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      Inhibition of cathepsin B by caspase-3 inhibitors blocks programmed cell death in Arabidopsis

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          Abstract

          Programmed cell death (PCD) is used by plants for development and survival to biotic and abiotic stresses. The role of caspases in PCD is well established in animal cells. Over the past 15 years, the importance of caspase-3-like enzymatic activity for plant PCD completion has been widely documented despite the absence of caspase orthologues. In particular, caspase-3 inhibitors blocked nearly all plant PCD tested. Here, we affinity-purified a plant caspase-3-like activity using a biotin-labelled caspase-3 inhibitor and identified Arabidopsis thaliana cathepsin B3 (AtCathB3) by liquid chromatography with tandem mass spectrometry (LC-MS/MS). Consistent with this, recombinant AtCathB3 was found to have caspase-3-like activity and to be inhibited by caspase-3 inhibitors. AtCathepsin B triple-mutant lines showed reduced caspase-3-like enzymatic activity and reduced labelling with activity-based caspase-3 probes. Importantly, AtCathepsin B triple mutants showed a strong reduction in the PCD induced by ultraviolet (UV), oxidative stress (H 2O 2, methyl viologen) or endoplasmic reticulum stress. Our observations contribute to explain why caspase-3 inhibitors inhibit plant PCD and provide new tools to further plant PCD research. The fact that cathepsin B does regulate PCD in both animal and plant cells suggests that this protease may be part of an ancestral PCD pathway pre-existing the plant/animal divergence that needs further characterisation.

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          Most cited references37

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          Lysosomal membrane permeabilization in cell death.

          Mitochondrial outer membrane permeabilization (MOMP) constitutes one of the major checkpoint(s) of apoptotic and necrotic cell death. Recently, the permeabilization of yet another organelle, the lysosome, has been shown to initiate a cell death pathway, in specific circumstances. Lysosomal membrane permeabilization (LMP) causes the release of cathepsins and other hydrolases from the lysosomal lumen to the cytosol. LMP is induced by a plethora of distinct stimuli including reactive oxygen species, lysosomotropic compounds with detergent activity, as well as some endogenous cell death effectors such as Bax. LMP is a potentially lethal event because the ectopic presence of lysosomal proteases in the cytosol causes digestion of vital proteins and the activation of additional hydrolases including caspases. This latter process is usually mediated indirectly, through a cascade in which LMP causes the proteolytic activation of Bid (which is cleaved by the two lysosomal cathepsins B and D), which then induces MOMP, resulting in cytochrome c release and apoptosome-dependent caspase activation. However, massive LMP often results in cell death without caspase activation; this cell death may adopt a subapoptotic or necrotic appearance. The regulation of LMP is perturbed in cancer cells, suggesting that specific strategies for LMP induction might lead to novel therapeutic avenues.
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            Morphological classification of plant cell deaths.

            Programmed cell death (PCD) is an integral part of plant development and of responses to abiotic stress or pathogens. Although the morphology of plant PCD is, in some cases, well characterised and molecular mechanisms controlling plant PCD are beginning to emerge, there is still confusion about the classification of PCD in plants. Here we suggest a classification based on morphological criteria. According to this classification, the use of the term 'apoptosis' is not justified in plants, but at least two classes of PCD can be distinguished: vacuolar cell death and necrosis. During vacuolar cell death, the cell contents are removed by a combination of autophagy-like process and release of hydrolases from collapsed lytic vacuoles. Necrosis is characterised by early rupture of the plasma membrane, shrinkage of the protoplast and absence of vacuolar cell death features. Vacuolar cell death is common during tissue and organ formation and elimination, whereas necrosis is typically found under abiotic stress. Some examples of plant PCD cannot be ascribed to either major class and are therefore classified as separate modalities. These are PCD associated with the hypersensitive response to biotrophic pathogens, which can express features of both necrosis and vacuolar cell death, PCD in starchy cereal endosperm and during self-incompatibility. The present classification is not static, but will be subject to further revision, especially when specific biochemical pathways are better defined.
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              Metacaspases.

              Metacaspases are cysteine-dependent proteases found in protozoa, fungi and plants and are distantly related to metazoan caspases. Although metacaspases share structural properties with those of caspases, they lack Asp specificity and cleave their targets after Arg or Lys residues. Studies performed over the past 10 years have demonstrated that metacaspases are multifunctional proteases essential for normal physiology of non-metazoan organisms. This article provides a comprehensive overview of the metacaspase function and molecular regulation during programmed cell death, stress and cell proliferation, as well as an analysis of the first metacaspase-mediated proteolytic pathway. To prevent further misapplication of caspase-specific molecular probes for measuring and inhibiting metacaspase activity, we provide a list of probes suitable for metacaspases.
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                Author and article information

                Journal
                Cell Death Differ
                Cell Death Differ
                Cell Death and Differentiation
                Nature Publishing Group
                1350-9047
                1476-5403
                01 September 2016
                08 April 2016
                1 September 2016
                : 23
                : 9
                : 1493-1501
                Affiliations
                [1 ]Faculty of Life Sciences, University of Manchester, Michael Smith Building , Oxford Road, Manchester M13 9PT, UK
                [2 ]College of Marine Life Science, Ocean University of China , No. 5 Yushan Road, Qingdao, China
                [3 ]Division of Plant Science, The James Hutton Institute, Invergowrie , Dundee DD2 5DA, UK
                [4 ]Department of Applied Genetics and Cell Biology, University of Natural Resources and Life Sciences , Vienna, Austria
                Author notes
                [* ]Faculty of Life Science, University of Manchester, Michael Smith Building , Oxford Road, Manchester M13 9PT. UK. Tel: +44 (0)161 275 3922; Fax: +44 (0)161 275 5082; E-mail: patrick.gallois@ 123456manchester.ac.uk
                [5]

                These two authors contributed equally to this work.

                [6]

                Current address: UMR 1347 Agroécologie, INRA, 17 rue Sully, BP 86510, 21065 Dijon Cedex, France.

                [7]

                Current address: Laboratory of Plant Biochemistry, State University of Moldova, Mateevici street 60, Chisinau, MD-2009, Republic of Moldova.

                [8]

                Current address: IBPC, Laboratoire de Biologie Moléculaire et Cellulaire des Eucaryotes, CNRS, Université Pierre et Marie Curie, FRE3354, 75005 Paris, France.

                Author information
                http://orcid.org/0000-0003-4490-7053
                http://orcid.org/0000-0002-6305-2807
                Article
                cdd201634
                10.1038/cdd.2016.34
                5072426
                27058316
                ea4149cc-a138-4ac1-b9b7-80fbb9394e69
                Copyright © 2016 Macmillan Publishers Limited

                This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/

                History
                : 26 June 2015
                : 10 February 2016
                : 01 March 2016
                Categories
                Original Paper

                Cell biology
                Cell biology

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