CHIP ubiquitylates NOXA and induces its lysosomal degradation in response to DNA damage
- Author(s)
- Albert, MC; Brinkmann, K; Pokrzywa, W; Gunther, SD; Kronke, M; Hoppe, T; Kashkar, H;
- Details
- Publication Year 2020-09-10,Volume 11,Issue #9,Page 740
- Journal Title
- Cell Death & Disease
- Publication Type
- Journal Article
- Abstract
- 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.
- Publisher
- NPG
- Research Division(s)
- Blood Cells And Blood Cancer
- PubMed ID
- 32913203
- Publisher's Version
- https://doi.org/10.1038/s41419-020-02923-x
- Open Access at Publisher's Site
https://doi.org/10.1038/s41419-020-02923-x- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2020-10-02 10:28:04
Last Modified: 2020-10-02 10:44:57