Oxidative Homeostasis Regulates the Response to Reductive Endoplasmic Reticulum Stress through Translation Control

• Oxidative quality control pathways are essential to counteract reductive ER stress
• Failure of oxidative quality leads to accumulation of peroxide during ER stress
• Non-canonical bimodal translation regulation by peroxide blocks the ER stress response
• This is prevented by activation of canonical PERK-dependent translation regulation

SummaryReductive stress leads to the loss of disulfide bond formation and induces the unfolded protein response of the endoplasmic reticulum (UPRER), necessary to regain proteostasis in the compartment. Here we show that peroxide accumulation during reductive stress attenuates UPRER amplitude by altering translation without any discernible effect on transcription. Through a comprehensive genetic screen in Saccharomyces cerevisiae, we identify modulators of reductive stress-induced UPRER and demonstrate that oxidative quality control (OQC) genes modulate this cellular response in the presence of chronic but not acute reductive stress. Using a combination of microarray and relative quantitative proteomics, we uncover a non-canonical translation attenuation mechanism that acts in a bipartite manner to selectively downregulate highly expressed proteins, decoupling the cell’s transcriptional and translational response during reductive ER stress. Finally, we demonstrate that PERK, a canonical translation attenuator in higher eukaryotes, helps in bypassing a ROS-dependent, non-canonical mode of translation attenuation.

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