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. 2021 Jun 9;22(12):6213. doi: 10.3390/ijms22126213

Figure 1.

Figure 1

Proposed working mechanisms of proteasomal deubiquitinase inhibitors and their comparison to proteasome inhibitor and PROTAC. (A) (Top) USP14’s multi-chain specific cleavage activity can be selectively targeted by USP14 inhibitors (e.g., IU1 is shown as an example), resulting in induced degradation of substrates. (Middle) Degradation-coupled RPN11 activity can be selectively inhibited such as by capzimin as shown. RPN11 inhibition can strongly suppress the proteasome-mediated substrate degradation. (Bottom) UCH37 specific inhibitors–which have not been developed yet–may exert differential effects on proteolysis depending on the type of ubiquitin conjugates. Unbranched or poorly ubiquitinated substrates might be highly subject to UCH37’s trimming activity, and its specific inhibition may lead to induced protein degradation. By contrast, degradation of branched ubiquitin conjugates is likely to be attenuated by UCH37 inhibition. (B,C) Proteasome inhibitor (e.g., bortezomib as shown) and PROTAC are depicted as examples of proteolysis suppressor and inducer, respectively. Color-coded circles in proteasome at B indicate each pair of proteasome’s active sites. PROTAC is a chimeric compound closely linking E3 and target substrate, thus facilitating the ubiquitination process. Inh, inhibitor. See the text for more details.