Autosis is a Na+,K+-ATPase-regulated form of cell death triggered by autophagy-inducing peptides, starvation, and hypoxia-ischemia
Autosis is a Na+,K+-ATPase-regulated form of cell death triggered by autophagy-inducing peptides, starvation, and hypoxia-ischemia
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DOI：
10.1073/pnas.1319661110
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发表时间：
2013-12-17
影响因子：
11.1
通讯作者：
Levine, Beth
中科院分区：
文献类型：
--
作者：
Liu, Yang;Shoji-Kawata, Sanae;Levine, Beth
一个长期存在的争议是，自噬是否是哺乳动物细胞死亡的真正原因。我们使用一种细胞穿透性自噬诱导肽，TAT-Beclin 1，来自自噬蛋白Beclin 1，来研究高水平的自噬是否通过自噬导致细胞死亡。在这里，我们展示了TAT-Beclin 1诱导的剂量依赖性死亡，这种死亡可以通过药物或遗传抑制自噬而被阻断，但不能抑制细胞凋亡或坏死性下垂。这种死亡被称为“自体”，具有独特的形态特征，包括早期自噬/自溶体增多和核卷曲，晚期核周间隙局灶性肿胀。我们还观察到在应激条件下细胞的自体死亡，包括体外营养缺乏细胞亚群和体内新生大鼠脑缺氧缺血后的海马神经元。对5000种已知生物活性化合物的化学筛选表明，Na+，K+-ATPase拮抗剂心脏糖苷在体外和体内都能抑制自体细胞死亡。此外，在体外，Na+，K+-ATPaseα1亚单位的基因敲除阻断了多肽和饥饿诱导的自体。因此，我们已经确定了一种独特的自噬依赖的细胞死亡形式，一类被食品和药物管理局批准的抑制这种死亡的化合物，以及Na+，K+-ATPase在其调节中的关键作用。这些发现对理解细胞在特定应激条件下如何死亡以及如何防止这种细胞死亡具有重要意义。
A long-standing controversy is whether autophagy is a bona fide cause of mammalian cell death. We used a cell-penetrating autophagy- inducing peptide, Tat-Beclin 1, derived from the autophagy protein Beclin 1, to investigate whether high levels of autophagy result in cell death by autophagy. Here we show that Tat-Beclin 1 induces dose-dependent death that is blocked by pharmacological or genetic inhibition of autophagy, but not of apoptosis or necroptosis. This death, termed "autosis," has unique morphological features, including increased autophagosomes/autolysosomes and nuclear convolution at early stages, and focal swelling of the perinuclear space at late stages. We also observed autotic death in cells during stress conditions, including in a subpopulation of nutrient-starved cells in vitro and in hippocampal neurons of neonatal rats subjected to cerebral hypoxia-ischemia in vivo. A chemical screen of similar to 5,000 known bioactive compounds revealed that cardiac glycosides, antagonists of Na+, K+-ATPase, inhibit autotic cell death in vitro and in vivo. Furthermore, genetic knockdown of the Na+, K+-ATPase alpha 1 subunit blocks peptide and starvation-induced autosis in vitro. Thus, we have identified a unique form of autophagy-dependent cell death, a Food and Drug Administration-approved class of compounds that inhibit such death, and a crucial role for Na+, K+-ATPase in its regulation. These findings have implications for understanding how cells die during certain stress conditions and how such cell death might be prevented.