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The deubiquitinase Usp27x stabilizes the BH 3‐only protein Bim and enhances apoptosis
Author(s) -
Weber Arnim,
Heinlein Melanie,
Dengjel Jörn,
Alber Claudia,
Singh Prafull Kumar,
Häcker Georg
Publication year - 2016
Publication title -
embo reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.584
H-Index - 184
eISSN - 1469-3178
pISSN - 1469-221X
DOI - 10.15252/embr.201541392
Subject(s) - deubiquitinating enzyme , apoptosis , mapk/erk pathway , downregulation and upregulation , phosphorylation , microbiology and biotechnology , ubiquitin , cancer research , chemistry , biology , biochemistry , gene
Bim is a pro‐apoptotic Bcl‐2 family member of the BH 3‐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.