Journal article

CHIP ubiquitylates NOXA and induces its lysosomal degradation in response to DNA damage

Marie-Christine Albert, Kerstin Brinkmann, Wojciech Pokrzywa, Saskia Diana Guenther, Martin Kroenke, Thorsten Hoppe, Hamid Kashkar



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 deg..

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Awarded by Deutsche Forschungsgemeinschaft

Awarded by European Research Council

Awarded by Foundation for Polish Science - European Union under the European Regional Development Fund

Funding Acknowledgements

We thank the CECAD Imaging Core facility and CECAD Proteomics Core Facility. Strep-Ubiquitin constructs were a kind gift of Prof. Mads Gyrd-Hansen (Oxford, UK). HA-NOXA3E construct was kindly provided by Prof. Eric Eldering (AMC, Netherlands). Flag-Ubiquitin constructs were kindly provided by Prof. David Komander (Cambridge, UK) to clone ORF-containing ubiquitin mutants into Strep-Vector. Rab constructs were kindly provided by Prof. Stefan Honing (University of Cologne, Germany). We thank Diana Wagner-Stippich, Maureen Menning, and Gabriele Stellbrink for technical assistance. We thank Jorg Hohefeld for his careful reading of our manuscript and his thoughtful comments. We also thank Matin Yasseri and Andrea Stefanie Renn for contributions to the project during their Master's theses. This work was supported by the Deutsche Forschungsgemeinschaft CRU 286, EXC 229 (CECAD) and SFB1218 (project number 269925409) (grants to H.K. and T.H.), the Deutsche Krebshilfe and SFB1403 (project number 414786233) (grant to H.K.), the European Research Council (consolidator 616499 grant to T.H.), the Foundation for Polish Science cofinanced by the European Union under the European Regional Development Fund (grant POIR.04.04.00-00-5EAB/18-00 to W.P.), Koeln Fortune (Postdoctoral fellowship to K.B.), and German Cancer Aid (Mildred-Scheel postdoctoral fellowship to K.B.) Open access funding provided by Projekt DEAL.