Faculty of Engineering and Natural Sciences, Biological Sciences and Bioengineering Program, Sabanci University, Orhanli-Tuzla, 34956, Istanbul, Turkey.
Apoptosis. 2012 Aug;17(8):810-20. doi: 10.1007/s10495-012-0735-0.
Autophagy is an evolutionarily conserved mechanism contributing to cell survival under stress conditions including nutrient and growth factor deprivation. Connections and cross-talk between cell death mechanisms and autophagy is under investigation. Here, we describe Atg3, an essential regulatory component of autophagosome biogenesis, as a new substrate of caspase-8 during receptor-mediated cell death. Both, tumor necrosis factor α and tumor necrosis factor-related apoptosis inducing ligand induced cell death was accompanied by Atg3 cleavage and this event was inhibited by a pan-caspase inhibitor (zVAD) or a caspase-8-specific inhibitor (zIETD). Indeed, caspase-8 overexpression led to Atg3 degradation and this event depended on caspase-8 enzymatic activity. Mutation of the caspase-8 cleavage site on Atg3 abolished its cleavage both in vitro and in vivo, demonstrating that Atg3 was a direct target of caspase-8. Autophagy was inactive during apoptosis and blockage of caspases or overexpression of a non-cleavable Atg3 protein reestablished autophagic activity upon death receptor stimulation. In this system, autophagy was important for cell survival since inhibition of autophagy increased cell death. Therefore, Atg3 provides a novel link between apoptosis and autophagy during receptor-activated cell death.
自噬是一种在应激条件下（包括营养和生长因子剥夺）有助于细胞存活的保守机制。细胞死亡机制和自噬之间的联系和串扰正在研究中。在这里，我们描述了 Atg3，它是自噬体生物发生的必需调节成分，作为受体介导的细胞死亡过程中 caspase-8 的一个新底物。肿瘤坏死因子 α 和肿瘤坏死因子相关凋亡诱导配体诱导的细胞死亡伴随着 Atg3 的切割，这一事件被泛半胱天冬酶抑制剂 (zVAD) 或 caspase-8 特异性抑制剂 (zIETD) 抑制。事实上，caspase-8 的过表达导致了 Atg3 的降解，这一事件依赖于 caspase-8 的酶活性。Atg3 上 caspase-8 切割位点的突变，无论是在体外还是体内，都阻止了其切割，这表明 Atg3 是 caspase-8 的直接靶标。在细胞凋亡过程中，自噬是无活性的，阻断半胱天冬酶或过表达一种不可切割的 Atg3 蛋白，在死亡受体刺激时重新建立自噬活性。在这个系统中，自噬对于细胞存活很重要，因为自噬的抑制增加了细胞死亡。因此，Atg3 为受体激活的细胞死亡过程中凋亡和自噬之间提供了一个新的联系。
