The BH3-only protein NOXA is a regulator of mitochondrial apoptosis by specifically antagonizing the anti-apoptotic protein MCL-1. Here we show that the E3 ubiquitin ligase CHIP controls NOXA stability after DNA damage. Our findings reveal that CHIP and MCL-1 are binding partners of NOXA and differentially define the fate of NOXA. Whereas NOXA is initially targeted to mitochondria upon MCL-1-binding, CHIP mediates ubiquitylation of cytosolic NOXA and promotes lysosomal degradation of NOXA, which is not bound by MCL-1. Our data indicate that MCL-1 defines NOXA abundance and its pro-apoptotic activity. Increased NOXA levels beyond this threshold are effectively removed by lysosomal protein degradation triggered via CHIP-mediated ubiquitylation. Together, these results shed new light on regulatory circuits controlling DNA damage response and identified the E3 ligase CHIP as a new molecular guardian, which restricts the cytosolic accumulation of NOXA upon genotoxic stress.

BH3-only 蛋白 NOXA 通过特异性拮抗抗凋亡蛋白 MCL-1 来调节线粒体凋亡。在这里，我们表明 E3 泛素连接酶 CHIP 控制 DNA 损伤后的 NOXA 稳定性。我们的研究结果表明，CHIP 和 MCL-1 是 NOXA 的结合伙伴，并不同地定义了 NOXA 的命运。虽然 NOXA 最初在 MCL-1 结合后靶向线粒体，但 CHIP 介导胞质 NOXA 的泛素化并促进 NOXA 的溶酶体降解，而 NOXA 不受 MCL-1 结合。我们的数据表明 MCL-1 定义了 NOXA 丰度及其促凋亡活性。通过 CHIP 介导的泛素化引发的溶酶体蛋白降解，可以有效去除超过该阈值的 NOXA 水平升高。一起，