What question did this study set out to answer?

To explore the effects of small-molecule 20S proteasome activators on XBP1 signaling during UPR activation.

February 2, 2026ChemBioChem0 citations

Increasing Proteasome Activity to Alter XBP1 Signaling of the UPR Pathway

KKKate A. KragnessUniversity of California, Irvine DTDarci J. TraderUniversity of California, Irvine

Key Points

To explore the effects of small-molecule 20S proteasome activators on XBP1 signaling during UPR activation.
Investigation of small‐molecule 20S proteasome activators.
Pre-treatment before IRE1 induction to assess modulation of XBP1 signaling.
Post-treatment after chemical induction of IRE1 to evaluate effects.
Pre-treatment with a 20S activator significantly reduces XBP1 signaling.
Post-treatment shows no detectable effect on XBP1 signaling.
Findings suggest a limited impact of proteasome activation on ongoing UPR.

Abstract

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.

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