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Lysosomal exocytosis and caspase-8-mediated apoptosis in UVA-irradiated keratinocytes
Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Division of Inflammation Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Dermatology and Venerology.
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2013 (English)In: Journal of Cell Science, ISSN 0021-9533, E-ISSN 1477-9137, Vol. 126, no 24, 5578-5584 p.Article in journal (Refereed) Published
Abstract [en]

Ultraviolet (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 Ca2+-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.

Place, publisher, year, edition, pages
Company of Biologists , 2013. Vol. 126, no 24, 5578-5584 p.
Keyword [en]
Keratinocyte; UV irradiation; Lysosome; Cathepsin; Endocytosis; Apoptosis
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-103290DOI: 10.1242/jcs.130633ISI: 000328686600005OAI: oai:DiVA.org:liu-103290DiVA: diva2:688496
Note

The previous status of this article was manuscript with the title Lysosomal exocytosis repairs the plasma membrane after UVA and is followed by caspase-8 induced apoptosis.

Available from: 2014-01-17 Created: 2014-01-16 Last updated: 2017-08-30
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, HannaWäster, PetraEriksson, IdaRosdahl, IngerÖllinger, Karin

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Appelqvist, HannaWäster, PetraEriksson, IdaRosdahl, IngerÖllinger, Karin
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ChemistryThe Institute of TechnologyDivision of Cell BiologyFaculty of Health SciencesDivision of Inflammation MedicineDepartment of Dermatology and VenerologyDepartment of Clinical Pathology and Clinical Genetics
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