Proteotoxic stress response is governed by ER-associated sorting of proteasome transcriptional activators.

Proteotoxic stress, characterized by the accumulation of damaged proteins, poses a significant challenge to cellular homeostasis. To mitigate proteotoxicity, eukaryotes rely on the proteasome, which is regulated by proteasome transcriptional activators. As proteotoxicity can originate in different compartments, cells must integrate signals from multiple locations, yet the mechanisms coordinating this response remain unclear. Here, we show that the proteasome autoregulatory feedback loop functions as a gatekeeper enabling the communication between the nucleus and chloroplast. At the endoplasmic reticulum (ER), the plant proteasome transcriptional activators NAC53 and NAC78 undergo either ER-associated degradation (ERAD) or are released for nuclear translocation. We define this dual mechanism as ER-associated sorting (ERAS). While NAC53/78 activate proteasome gene expression, they repress photosynthesis-associated nuclear genes during proteotoxicity through a conserved cis-element. Together, our findings reveal a trade-off between proteasome activity and energy metabolism and establish a framework in which the proteasome feedback loop coordinates subcellular proteostasis and growth-defense balance.