School of Biological Sciences, Seoul National University, Seoul, Korea.
Cell Death Differ. 2011 Aug;18(8):1326-36. doi: 10.1038/cdd.2011.3. Epub 2011 Feb 4.
Apoptosis inducing factor (AIF) is a mitochondrial oxidoreductase that scavenges reactive oxygen species under normal conditions. Under certain stresses, such as exposure to N-methyl-N'-nitro-N'-nitrosoguanidine (MNNG), AIF is truncated and released from the mitochondria and translocated into the nucleus, where the truncated AIF (tAIF) induces caspase-independent cell death. However, it is unknown how cells decide to kill themselves or operate ways to survive when they encounter stresses that induce the release of tAIF. Here, we demonstrated that USP2 and CHIP contribute to the control of tAIF stability. USP2 deubiquitinated and stabilized tAIF, thus promoting AIF-mediated cell death. In contrast, CHIP ubiquitinated and destabilized tAIF, thus preventing the cell death. Consistently, CHIP-deficient cells showed an increased sensitivity to MNNG. On the other hand, knockdown of USP2 attenuated MNNG-induced cell death. Moreover, exposure to MNNG caused a dramatic decrease in CHIP level, but not that of USP2, concurrent with cell shrinkage and chromatin condensation. These findings indicate that CHIP and USP2 show antagonistic functions in the control of AIF-mediated cell death, and implicate the role of the enzymes as a switch for cells to live or die under stresses that cause tAIF release.
凋亡诱导因子（AIF）是一种线粒体氧化还原酶，在正常条件下清除活性氧。在某些应激条件下，如暴露于 N-甲基-N′-硝基-N′-亚硝基胍（MNNG），AIF 被截断并从线粒体释放，并转移到细胞核中，在细胞核中，截断的 AIF（tAIF）诱导 caspase 非依赖性细胞死亡。然而，当细胞遇到诱导 tAIF 释放的应激时，细胞如何决定自杀或寻找生存方式尚不清楚。在这里，我们证明 USP2 和 CHIP 有助于控制 tAIF 的稳定性。USP2 去泛素化并稳定 tAIF，从而促进 AIF 介导的细胞死亡。相比之下，CHIP 泛素化并使 tAIF 不稳定，从而防止细胞死亡。一致地，CHIP 缺陷细胞对 MNNG 表现出更高的敏感性。另一方面，USP2 的敲低减弱了 MNNG 诱导的细胞死亡。此外，暴露于 MNNG 导致 CHIP 水平急剧下降，但 USP2 水平没有下降，同时伴有细胞收缩和染色质浓缩。这些发现表明，CHIP 和 USP2 在控制 AIF 介导的细胞死亡中表现出拮抗作用，并暗示这些酶作为一种开关，在导致 tAIF 释放的应激下，使细胞存活或死亡。
