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Lysosome-Mediated Apoptosis is Associated with Cathepsin D-Specific Processing of Bid at Phe24,Trp48, and Phe183
Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology. Linköping University, Faculty of Health Sciences.
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2012 (English)In: Annals of Clinical and Laboratory Science, ISSN 0091-7370, E-ISSN 1550-8080, Vol. 42, no 3, 231-242 p.Article in journal (Refereed) Published
Abstract [en]

Bax-mediated permeabilization of the outer mitochondrial membrane and release of apoptogenic factors into the cytosol are key events that occur during apoptosis. Likewise, apoptosis is associated with permeabilization of the lysosomal membrane and release of lysosomal cathepsins into the cytosol. This report identifies proteolytically active cathepsin D as an important component of apoptotic signaling following lysosomal membrane permeabilization in fibroblasts. Lysosome-mediated cell death is associated with degradation of Bax sequestering 14-3-3 proteins, cleavage of the Box activator Bid, and translocation of Box to mitochondria, all of which were cathepsin D-dependent. Processing of Bid could be reproduced by enforced lysosomal membrane permeabilization, using the lysosomotropic detergent O-methyl-serine dodecylamine hydrochloride (MSDH). We identified three cathepsin D-specific cleavage sites in Bid, Phe24, Trp48, and Phe183. Cathepsin D-cleaved Bid induced Bax-mediated release of cytochrome c from purified mitochondria, indicating that the fragments generated are functionally active. Moreover, apoptosis was associated with cytosolic acidification, thereby providing a more favorable environment for the cathepsin D-mediated cleavage of Bid. Our study suggests that cytosolic cathepsin D triggers Bax-mediated cytochrome c release by proteolytic activation of Bid.

Place, publisher, year, edition, pages
Institute for Clinical Science , 2012. Vol. 42, no 3, 231-242 p.
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-80794ISI: 000307091500001OAI: oai:DiVA.org:liu-80794DiVA: diva2:548234
Note

Funding Agencies|Swedish Cancer Society||Swedish Research Council||Swedish Society for Medical Research||County Council of Ostergotland||foundation of Lars Hierta||foundation of Tore Nilson||foundation of Magn||foundation of Bergvall||foundation of Stohne||foundation of Hedberg||

The original title of this article in Manuscript was: Cathepsin D-specific processing of Bid at Phe24, Trp48, and Phe183

Available from: 2012-08-30 Created: 2012-08-30 Last updated: 2017-12-07Bibliographically approved
In thesis
1. Lysosomal Membrande Stability and Cathepsins in Cell Death
Open this publication in new window or tab >>Lysosomal Membrande Stability and Cathepsins in Cell Death
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Lysosomes are acidic organelles that are critically involved in a number of physiological processes, including macromolecule degradation, endocytosis, autophagy, exocytosis and cholesterol homeostasis. Several pathological conditions, such as cancer, neurodegenerative disorders and lysosomal storage diseases, involve lysosomal disturbances, indicating the importance of the organelle for correct cellular function. The aim of this thesis was to investigate the role of lysosomes in cell death signaling.

Previous studies have shown that permeabilization of the lysosomal membrane and release of hydrolytic enzymes such as cathepsin D to the cytosol occurs during apoptosis. We identified Bid and 14-3-3 proteins as cytosolic targets of cathepsin D in human fibroblasts. Truncated Bid, generated by cathepsin D proteolytic cleavage, stimulates Bax-mediated release of pro-apoptotic factors from the mitochondria, thereby engaging the intrinsic pathway to apoptosis.

Since the presence of cathepsins in the cytosol is sufficient to induce apoptosis, the permeability of the lysosomal membrane influences the fate of the cell. In this thesis, we demonstrated that the stability of the lysosomal membrane can be manipulated by altering the lysosomal cholesterol content. Cells with high lysosomal cholesterol content were less prone to undergo apoptosis when challenged with stimuli known to induce lysosome-mediated cell death. In addition, cholesterol accumulation was associated with increased expression of lysosome-associated membrane proteins and storage of other lipids; however, these factors did not contribute to lysosomal stabilization.

Lysosomal membrane permeabilization and cathepsins contribute to ultraviolet (UV) irradiation-induced apoptosis. We demonstrate plasma membrane damage induced by UVA irradiation to be rapidly repaired by lysosomal exocytosis in human keratinocytes. Despite efficient plasma membrane resealing, the cells underwent apoptosis, which was dependent on early activation of caspase-8. The activation of caspase-8 was lysosome-dependent and occurred in vesicles positive for lysosomal markers.

This thesis demonstrates the importance of lysosomal stability for apoptosis regulation and that this stability can be influenced by drug intervention. Modulation of the lysosomal membrane permeability may have potential for use as a therapeutic strategy in conditions associated with accelerated or repressed apoptosis.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2012. 160 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1325
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-85008 (URN)978-91-7519-803-3 (ISBN)
Public defence
2012-11-28, Eken, Hälsouniversitetet, Campus US, Linköpings universitet, Linköping, 09:00 (Swedish)
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Available from: 2012-10-30 Created: 2012-10-30 Last updated: 2017-08-30Bibliographically approved

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Appelqvist, HannaJohansson, Ann-CharlotteLinderoth, EmmaJohansson, UnoKågedal, KatarinaÖllinger, Karin

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Experimental PathologyFaculty of Health SciencesDepartment of Clinical and Experimental MedicineDepartment of Clinical Pathology and Clinical Genetics
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