Mild cytosolic stress modulates protein quality control by altering ubiquitin–proteasome system (UPS)–mediated degradation. This study demonstrates that heat shock or oxidative stress inhibits ER‑associated degradation of wild‑type connexin32 (Cx32) prior to its dislocation into the cytosol. Similar stress conditions reduced turnover of disease‑associated mutants of Cx32 and CFTR, as well as wild‑type CFTR and unassembled immunoglobulin light chain. While stress‑stabilized wild‑type proteins could proceed through the secretory pathway, mutant or unassembled substrates could not. Cytosolic stress also slowed UPS‑mediated degradation of select cytosolic proteins through a mechanism dependent on ubiquitination. These findings identify stress‑induced inhibition of substrate polyubiquitination as a key regulatory step linking the heat shock response with ER‑associated degradation.
