TY  - JOUR
AU  - Albert, M-C
AU  - Brinkmann, K
AU  - Pokrzywa, W
AU  - Guenther, SD
AU  - Kroenke, M
AU  - Hoppe, T
AU  - Kashkar, H
Y2  - 2020/11/17
Y1  - 2020/09/10
SN  - 2041-4889
UR  - http://hdl.handle.net/11343/251617
AB  - 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.
LA  - English
PB  - SPRINGERNATURE
T1  - CHIP ubiquitylates NOXA and induces its lysosomal degradation in response to DNA damage
DO  - 10.1038/s41419-020-02923-x
IS  - Cell Death and Disease
VL  - 11
IS  - 9
L1  - /bitstream/handle/11343/251617/PMC7484759.pdf?sequence=1&isAllowed=y
ER  -