Figure 5.

Model of the regulation of CARD8 by the 20S proteasome. In unstressed cells, the 20S proteasome removes the disordered region to generate CARD8^p44, which (like CARD8^FL) acts as an inhibitor in the DPP8/9 ternary complex (dashed blue lines). In VbP-stressed cells, the 20S degrades the entire CARD8^NT fragment, possibly due to ZU5 domain misfolding, releasing CARD8^CT from autoinhibition. Low levels of the CT fragment are captured in the ternary complex (dashed red line). Increased degradation of the full NT fragment enables the CT fragment to bypass the ternary complex (solid red line). MLN4924 blocks protein neddylation and thereby inhibits E3 ligases (solid gray line), which we speculate globally affects proteostasis and thereby interferes with 20S proteasome activity (dashed gray lines). VbP, Val-boroPro; CT, C-terminal; DPP8/9, dipeptidyl peptidase 8 or 9; NT, N-terminal; ZUC, ZU5-UPA-CARD.