Li, J;
Zhang, Y;
Da Silva Sil Dos Santos, B;
Wang, F;
Ma, Y;
Perez, C;
Yang, Y;
... Deshaies, R; + view all
(2018)
Epidithiodiketopiperazines inhibit protein degradation by targeting proteasome deubiquitinase Rpn11.
Cell Chemical Biology
, 25
(11)
pp. 1350-1358.
10.1016/j.chembiol.2018.07.012.
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Abstract
The 26S proteasome is the major proteolytic machine for breaking down cytosolic and nuclear proteins in eukaryotes. Due to the lack of a suitable assay, it is difficult to measure routinely and quantitatively the breakdown of proteins by the 26S proteasome in vitro. In the present study, we developed an assay to monitor proteasome-mediated protein degradation. Using this assay, we discovered that epidithiodiketopiperazine (ETPs) blocked the degradation of our model substrate in vitro. Further characterization revealed that ETPs inhibited proteasome function by targeting the essential proteasomal deubiquitinase Rpn11 (POH1/PSMD14). ETPs also inhibited other JAMM (JAB1/MPN/Mov34 metalloenzyme) proteases such as Csn5 and AMSH. An improved ETP with fewer non-specific effects, SOP11, stabilized a subset of proteasome substrates in cells, induced the unfolded protein response, and led to cell death. SOP11 represents a class of Rpn11 inhibitor and provides an alternative route to develop proteasome inhibitors.
| Type: | Article |
|---|---|
| Title: | Epidithiodiketopiperazines inhibit protein degradation by targeting proteasome deubiquitinase Rpn11 |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1016/j.chembiol.2018.07.012 |
| Publisher version: | http://dx.doi.org/10.1016/j.chembiol.2018.07.012 |
| Language: | English |
| Additional information: | This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions. |
| Keywords: | proteasome, Rpn11, POH1, PSMD14, ubiquitin, Capzimin, epidithiodiketopiperazine, gliotoxin, protein degradation, JAMM protease |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy > Pharma and Bio Chemistry |
| URI: | https://discovery-pp.ucl.ac.uk/id/eprint/10054385 |
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