Phosphatidic acid mediates the targeting of tBid to induce lysosomal membrane permeabilization and apoptosis
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 t...
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| Format: | Article |
| Language: | English |
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Elsevier
2012-10-01
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| Series: | Journal of Lipid Research |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0022227520431876 |
| _version_ | 1818731807571443712 |
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| author | Kai Zhao Hejiang Zhou Xingyu Zhao Dennis W. Wolff Yaping Tu Huili Liu Taotao Wei Fuyu Yang |
| author_facet | Kai Zhao Hejiang Zhou Xingyu Zhao Dennis W. Wolff Yaping Tu Huili Liu Taotao Wei Fuyu Yang |
| author_sort | Kai Zhao |
| collection | DOAJ |
| description | 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. |
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| institution | Directory Open Access Journal |
| issn | 0022-2275 |
| language | English |
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| spelling | doaj.art-95a81332e801493a86f0e99b725024f52022-12-21T21:28:50ZengElsevierJournal of Lipid Research0022-22752012-10-01531021022114Phosphatidic acid mediates the targeting of tBid to induce lysosomal membrane permeabilization and apoptosisKai Zhao0Hejiang Zhou1Xingyu Zhao2Dennis W. Wolff3Yaping Tu4Huili Liu5Taotao Wei6Fuyu Yang7National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Chaoyang District, Beijing 100101, ChinaNational Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Chaoyang District, Beijing 100101, China; Graduate University of Chinese Academy of Sciences, Shijingshan District, Beijing 100049, ChinaNational Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Chaoyang District, Beijing 100101, ChinaDepartment of Pharmacology, Creighton University School of Medicine, Omaha, NE 68178; andNational Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Chaoyang District, Beijing 100101, China; Department of Pharmacology, Creighton University School of Medicine, Omaha, NE 68178; andState Key Laboratory of Magnetic Resonance and Atomic and Molecular Physics, Wuhan Centre for Magnetic Resonance, Wuhan Institute of Physics and Mathematics, Chinese Academy of Sciences, Wuhan 430071, ChinaTo whom correspondence should be addressed.; National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Chaoyang District, Beijing 100101, ChinaTo whom correspondence should be addressed.; National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Chaoyang District, Beijing 100101, ChinaUpon 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.http://www.sciencedirect.com/science/article/pii/S0022227520431876Bidchymotrypsinlysosomeenzymology |
| spellingShingle | Kai Zhao Hejiang Zhou Xingyu Zhao Dennis W. Wolff Yaping Tu Huili Liu Taotao Wei Fuyu Yang Phosphatidic acid mediates the targeting of tBid to induce lysosomal membrane permeabilization and apoptosis Journal of Lipid Research Bid chymotrypsin lysosome enzymology |
| title | Phosphatidic acid mediates the targeting of tBid to induce lysosomal membrane permeabilization and apoptosis |
| title_full | Phosphatidic acid mediates the targeting of tBid to induce lysosomal membrane permeabilization and apoptosis |
| title_fullStr | Phosphatidic acid mediates the targeting of tBid to induce lysosomal membrane permeabilization and apoptosis |
| title_full_unstemmed | Phosphatidic acid mediates the targeting of tBid to induce lysosomal membrane permeabilization and apoptosis |
| title_short | Phosphatidic acid mediates the targeting of tBid to induce lysosomal membrane permeabilization and apoptosis |
| title_sort | phosphatidic acid mediates the targeting of tbid to induce lysosomal membrane permeabilization and apoptosis |
| topic | Bid chymotrypsin lysosome enzymology |
| url | http://www.sciencedirect.com/science/article/pii/S0022227520431876 |
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