Increasing Proteasome Activity to Alter XBP1 Signaling of the UPR Pathway

Enhanced proteasome activity is known to confer resistance to cellular stress in vitro and in vivo, but such effects have largely been achieved through genetic upregulation of proteasome subunits and assembly factors. Here, we investigate whether small‐molecule 20S proteasome activators can modulate XBP1 signaling during IRE1‐driven unfolded protein response (UPR) activation. We show that pre‐treatment with a 20S activator prior to IRE1 induction significantly attenuates XBP1 signaling, whereas treatment after chemical induction of IRE1 produces no detectable effect. These findings indicate that proteasome activators can bolster proteasome activity under endoplasmic reticulum (ER) stress, but their ability to modulate an ongoing UPR is limited. This work highlights a potential temporal window in which proteasome activation may influence stress‐adaptive signaling.