Phosphatidic acid mediates the targeting of tBid to induce lysosomal membrane permeabilization and apoptosis

Kai Zhao, Hejiang Zhou, Xingyu Zhao, Dennis W. Wolff, Yaping Tu, Huili Liu, Taotao Wei, Fuyu Yang

Research output: Contribution to journalArticle

29 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)2102-2114
Number of pages13
JournalJournal of Lipid Research
Volume53
Issue number10
DOIs
StatePublished - Oct 2012

Fingerprint

Phosphatidic Acids
Apoptosis
Membranes
Dextrans
Fluorescein
Unilamellar Liposomes
Lipid bilayers
Chymotrypsin
Lipid Bilayers
Lysosomes
Cathepsins
Lipids
Caspase 8
Oligomerization
Constitution and Bylaws
Membrane Lipids
Cytosol
Phospholipids
Amplification
Peptide Hydrolases

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Cell Biology
  • Endocrinology

Cite this

Phosphatidic acid mediates the targeting of tBid to induce lysosomal membrane permeabilization and apoptosis. / Zhao, Kai; Zhou, Hejiang; Zhao, Xingyu; Wolff, Dennis W.; Tu, Yaping; Liu, Huili; Wei, Taotao; Yang, Fuyu.

In: Journal of Lipid Research, Vol. 53, No. 10, 10.2012, p. 2102-2114.

Research output: Contribution to journalArticle

Zhao, Kai ; Zhou, Hejiang ; Zhao, Xingyu ; Wolff, Dennis W. ; Tu, Yaping ; Liu, Huili ; Wei, Taotao ; Yang, Fuyu. / Phosphatidic acid mediates the targeting of tBid to induce lysosomal membrane permeabilization and apoptosis. In: Journal of Lipid Research. 2012 ; Vol. 53, No. 10. pp. 2102-2114.
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