Lysosome-Mediated Apoptosis is Associated with Cathepsin D-Specific Processing of Bid at Phe24,Trp48, and Phe183
2012 (English)In: Annals of Clinical and Laboratory Science, ISSN 0091-7370, Vol. 42, no 3, 231-242 p.Article in journal (Refereed) Published
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 CategoryMedical and Health Sciences
IdentifiersURN: urn:nbn:se:liu:diva-80794ISI: 000307091500001OAI: oai:DiVA.org:liu-80794DiVA: diva2:548234
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 Phe1832012-08-302012-08-302012-10-30Bibliographically approved