Lysosomes and lysosomal cathepsins in cell death

Repnik, Urška; Stoka, Veronika; Türk, Vito; Turk, Boris

doi:10.1016/j.bbapap.2011.08.016

Cited by 347 publications

(272 citation statements)

References 170 publications

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“…Lysosome impairment induced by small molecules, such as lysosomotropic agents, results in massive release of lysosomal hydrolases into the cell cytoplasm and triggers cell death responses 2,3 . These treatments inactivate lysosomes globally within a cell (all lysosomes can become targeted) and abrogate the ability of a cell to complete autophagic responses as that requires the presence of active lysosomes.…”

Section: Spatiotemporally Controlled Induction Of Lysosomal Damagementioning

confidence: 99%

“…Because of the large variety of hydrolytic enzymes contained within lysosomal lumens (to carry out the degradation of biomolecules), it was proposed more than 50 years ago by Nobel laureate Christian de Duve that release of lysosomal hydrolases from broken lysosomes into the cell cytoplasm would be detrimental to a cell 1 . Indeed, it is now established that treatment of cells with lysosomotropic agents that destabilize lysosomal membranes in detergent-like fashions cause the release of lysosomal hydrolases such as cathepsins into the cell cytoplasm, leading to apoptosis or necrosis 2,3 . This led us to hypothesize that the existence of lysosome-maintenance mechanisms will alleviate cells from potentially harmful effects of impaired lysosomes.…”

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confidence: 99%

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Spatiotemporally controlled induction of autophagy-mediated lysosome turnover

et al. 2013

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Lysosomes are the major degradative compartments within cells, harbouring a wide variety of hydrolytic enzymes within their lumen. Release of lysosomal hydrolases from lysosomes into the cell cytoplasm results in cell death. Here we report that damaged lysosomes undergo autophagic turnover. Using a light-induced lysosome impairing scheme that can be controlled spatially and temporally within a cell, we show that damaged lysosomes are selectively ubiquitinated, recruit autophagic proteins and are eventually incorporated into autolysosomes for degradation. We propose that autophagic removal of lysosomes, which we term lysophagy, is a surveillance mechanism that alleviates cells from the adverse effects of lysosomal damage. We envision our method to induce lysosomal damage will enable detailed molecular studies of the lysophagy pathway in the future.

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Section: Spatiotemporally Controlled Induction Of Lysosomal Damagementioning

confidence: 99%

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confidence: 99%

Spatiotemporally controlled induction of autophagy-mediated lysosome turnover

et al. 2013

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“…Collectively, it is now clear that LMP is tightly associated with cell death, but the molecular mechanisms downstream of LMP differ and depend on the LMP trigger and cell type (Turk and Turk, 2009;Repnik et al, 2012;Aits and Jaattela, 2013;Ashoor et al, 2013). …”

Section: Lysosomal Membrane Permeabilization and Lysosomotropic Reagentsmentioning

confidence: 99%

“…Lysosomal integral membrane proteins (LIMPs) and lysosomal associated membrane proteins (LAMPs) are protected against the attack of proteases by heavy glycosylation, which forms gylcocalyx. Membrane is additionally stabilized by heat shock protein 70 kDa (Hsp70) and cholesterol (Saftig et al, 2010;Repnik et al, 2012;Galluzzi et al, 2014;Mrschtik and Ryan, 2015).…”

Section: Introduction: Lysosomes and Lysosomal Biologymentioning

confidence: 99%

Lysosomes in programmed cell death pathways: from initiators to amplifiers

Kavčič

Pegan

Turk

2016

Biological Chemistry

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Lysosome is the central organelle for intracellular degradation of biological macromolecules and organelles. The material destined for degradation enters the lysosomes primarily via endocytosis, autophagy and phagocytosis, and is degraded through the concerted action of more than 50 lysosomal hydrolases. However, lysosomes are also linked with numerous other processes, including cell death, inflammasome activation and immune response, as well as with lysosomal secretion and cholesterol recycling. Among them programmed cell death pathways including apoptosis have received major attention. In most of these pathways, cell death was accompanied by lysosomal membrane permeabilization and release of lysosomal constituents with an involvement of lysosomal hydrolases, including the cathepsins. However, it is less clear, whether lysosomal membrane permeabilization is really critical for the initiation of cell death programme(s). Therefore, the role of lysosomal membrane permeabilization in various programmed cell death pathways is reviewed, as well as the mechanisms leading to it.

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“…First, they might leak out of the vesicular compartments during the intracellular sorting process or under certain cellular conditions that damage vesicular membranes. However, such leakage from the lysosomal compartment is widely considered as an event that is restricted to cell death 5,6 . Second, nucleo-cytosolic cathepsins may not enter the ER at all.…”

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confidence: 99%

Out-of-frame start codons prevent translation of truncated nucleo-cytosolic cathepsin L in vivo

et al. 2014

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The lysosomal protease cathepsin L has been reported to cleave various functionally important cytosolic or nuclear proteins. To explain nucleo-cytosolic localization of cathepsin L, it has been hypothesized that skipping of the first start codon during translation initiation results in an N-terminally truncated protein lacking the endoplasmic reticulum-import signal. Here we demonstrate that out-of-frame AUGs prevent translation of truncated cathepsin L in cell culture as well as in a new knock-in mouse model. We further evaluate potential roles of nuclear cathepsin L during early embryonic development. Our analysis reveals normal epiblast development of cathepsin L-deficient embryos, but uncovers a pronounced lysosomal storage phenotype in the extra-embryonic tissue of the visceral endoderm. In conclusion, the phenotypes of cathepsin L deficiency can be fully assigned to lack of canonically targeted cathepsin L, while the biogenesis and functionality of nucleo-cytosolic cathepsin L remain elusive.

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Lysosomes and lysosomal cathepsins in cell death

Cited by 347 publications

References 170 publications

Spatiotemporally controlled induction of autophagy-mediated lysosome turnover

Spatiotemporally controlled induction of autophagy-mediated lysosome turnover

Lysosomes in programmed cell death pathways: from initiators to amplifiers

Out-of-frame start codons prevent translation of truncated nucleo-cytosolic cathepsin L in vivo

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