Autophagy induced during apoptosis degrades mitochondria and inhibits type I interferon secretion
Autophagy induced during apoptosis degrades mitochondria and inhibits type I interferon secretion
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DOI：
10.1038/s41418-017-0017-z
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发表时间：
2018-03-01
影响因子：
12.4
通讯作者：
Vaux, David L.
中科院分区：
文献类型：
--
作者：
Lindqvist, Lisa M.;Frank, Daniel;Vaux, David L.
经历Bax/ bak介导的细胞凋亡的细胞表现出自噬的迹象，但其如何被激活及其意义尚不清楚。通过用BH3-only蛋白或BH3模拟化合物直接激活Bax/Bak，我们发现线粒体损伤与细胞内[AMP]/[ATP]的快速增加、5' AMP活化蛋白激酶（AMPK）的磷酸化以及unc-51样自噬激活激酶1 （ULK1）的激活相关。因此，自噬通量在凋亡途径的早期被触发，因为凋亡体和半胱天冬酶的激活并不需要诱导自噬通量。Bax/ bak触发的自噬以atg5 /7依赖的方式导致受损线粒体的清除，而不需要Parkin。重要的是，Bax/ bak介导的自噬抑制了线粒体损伤产生的促炎细胞因子干扰素- β (ifn - β)的分泌，但不抑制另一种细胞因子白细胞介素-6 （IL-6）的分泌。这些发现表明，Bax/Bak刺激的自噬对于确保细胞凋亡过程中的免疫沉默至关重要。
Cells undergoing Bax/Bak-mediated apoptosis exhibit signs of autophagy, but how it is activated and its significance is unknown. By directly activating Bax/Bak with BH3-only proteins or BH3 mimetic compounds, we demonstrate that mitochondrial damage correlated with a rapid increase in intracellular [AMP]/[ATP], phosphorylation of 5' AMP-activated protein kinase (AMPK), and activation of unc-51 like autophagy activating kinase 1 (ULK1). Consequently, autophagic flux was triggered early in the apoptotic pathway, as activation of the apoptosome and caspases were not necessary for its induction. Bax/Bak-triggered autophagy resulted in the clearance of damaged mitochondria in an ATG5/7-dependent manner that did not require Parkin. Importantly, Bax/Bak-mediated autophagy inhibited the secretion of the pro-inflammatory cytokine interferon-beta (IFN-beta) produced in response to mitochondrial damage, but not another cytokine interleukin-6 (IL-6). These findings show that Bax/Bak stimulated autophagy is essential for ensuring immunological silence during apoptosis.