Cathepsin D Primes Caspase-8 Activation by Multiple Intra-chain Proteolysis

Conus, Sébastien; Pop, Cristina; Snipas, Scott J.; Salvesen, Guy S.; Simon, Hans‐Uwe

doi:10.1074/jbc.m111.306399

Cited by 47 publications

(29 citation statements)

References 46 publications

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“…In melanocytes, UVA-induced apoptosis is mediated by lysosomal membrane permeabilization and release of cathepsins to the cytosol (Bivik et al, 2007). It has been suggested that cathepsin D activates caspase-8 in in vitro experiments (Conus et al, 2008;Conus et al, 2012), which further supports our findings. Cathepsin inhibitors would not only prevent the proteolytic activity of the proteases in the lysosomes but also when cathepsins have been released to the cytosol following lysosomal membrane permeabilization.…”

Section: Discussionsupporting

confidence: 79%

Lysosomal exocytosis and caspase-8 mediated apoptosis in UVA-irradiated keratinocytes

Appelqvist¹,

Wäster²,

Eriksson³

et al. 2013

Journal of Cell Science

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SummaryUltraviolet (UV) irradiation is a major environmental carcinogen involved in the development of skin cancer. To elucidate the initial signaling during UV-induced damage in human keratinocytes, we investigated lysosomal exocytosis and apoptosis induction. UVA, but not UVB, induced plasma membrane damage, which was repaired by Ca 2+ -dependent lysosomal exocytosis. The lysosomal exocytosis resulted in extracellular release of cathepsin D and acid sphingomyelinase (aSMase). Two hours after UVA irradiation, we detected activation of caspase-8, which was reduced by addition of anti-aSMAse. Furthermore, caspase-8 activation and apoptosis was reduced by prevention of endocytosis and by the use of cathepsin inhibitors. We conclude that lysosomal exocytosis is part of the keratinocyte response to UVA and is followed by cathepsin-dependent activation of caspase-8. The findings have implications for the understanding of UV-induced skin damage and emphasize that UVA and UVB initiate apoptosis through different signaling pathways in keratinocytes.

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Section: Discussionsupporting

confidence: 79%

Lysosomal exocytosis and caspase-8 mediated apoptosis in UVA-irradiated keratinocytes

Appelqvist¹,

Wäster²,

Eriksson³

et al. 2013

Journal of Cell Science

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“…Furthermore, our hypothesis is able to explain previous observations regarding CD cleavage. For instance, the recently reported CD-cleaved sites identified in caspase-8 [13], Bid [39] and Aven [40] contain hydrophobic residues at either P1 or P1’ and are associated with an HSN of more than 1.0. We also carefully examined the sites of CD cleavage reported by Impens et al [33].…”

Section: Discussionmentioning

confidence: 99%

“…Because of dual locations of CD, being either located in organelles such as in the cytoplasm, lysosomes and phagosomes, or secreted into the ECM, it participates in a number of physiological processes, including cell proliferation [12], apoptosis [13], [14], senescence [15] and tissue homeostasis [16]. CD is also known to take part in various pathological processes; it is likely involved in cancer development as well as metastasis [12], [17], atherosclerosis [18], [19] and Alzheimer’s disease [20], [21].…”

Section: Introductionmentioning

confidence: 99%

Proteolytic Characteristics of Cathepsin D Related to the Recognition and Cleavage of Its Target Proteins

et al. 2013

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Cathepsin D (CD) plays an important role in both biological and pathological processes, although the cleavage characteristics and substrate selection of CD have yet to be fully explored. We employed liquid chromatography-tandem mass spectrometry (LC-MS/MS) to identify the CD cleavage sites in bovine serum albumin (BSA). We found that the hydrophobic residues at P1 were not only a preferential factor for CD cleavage but that the hydrophobicity at P1’ also contributed to CD recognition. The concept of hydrophobic scores of neighbors (HSN) was proposed to describe the hydrophobic microenvironment of CD recognition sites. The survey of CD cleavage characteristics in several proteins suggested that the HSN was a sensitive indicator for judging the favorable sites in peptides for CD cleavage, with HSN values of 0.5–1.0 representing a likely threshold. Ovalbumin (OVA), a protein resistant to CD cleavage in its native state, was easily cleaved by CD after denaturation, and the features of the cleaved peptides were quite similar to those found in BSA, where a higher HSN value indicated greater cleavability. We further conducted two-dimensional gel electrophoresis (2DE) to find more proteins that were insensitive to CD cleavage in CD-knockdown cells. Based on an analysis of secondary and three-dimensional structures, we postulated that intact proteins with a structure consisting of all α-helices would be relatively accessible to CD cleavage.

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“…19, 20 Removal of the 44 amino acid N-terminal propeptide produces the 48kD intermediate form and a further proteolytic cleavage results in the CTSD mature form (CTSD-m) consisting of a 34kD and a 14kD chain. 20 With the creation of Ctsd global knockout mice, 21 CTSD has been studied for its role in immune homeostasis 22 , apoptosis, 23 cancer development, 24, 25 neurodegeneration, 26, 27 and retina diseases. 28 Changes in myocardial CTSD expression are also frequently used as an indicator of autophagic activity, assuming a key role for CTSD in lysosomal degradation of autophagosomes; 29–31 however, this assumption has not been formally tested.…”

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confidence: 99%

Myocardial Upregulation of Cathepsin D by Ischemic Heart Disease Promotes Autophagic Flux and Protects Against Cardiac Remodeling and Heart Failure

Yuan

et al. 2017

Circ: Heart Failure

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Background Lysosomal dysfunction is implicated in human heart failure for which ischemic heart disease is the leading cause. Altered myocardial expression of cathepsin D (CTSD), a major lysosomal protease, was observed in human heart failure but its pathophysiological significance has not been determined. Methods and Results Western blot analyses revealed an increase in the precursor but not the mature form of CTSD in myocardial samples from explanted human failing hearts with ischemic heart disease, which is recapitulated in chronic myocardial infarction produced via coronary artery ligation in Ctsd+/+ but not Ctsd+/− mice. Mice deficient of Ctsd displayed impaired myocardial autophagosome removal, reduced autophagic flux, and restrictive cardiomyopathy. After induction of myocardial infarction, weekly serial echocardiography detected earlier occurrence of left ventricle chamber dilatation, greater decreases in ejection fraction and fractional shortening, and lesser wall thickening throughout the first 4 weeks; pressure-volume relationship analyses at 4-week revealed greater decreases in systolic and diastolic functions, stroke work, stroke volume, and cardiac output; greater increases in the ventricular weight to body weight and the lung weight to body weight ratios and larger scar size were also detected in Ctsd+/− mice compared with Ctsd+/+ mice. Significant increases of myocardial autophagic flux detected at 1 and 4 weeks after induction of myocardial infarction in the Ctsd+/+ mice were diminished in the Ctsd+/− mice. Conclusions Myocardial CTSD upregulation induced by myocardial infarction protects against cardiac remodeling and malfunction, which is at least in part through promoting myocardial autophagic flux.

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Cathepsin D Primes Caspase-8 Activation by Multiple Intra-chain Proteolysis

Cited by 47 publications

References 46 publications

Lysosomal exocytosis and caspase-8 mediated apoptosis in UVA-irradiated keratinocytes

Lysosomal exocytosis and caspase-8 mediated apoptosis in UVA-irradiated keratinocytes

Proteolytic Characteristics of Cathepsin D Related to the Recognition and Cleavage of Its Target Proteins

Myocardial Upregulation of Cathepsin D by Ischemic Heart Disease Promotes Autophagic Flux and Protects Against Cardiac Remodeling and Heart Failure

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