CHIP ubiquitylates NOXA and induces its lysosomal degradation in response to DNA damage
AuthorAlbert, M-C; Brinkmann, K; Pokrzywa, W; Guenther, SD; Kroenke, M; Hoppe, T; Kashkar, H
Source TitleCell Death and Disease
University of Melbourne Author/sBrinkmann, Kerstin
AffiliationMedical Biology (W.E.H.I.)
Document TypeJournal Article
CitationsAlbert, M. -C., Brinkmann, K., Pokrzywa, W., Guenther, S. D., Kroenke, M., Hoppe, T. & Kashkar, H. (2020). CHIP ubiquitylates NOXA and induces its lysosomal degradation in response to DNA damage. CELL DEATH & DISEASE, 11 (9), https://doi.org/10.1038/s41419-020-02923-x.
Access StatusOpen Access
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.
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