Hypoxia-Induced Autophagy Is Mediated through Hypoxia-Inducible Factor Induction of BNIP3 and BNIP3L via Their BH3 Domains
Hypoxia-Induced Autophagy Is Mediated through Hypoxia-Inducible Factor Induction of BNIP3 and BNIP3L via Their BH3 Domains
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DOI：
10.1128/mcb.00166-09
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发表时间：
2009-05-15
影响因子：
5.3
通讯作者：
Mazure, Nathalie M.
中科院分区：
文献类型：
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作者：
Bellot, Gregory;Garcia-Medina, Raquel;Mazure, Nathalie M.
虽然缺氧诱导因子（HIF）是细胞对缺氧的生存反应中的一个主要参与者，但HIF也与细胞死亡有关。一些研究表明，HIF诱导的假定的仅含BH3结构域的促凋亡基因bnip3和bnip3l与缺氧介导的细胞死亡有关。我们和其他人一样，不支持这一论断。在此，我们明确证明缺氧微环境通过诱导自噬促进生存而非导致细胞死亡。自噬的一个主要参与者Beclin1的缺失会增加缺氧条件下的细胞死亡。此外，BNIP3和/或BNIP3L的缺失会引发细胞死亡，并且BNIP3和BNIP3L对缺氧诱导的自噬至关重要。首先，虽然小干扰RNA介导的BNIP3或BNIP3L的缺失对自噬影响很小，但这两个HIF靶点的联合沉默会抑制缺氧介导的自噬。其次，在常氧条件下BNIP3和BNIP3L的异位表达会激活自噬。第三，BNIP3或BNIP3L的20聚体BH3肽在常氧条件下足以启动自噬。在此，我们提出一个模型，即缺氧诱导的BNIP3/BNIP3L的非典型BH3结构域被设计为通过破坏Bcl - 2 - Beclin1复合物来诱导自噬，而不引发细胞死亡。通过BNIP3和BNIP3L的缺氧诱导自噬显然是一种促进肿瘤进展的生存机制。
While hypoxia-inducible factor (HIF) is a major actor in the cell survival response to hypoxia, HIF also is associated with cell death. Several studies implicate the HIF-induced putative BH3-only proapoptotic genes bnip3 and bnip3l in hypoxia-mediated cell death. We, like others, do not support this assertion. Here, we clearly demonstrate that the hypoxic microenvironment contributes to survival rather than cell death by inducing autophagy. The ablation of Beclin1, a major actor of autophagy, enhances cell death under hypoxic conditions. In addition, the ablation of BNIP3 and/or BNIP3L triggers cell death, and BNIP3 and BNIP3L are crucial for hypoxia-induced autophagy. First, while the small interfering RNA-mediated ablation of either BNIP3 or BNIP3L has little effect on autophagy, the combined silencing of these two HIF targets suppresses hypoxia-mediated autophagy. Second, the ectopic expression of both BNIP3 and BNIP3L in normoxia activates autophagy. Third, 20-mer BH3 peptides of BNIP3 or BNIP3L are sufficient in initiating autophagy in normoxia. Herein, we propose a model in which the atypical BH3 domains of hypoxia-induced BNIP3/BNIP3L have been designed to induce autophagy by disrupting the Bcl-2-Beclin1 complex without inducing cell death. Hypoxia-induced autophagy via BNIP3 and BNIP3L is clearly a survival mechanism that promotes tumor progression.