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The proteasome has an essential role in proteostasis maintenance and is critical for cell survival under proteotoxic conditions including hyperosmotic stress. However, it is unknown how proteasome activity is linked to cell survival/death under hyperosmotic stress. We have previously reported that apoptosis signal-regulating kinase 3 (ASK3) contributes to cell survival through its inactivation under hyperosmotic stress. 19S regulatory particle subunits of the proteasome were enriched in the ASK3 inactivator candidates identified through our genome-wide small interfering RNA (siRNA) screen. In this study, we demonstrate that the proteasome regulates ASK3 inactivation through its proteolytic activity. Intriguingly, the proteasome inactivates ASK3 via degradation of not ASK3 per se but another ASK family member ASK1 which activates ASK3 in a kinase activity-dependent manner. Furthermore, the elevated ASK1 level under proteasome inhibition sensitizes cells to hyperosmotic stress. These findings suggest that ASK family maintenance links proteasome capacity to cell fate bifurcation under hyperosmotic stress.