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Lysosomal membrane permeabilization in cell death

Abstract

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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Figure 1
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Abbreviations

AIF:

apoptosis-inducing factor

AO:

acridine orange

CB:

cathepsin B

CD:

cathepsin D

CL:

cathepsin L

FAN:

factor associated with neutral sphingomyelinase activation

LAPF:

lysosome-associated protein containing PH and FYVE domains

LMP:

lysosomal membrane permeabilization

MOMP:

mitochondrial outer membrane permeabilization

PDT:

photodynamic therapy

TNF-α:

tumor necrosis factor alpha

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Acknowledgements

Research in our labs is supported by grants from Ministry of Science (BFU-2006-00508) and from Fundación La Caixa (BM06-125-1) to PB and Ligue Nationale contre le Cancer (Equipe labellisée), European Commission (Active p53, Apo-Sys, RIGHT, TransDeath, ChemoRes, DeathTrain), Agence Nationale pour la Recherche, Institut National contre le Cancer, Cancéropôle Ile-de-France and Fondation pour la Recherche Médicale to GK. We thank Ana Robles and Nick Joza for editing of the paper.

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Boya, P., Kroemer, G. Lysosomal membrane permeabilization in cell death. Oncogene 27, 6434–6451 (2008). https://doi.org/10.1038/onc.2008.310

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Keywords

  • lysosomal membrane permeabilization
  • cathepsins
  • programmed cell death
  • apoptosis
  • autophagy

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