Susceptibility of lysosomes to rupture is a determinant for plasma membrane disruption in tumor necrosis factor alpha-induced cell death
Susceptibility of lysosomes to rupture is a determinant for plasma membrane disruption in tumor necrosis factor alpha-induced cell death
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DOI：
10.1128/mcb.23.2.665-676.2003
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发表时间：
2003-01-01
影响因子：
5.3
通讯作者：
Han, JH
中科院分区：
文献类型：
--
作者：
Ono, K;Kim, SO;Han, JH
由于细胞内内容物的释放可以诱导局部炎症反应，因此了解导致细胞死亡中质膜完整性丧失的机制是重要的。我们以前表明，L929细胞质膜Ca 2 + ATP酶4（PMCA 4）的缺陷削弱了肿瘤坏死因子α（TNF-α）诱导的溶酶体扩大，并减少了细胞死亡。溶酶体的变化可以通过测量每个细胞的细胞内酸性区室（VAC）的总体积来确定，我们在这里表明，由于PMCA 4缺乏而导致的VAC增加的抑制不仅减少了细胞死亡，而且还将TNF-α诱导的细胞死亡从涉及质膜破坏的过程转化为具有几乎完整质膜的细胞死亡。溶酶体大小在细胞死亡期间确定质膜完整性的重要性得到以下观察结果的支持：减少VAC的化学抑制剂也减少了野生型L929细胞中TNF-α诱导的质膜破坏，而由于基因突变、衰老、细胞培养条件、细胞毒性和细胞毒性引起的VAC增加。和化学抑制剂都改变了细胞死亡的形态，从最初几乎完整的质膜变成了许多不同细胞中的膜破裂。此外，ATP耗竭介导的从凋亡到坏死的变化也与VAC的增加有关。溶酶体大小的增加可能是由于垂死细胞的细胞内自我消化。大的溶酶体容易破裂，破裂的溶酶体释放的水解酶可引起质膜破裂。
Since a release of intracellular contents can induce local inflammatory responses, mechanisms that lead to loss of plasma membrane integrity in cell death are important to know. We showed previously that deficiency of the plasma membrane Ca2+ ATPase 4 (PMCA4) in L929 cells impaired tumor necrosis factor alpha (TNF-alpha)-induced enlargement of lysosomes and reduced cell death. The lysosomal changes can be determined by measuring the total volume of intracellular acidic compartments per cell (VAC), and we show here that inhibition of the increase in VAC due to PMCA4 deficiency not only reduced cell death but also converted TNF-alpha-induced cell death from a process involving disruption of the plasma membrane to a cell demise with a nearly intact plasma membrane. The importance of the size of lysosomes in determining plasma membrane integrity during cell death was supported by the observations that chemical inhibitors that reduce VAC also reduced the plasma membrane disruption induced by TNF-alpha in wild-type L929 cells, while increases in VAC due to genetic mutation, senescence, cell culture conditions, and chemical inhibitors all changed the morphology of cell death from one with an originally nearly intact plasma membrane to one with membrane disruption in a number of different cells. Moreover, the ATP depletion-mediated change from apoptosis to necrosis is also associated with the increases of VAC. The increase in lysosomal size may due to intracellular self-digestion of dying cells. Big lysosomes are easy to rupture, and the release of hydrolytic enzymes from ruptured lysosomes can cause plasma membrane disruption.