Stress-induced apoptosis is impaired in cells with a lysosomal targeting defect but is not affected in cells synthesizing a catalytically inactive cathepsin D

Tardy, Claudine; Tyynelä, Jaana; Hasilík, Andrej; Levade, Thierry

doi:10.1038/sj.cdd.4401272

Cited by 31 publications

(21 citation statements)

References 67 publications

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“…Altogether, these findings suggest that stress-induced ceramide generation precedes activation of the lysosomal pathway, in agreement with our previous study (53). However, further investigations are needed to clarify how, where, and with which proteases the ceramide pathway is connected with the lysosome in TNFinduced apoptosis.…”

Section: Figsupporting

confidence: 92%

“…Previous studies showed that pepstatin A, an aspartic protease inhibitor, did not inhibit TNF-induced cell death (53). As shown in Fig.…”

Section: Effect Of Cathepsin Inhibitors On Tnf-induced Cell Death In mentioning

confidence: 66%

“…1, A-C) or untransformed (Fig. 1D) fibroblasts derived from normal individuals with those on fibroblasts isolated from ICD patients, in which the activity of almost all lysosomal enzymes is severely impaired (53). The cytotoxic effect of TNF on control cells, in the presence of cycloheximide, was time (Fig.…”

Section: I-cell Disease Fibroblasts Are Partially Resistant To Tnfmentioning

confidence: 89%

“…1, B and D), suggesting that some lysosomal enzymes are key effectors of TNF-induced cytotoxicity in human fibroblasts. In addition, ICD fibroblasts were also partially resistant to staurosporine-induced cell death (53).…”

Section: I-cell Disease Fibroblasts Are Partially Resistant To Tnfmentioning

confidence: 98%

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Mannose 6-Phosphorylated Proteins Are Required for Tumor Necrosis Factor-induced Apoptosis

Tardy¹,

Autefage

Garcia

et al. 2004

Journal of Biological Chemistry

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Whereas caspases are essential components in apoptosis, other proteases seem to be involved in programmed cell death. This study investigated the role of lysosomal mannose 6-phosphorylated proteins in tumor necrosis factor (TNF)-induced apoptosis. We report that fibroblasts isolated from patients affected with inclusion-cell disease (ICD), having a deficient activity of almost all lysosomal hydrolases, are resistant to the toxic effect of TNF. These mutant cells exhibited a defect in TNF-induced caspase activation, Bid cleavage, and release of cytochrome c. In contrast, TNF-induced p42/ p44 MAPK activation and CD54 expression remained unaltered. Human ICD lymphoblasts and fibroblasts derived from mice nullizygous for Igf2 and the two mannose 6-phosphate (M6P) receptors, Mpr300 and Mpr46, which develop an ICD-like phenotype, were also resistant to CD95 ligand and TNF, respectively. Moreover, correction of the lysosomal enzyme defect of ICD fibroblasts, using a medium enriched in M6P-containing proteins, enabled restoration of sensitivity to TNF. This effect was blocked by exogenous M6P but not by cathepsin B or L inhibitors. Altogether, these findings suggest that some M6P-bearing glycoproteins modulate the susceptibility to TNF-induced apoptosis. As a matter of fact, exogenous tripeptidyl peptidase 1, a lysosomal carboxypeptidase, could sensitize ICD fibroblasts to TNF. These observations highlight the hitherto unrecognized role of some mannose 6-phosphorylated proteins such as tripeptidyl peptidase 1 in the apoptotic cascade triggered by TNF.

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Section: Figsupporting

confidence: 92%

“…Previous studies showed that pepstatin A, an aspartic protease inhibitor, did not inhibit TNF-induced cell death (53). As shown in Fig.…”

Section: Effect Of Cathepsin Inhibitors On Tnf-induced Cell Death In mentioning

confidence: 66%

Section: I-cell Disease Fibroblasts Are Partially Resistant To Tnfmentioning

confidence: 89%

Section: I-cell Disease Fibroblasts Are Partially Resistant To Tnfmentioning

confidence: 98%

See 2 more Smart Citations

Mannose 6-Phosphorylated Proteins Are Required for Tumor Necrosis Factor-induced Apoptosis

Tardy¹,

Autefage

Garcia

et al. 2004

Journal of Biological Chemistry

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“…These data suggests that CD promote apoptosis induced by cytotoxic and stress agents. It should be noted, however, that the central role of CD in induced apoptosis has been challenged by other reports [128,129]. Moreover, anti-apoptotic role of CD has been also described.…”

Section: Apoptosismentioning

confidence: 92%

Cathepsin D—Many functions of one aspartic protease

Beneš

Větvička

Fusek

2008

Critical Reviews in Oncology/Hematology

532

474

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For years, it has been held that cathepsin D (CD) is involved in rather nonspecific protein degradation in a strongly acidic milieu of lysosomes. Studies with CD knock-out mice revealed that CD is not necessary for embryonal development but it is indispensable for postnatal tissue homeostasis. Mutation that abolishes CD enzymatic activity causes neuronal ceroid lipofuscinosis (NCL) characterized by severe neurodegeneration, developmental regression, visual loss and epilepsy in both animals and humans.In the last decade, however, an increasing number of studies demonstrated that enzymatic function of CD is not restricted solely to acidic milieu of lysosomes with important consequences in regulation of apoptosis. In addition to CD enzymatic activity, it has been shown that apoptosis is also regulated by catalytically inactive mutants of CD which suggests that CD interacts with other important molecules and influences cell signaling.Moreover, procathepsin D, secreted from cancer cells, acts as a mitogen on both cancer and stromal cells and stimulates their pro-invasive and pro-metastatic properties. Numerous studies found that pCD/CD level represents an independent prognostic factor in a variety of cancers and is therefore considered to be a potential target of anti-cancer therapy.Studies dealing with functions of cathepsin D are complicated by the fact that there are several simultaneous forms of CD in a cell -pCD, intermediate enzymatically active CD and mature heavy and light chain CD. It became evident that these forms may differently regulate the above mentioned processes.In this article, we review the possible functions of CD and its various forms in cells and organisms during physiological and pathological conditions.

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Identifying Targets in α‐Synuclein Metabolism to Treat Parkinson Disease and Related Disorders

Tomlinson

Cullen²,

Schlossmacher

2010

Protein Misfolding Diseases

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Stress-induced apoptosis is impaired in cells with a lysosomal targeting defect but is not affected in cells synthesizing a catalytically inactive cathepsin D

Cited by 31 publications

References 67 publications

Mannose 6-Phosphorylated Proteins Are Required for Tumor Necrosis Factor-induced Apoptosis

Mannose 6-Phosphorylated Proteins Are Required for Tumor Necrosis Factor-induced Apoptosis

Cathepsin D—Many functions of one aspartic protease

Identifying Targets in α‐Synuclein Metabolism to Treat Parkinson Disease and Related Disorders

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