UBE2Z Activators

Proteasome inhibitors such as MG132, bortezomib, and epoxomicin, increase the pool of ubiquitinated proteins by blocking their degradation. This accumulation can indirectly heighten the demand for UBE2Z's activity as the cell attempts to manage the excess of ubiquitinated substrates. Similarly, compounds like TAK-243, which inhibit the ubiquitin-activating enzyme E1, lead to a buildup of ubiquitin-conjugated proteins that may also necessitate enhanced UBE2Z action to maintain cellular homeostasis. The activity of UBE2Z is also indirectly affected by thalidomide, lenalidomide, and pomalidomide. These agents modulate the substrate specificity of E3 ligases, potentially altering the ubiquitination landscape and the types of proteins that UBE2Z helps to tag with ubiquitin. By influencing the selection of substrates for ubiquitination, these can indirectly increase the catalytic workload on UBE2Z.

Further along the ubiquitin-proteasome pathway, MLN4924 disrupts the activation of NEDD8, a ubiquitin-like protein that regulates the activity of cullin-RING ligases. This interference can cause changes in the ubiquitination process that may indirectly implicate UBE2Z activity due to altered dynamics in substrate availability and turnover. Inhibitors of deubiquitinases, such as IU1, which targets USP14, lead to the accumulation of ubiquitinated proteins by preventing their deubiquitination, again potentially increasing the functional demands placed on UBE2Z. Autophagy inhibitors like chloroquine contribute to the elevated levels of ubiquitinated substrates, which can indirectly enhance the need for UBE2Z's ubiquitin-conjugating activity.