VPS37A基因编码的是内体分拣复合物（ESCRT）-I复合物的一个亚单位，该基因在人类实体肿瘤中经常丧失。我们先前已经证明了VPS37A在指导ESCRT膜裂解机制以封闭噬菌体完成自噬小体的作用。在这里，我们报告了VPS37A缺陷细胞在吞噬体上积累的凋亡起始子CASP8（半胱天冬氨酸蛋白酶8），并通过细胞内死亡诱导信号复合物（iDISC）介导的CASP8激活，在内质网（ER）应激的作用下迅速凋亡。利用CRISPR-Cas9基因编辑和比较转录组分析，我们鉴定了ATF4介导的应激反应途径作为在抑制自噬小体关闭后引发iDISC介导的凋亡的关键调节因子。值得注意的是，ATF4介导的iDISC激活独立于死亡受体TNFRSF10B/DR5的上调，但需要促凋亡的转录因子DDIT3/CHOP来增强线粒体放大途径，以在受到ER应激诱导剂刺激的VPS37A缺陷细胞中充分激活CASP8。我们的分析还揭示了NFKB/NF-kB信号通路的上调作为抑制iDISC激活和促进VPS37A缺失细胞存活的潜在机制。这些发现对未来开发治疗人类肿瘤的新策略有重要意义，特别是那些患有VPS37A缺失的肿瘤。

The VPS37A gene encodes a subunit of the endosomal sorting complex required for transport (ESCRT)-I complex that is frequently lost in a wide variety of human solid cancers. We have previously demonstrated the role of VPS37A in directing the ESCRT membrane scission machinery to seal the phagophore for autophagosome completion. Here, we report that VPS37A-deficient cells exhibit an accumulation of the apoptotic initiator CASP8 (caspase 8) on the phagophore and are primed to undergo rapid apoptosis through the intracellular death-inducing signaling complex (iDISC)-mediated CASP8 activation upon exposure to endoplasmic reticulum (ER) stress. Using CRISPR-Cas9 gene editing and comparative transcriptome analysis, we identified the ATF4-mediated stress response pathway as a crucial mediator to elicit iDISC-mediated apoptosis following the inhibition of autophagosome closure. Notably, ATF4-mediated iDISC activation occurred independently of the death receptor TNFRSF10B/DR5 upregulation but required the pro-apoptotic transcriptional factor DDIT3/CHOP to enhance the mitochondrial amplification pathway for full-activation of CASP8 in VPS37A-deficient cells stimulated with ER stress inducers. Our analysis also revealed the upregulation of NFKB/NF-kB signaling as a potential mechanism responsible for restraining iDISC activation and promoting cell survival upon VPS37A depletion. These findings have important implications for the future development of new strategies to treat human cancers, especially those with VPS37A loss.