The deubiquitinase Usp27x stabilizes the BH3‐only protein Bim and enhances apoptosis |
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Authors: | Arnim Weber Melanie Heinlein Jörn Dengjel Claudia Alber Prafull Kumar Singh Georg Häcker |
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Affiliation: | 1. Institute of Medical Microbiology and Hygiene, University Medical Center Freiburg, Freiburg, Germany;2. Department of Dermatology, Medical Center, University of Freiburg, Freiburg, Germany;3. Center for Biological Systems Analysis (ZBSA), Freiburg Institute for Advanced Studies (FRIAS), University of Freiburg, Freiburg, Germany;4. Spemann Graduate School of Biology and Medicine (SGBM), University of Freiburg, Freiburg, Germany;5. Faculty of Biology, University of Freiburg, Freiburg, Germany;6. BIOSS Centre for Biological Signalling Studies, University of Freiburg, Freiburg, Germany |
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Abstract: | Bim is a pro‐apoptotic Bcl‐2 family member of the BH3‐only protein subgroup. Expression levels of Bim determine apoptosis susceptibility in non‐malignant and in tumour cells. Bim protein expression is downregulated by proteasomal degradation following ERK‐dependent phosphorylation and ubiquitination. Here, we report the identification of a deubiquitinase, Usp27x, that binds Bim upon its ERK‐dependent phosphorylation and can upregulate its expression levels. Overexpression of Usp27x reduces ERK‐dependent Bim ubiquitination, stabilizes phosphorylated Bim, and induces apoptosis in PMA‐stimulated cells, as well as in tumour cells with a constitutively active Raf/ERK pathway. Loss of endogenous Usp27x enhances the Bim‐degrading activity of oncogenic Raf. Overexpression of Usp27x induces low levels of apoptosis in melanoma and non‐small cell lung cancer (NSCLC) cells and substantially enhances apoptosis induced in these cells by the inhibition of ERK signalling. Finally, deletion of Usp27x reduces apoptosis in NSCLC cells treated with an EGFR inhibitor. Thus, Usp27x can trigger via its proteolytic activity the deubiquitination of Bim and enhance its levels, counteracting the anti‐apoptotic effects of ERK activity, and therefore acts as a tumour suppressor. |
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Keywords: | apoptosis Bcl‐2 Bim deubiquitinase Usp27x |
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