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

Publication date: Available online 30 June 2016
Source:Cell Reports
Author(s): Shuvadeep Maity, Asher Rajkumar, Latika Matai, Ajay Bhat, Asmita Ghosh, Ganesh Agam, Simarjot Kaur, Niraj R. Bhatt, Arnab Mukhopadhyay, Shantanu Sengupta, Kausik Chakraborty
Reductive stress leads to the loss of disulfide bond formation and induces the unfolded protein response of the endoplasmic reticulum (UPR^ER), necessary to regain proteostasis in the compartment. Here we show that peroxide accumulation during reductive stress attenuates UPR^ER 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 UPR^ER 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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Teaser

Maity et al. show that oxidative stress plays an important role in controlling the cellular response to ER stress. They show that this happens through a non-canonical translation regulation by reactive oxygen species that decrease the level of abundant proteins and increase the level of non-abundant ones.


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