Universität zu Köln

Albert, Marie-Christine, Brinkmann, Kerstin, Pokrzywa, Wojciech ORCID: 0000-0002-5110-4462, Guenther, Saskia Diana, Kroenke, Martin, Hoppe, Thorsten ORCID: 0000-0002-4734-9352 and Kashkar, Hamid (2020). CHIP ubiquitylates NOXA and induces its lysosomal degradation in response to DNA damage. Cell Death Dis., 11 (9). LONDON: SPRINGERNATURE. ISSN 2041-4889

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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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Albert, Marie-Christine UNSPECIFIED UNSPECIFIED UNSPECIFIED Brinkmann, Kerstin UNSPECIFIED UNSPECIFIED UNSPECIFIED Pokrzywa, Wojciech UNSPECIFIED orcid.org/0000-0002-5110-4462 UNSPECIFIED Guenther, Saskia Diana UNSPECIFIED UNSPECIFIED UNSPECIFIED Kroenke, Martin UNSPECIFIED UNSPECIFIED UNSPECIFIED Hoppe, Thorsten UNSPECIFIED orcid.org/0000-0002-4734-9352 UNSPECIFIED Kashkar, Hamid UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-319389
DOI:	10.1038/s41419-020-02923-x
Journal or Publication Title:	Cell Death Dis.
Volume:	11
Number:	9
Date:	2020
Publisher:	SPRINGERNATURE
Place of Publication:	LONDON
ISSN:	2041-4889
Language:	English
Faculty:	Faculty of Mathematics and Natural Sciences
Divisions:	Faculty of Mathematics and Natural Sciences > Department of Biology > Institute for Genetics
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language BH3-ONLY PROTEINS; UBIQUITIN LIGASE; APOPTOSIS; FAMILY; IDENTIFICATION; CELLS; XIAP Multiple languages Cell Biology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/31938