title: The deubiquitinase Usp27x stabilizes the BH3-only protein Bim and enhances apoptosis.
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.
authors.affiliation: Institute of Medical Microbiology and Hygiene, University Medical Center Freiburg, Freiburg, Germany arnim.weber@uniklinik-freiburg.de georg.haecker@uniklinik-freiburg.de.
authors.forename: Arnim
authors.identifier: 0000-0002-1723-6496
authors.initials: A
authors.lastname: Weber
authors.affiliation: Institute of Medical Microbiology and Hygiene, University Medical Center Freiburg, Freiburg, Germany.
authors.forename: Melanie
authors.identifier: 0000-0001-6194-7159
authors.initials: M
authors.lastname: Heinlein
authors.affiliation: Department of Dermatology, Medical Center, University of Freiburg, Freiburg, Germany Center for Biological Systems Analysis (ZBSA), Freiburg Institute for Advanced Studies (FRIAS) University of Freiburg, Freiburg, Germany.
authors.forename: Jörn
authors.initials: J
authors.lastname: Dengjel
authors.affiliation: Institute of Medical Microbiology and Hygiene, University Medical Center Freiburg, Freiburg, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Alber
authors.affiliation: Institute of Medical Microbiology and Hygiene, University Medical Center Freiburg, Freiburg, Germany Spemann Graduate School of Biology and Medicine (SGBM), University of Freiburg, Freiburg, Germany Faculty of Biology, University of Freiburg, Freiburg, Germany.
authors.forename: Prafull Kumar
authors.identifier: 0000-0002-0529-9748
authors.initials: PK
authors.lastname: Singh
authors.affiliation: Institute of Medical Microbiology and Hygiene, University Medical Center Freiburg, Freiburg, Germany BIOSS Centre for Biological Signalling Studies, University of Freiburg, Freiburg, Germany arnim.weber@uniklinik-freiburg.de georg.haecker@uniklinik-freiburg.de.
authors.forename: Georg
authors.identifier: 0000-0003-1058-5746
authors.initials: G
authors.lastname: Häcker
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D000072224:Bcl-2-Like Protein 11 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D000072017:Deubiquitinating Enzymes / Q000235:genetics / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D055786:Gene Knockout Techniques; D006801:Humans; D008545:Melanoma / Q000235:genetics / Q000378:metabolism; D051379:Mice; D011485:Protein Binding; D055550:Protein Stability; D059748:Proteolysis; D048493:Proto-Oncogene Proteins B-raf / Q000378:metabolism; D015398:Signal Transduction; D054875:Ubiquitination
chemical_list: D000072224:Bcl-2-Like Protein 11; D048493:Proto-Oncogene Proteins B-raf; D048049:Extracellular Signal-Regulated MAP Kinases; D000072017:Deubiquitinating Enzymes
keywords: Bcl‐2; Bim; Usp27x; apoptosis; deubiquitinase