Chaperone-mediated autophagy prevents apoptosis by degrading BBC3/PUMA
Chaperone-mediated autophagy prevents apoptosis by degrading BBC3/PUMA
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分子伴侣介导的自噬通过降解 BBC3/PUMA 来防止细胞凋亡
DOI：
10.1080/15548627.2015.1075688
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发表时间：
2015-07
期刊：
影响因子：
13.3
通讯作者：
You, Han
中科院分区：
文献类型：
--
作者：
Wu, Mian;Wang, Zhanxiang;Han, Jiahuai;You, Han
自噬是一种潜在的有害途径，与凋亡一起，可以被类似的应激刺激激活，从而导致细胞死亡。决定细胞在自噬和凋亡之间命运选择的分子线索在很大程度上仍然未知。在这里，我们报告说，促凋亡蛋白BBC 3/BCL 2结合成分3（BCL 2）是一个真正的伴侣介导的自噬（CMA）的底物。BBC 3与HSPA 8/HSC 70（热休克70 kDa蛋白8）缔合，导致其溶酶体移位和摄取。CMA的抑制导致BBC 3的稳定，这反过来使肿瘤细胞敏感以经历凋亡。我们进一步证明，在TNF（肿瘤坏死因子）处理后，IKBKB/IKKβ（B细胞中κ轻链多肽基因增强子的抑制剂，激酶β）介导的BBC 3 Ser 10磷酸化通过阻断CMA对其的降解对BBC 3稳定至关重要。从机制上讲，Ser 10磷酸化促进了BBC 3从胞质溶胶到线粒体的易位。BBC 3的稳定性导致Ser 10磷酸化或CMA抑制增强TNF诱导的细胞凋亡。因此，我们的研究结果表明，BBC 3的选择性降解的基础上的CMA的促生存作用，并定义了以前不受重视的促凋亡作用的IKBKB，通过磷酸化介导的BBC 3的稳定，从而促进肿瘤坏死因子触发的细胞凋亡。
Autophagy is a potentially inimical pathway and together with apoptosis, may be activated by similar stress stimuli that can lead to cell death. The molecular cues that dictate the cell fate choice between autophagy and apoptosis remain largely unknown. Here we report that the proapoptotic protein BBC3/PUMA (BCL2 binding component 3) is a bona fide substrate of chaperone-mediated autophagy (CMA). BBC3 associates with HSPA8/HSC70 (heat shock 70kDa protein 8), leading to its lysosome translocation and uptake. Inhibition of CMA results in stabilization of BBC3, which in turn sensitizes tumor cells to undergo apoptosis. We further demonstrate that upon TNF (tumor necrosis factor) treatment, IKBKB/IKKβ (inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase β)-mediated BBC3 Ser10 phosphorylation is crucial for BBC3 stabilization via blocking its degradation by CMA. Mechanistically, Ser10 phosphorylation facilitates BBC3 translocation from the cytosol to mitochondria. BBC3 stabilization resulting from either Ser10 phosphorylation or CMA inhibition potentiates TNF-induced apoptotic cell death. Our findings thus reveal that the selective degradation of BBC3 underlies the prosurvival role of CMA and define a previously unappreciated proapoptotic role of IKBKB that acts through phosphorylation-mediated stabilization of BBC3, thereby promoting TNF-triggered apoptosis.
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