期刊
JOURNAL OF LIPID RESEARCH
卷 53, 期 10, 页码 2102-2114出版社
ELSEVIER
DOI: 10.1194/jlr.M027557
关键词
Bid; chymotrypsin; lysosome; enzymology
资金
- National Basic Research Program of China [2010CB833701, 2012CB934003]
- National Natural Science Foundation of China [31070736, 31100595]
Upon apoptotic stimuli, lysosomal proteases, including cathepsins and chymotrypsin, are released into cytosol due to lysosomal membrane permeabilization (LMP), where they trigger apoptosis via the lysosomal-mitochondrial pathway of apoptosis. Herein, the mechanism of LMP was investigated. We found that caspase 8-cleaved Bid (tBid) could result in LMP directly. Although Bax or Bak might modestly enhance tBid-triggered LMP, they are not necessary for LMP. To study this further, large unilamellar vesicles (LUVs), model membranes mimicking the lipid constitution of lysosomes, were used to reconstitute the membrane permeabilization process in vitro. We found that phosphatidic acid (PA), one of the major acidic phospholipids found in lysosome membrane, is essential for tBid-induced LMP. PA facilitates the insertion of tBid deeply into lipid bilayers, where it undergoes homo-oligomerization and triggers the formation of highly curved nonbilayer lipid phases. These events induce LMP via pore formation mechanisms because encapsulated fluorescein-conjugated dextran (FD)-20 was released more significantly than FD-70 or FD-250 from LUVs due to its smaller molecular size. On the basis of these data, we proposed tBid-PA interactions in the lysosomal membranes form lipidic pores and result in LMP. We further noted that chymotrypsin-cleaved Bid is more potent than tBid at binding to PA, inserting into the lipid bilayer, and promoting LMP. This amplification mechanism likely contributes to the culmination of apoptotic signaling. Zhao, K., H. Zhou, X. Zhao, D. W. Wolff, Y. Tu, H. Liu, T. Wei, and F. Yang. Phosphatidic acid mediates the targeting of tBid to induce lysosomal membrane permeabilization and apoptosis. J. Lipid Res. 2012. 53: 2102-2114.
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