophagy, and apoptosis within the same cell. Generally autophagy blocks the induction of apoptosis, and apoptosis-associated caspase activation shuts off the autophagic process. However, in special cases, autophagy or autophagy-relevant proteins may help to induce apoptosis or necrosis, and autophagy has been shown to degrade the cytoplasm excessively, leading to 'autophagic cell death'. The dialogue between autophagy and cell death pathways influences the normal clearance of dying cells, as well as immune recognition of dead cell antigens. Therefore, the disruption of the relationship between autophagy and apoptosis has important pathophysiological consequences.
1,721 citations
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TL;DR: Comparing and contrast apoptosis pathways in Caenorhabditis elegans, Drosophila melanogaster, and mammals that indicate major mysteries remaining to be solved are compared.
Abstract: Mitochondria play key roles in activating apoptosis in mammalian cells. Bcl-2 family members regulate the release of proteins from the space between the mitochondrial inner and outer membrane that, once in the cytosol, activate caspase proteases that dismantle cells and signal efficient phagocytosis of cell corpses. Here we review the extensive literature on proteins released from the intermembrane space and consider genetic evidence for and against their roles in apoptosis activation. We also compare and contrast apoptosis pathways in Caenorhabditis elegans, Drosophila melanogaster, and mammals that indicate major mysteries remaining to be solved.
1,470 citations