title: Oxidative Homeostasis Regulates the Response to Reductive Endoplasmic Reticulum Stress through Translation Control.
abstract: 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.
authors.affiliation: CSIR-Institute of Genomics and Integrative Biology, South Campus, Mathura Road, New Delhi 110025, India.
authors.forename: Shuvadeep
authors.initials: S
authors.lastname: Maity
authors.affiliation: CSIR-Institute of Genomics and Integrative Biology, South Campus, Mathura Road, New Delhi 110025, India; Academy of Scientific and Innovative Research, CSIR- Institute of Genomics and Integrative Biology, Mathura Road Campus, New Delhi 110025, India.
authors.forename: Asher
authors.initials: A
authors.lastname: Rajkumar
authors.affiliation: CSIR-Institute of Genomics and Integrative Biology, South Campus, Mathura Road, New Delhi 110025, India; Academy of Scientific and Innovative Research, CSIR- Institute of Genomics and Integrative Biology, Mathura Road Campus, New Delhi 110025, India.
authors.forename: Latika
authors.initials: L
authors.lastname: Matai
authors.affiliation: CSIR-Institute of Genomics and Integrative Biology, South Campus, Mathura Road, New Delhi 110025, India; Academy of Scientific and Innovative Research, CSIR- Institute of Genomics and Integrative Biology, Mathura Road Campus, New Delhi 110025, India.
authors.forename: Ajay
authors.initials: A
authors.lastname: Bhat
authors.affiliation: CSIR-Institute of Genomics and Integrative Biology, South Campus, Mathura Road, New Delhi 110025, India; Academy of Scientific and Innovative Research, CSIR- Institute of Genomics and Integrative Biology, Mathura Road Campus, New Delhi 110025, India.
authors.forename: Asmita
authors.initials: A
authors.lastname: Ghosh
authors.affiliation: CSIR-Institute of Genomics and Integrative Biology, South Campus, Mathura Road, New Delhi 110025, India.
authors.forename: Ganesh
authors.initials: G
authors.lastname: Agam
authors.affiliation: CSIR-Institute of Genomics and Integrative Biology, South Campus, Mathura Road, New Delhi 110025, India.
authors.forename: Simarjot
authors.initials: S
authors.lastname: Kaur
authors.affiliation: CSIR-Institute of Genomics and Integrative Biology, South Campus, Mathura Road, New Delhi 110025, India; Academy of Scientific and Innovative Research, CSIR- Institute of Genomics and Integrative Biology, Mathura Road Campus, New Delhi 110025, India.
authors.forename: Niraj R
authors.initials: NR
authors.lastname: Bhatt
authors.affiliation: Molecular Aging Laboratory, National Institute of Immunology, New Delhi 110067, India.
authors.forename: Arnab
authors.initials: A
authors.lastname: Mukhopadhyay
authors.affiliation: CSIR-Institute of Genomics and Integrative Biology, South Campus, Mathura Road, New Delhi 110025, India; Academy of Scientific and Innovative Research, CSIR- Institute of Genomics and Integrative Biology, Mathura Road Campus, New Delhi 110025, India.
authors.forename: Shantanu
authors.initials: S
authors.lastname: Sengupta
authors.affiliation: CSIR-Institute of Genomics and Integrative Biology, South Campus, Mathura Road, New Delhi 110025, India; Academy of Scientific and Innovative Research, CSIR- Institute of Genomics and Integrative Biology, Mathura Road Campus, New Delhi 110025, India. Electronic address: kausik@igib.res.in.
authors.forename: Kausik
authors.initials: K
authors.lastname: Chakraborty
mesh_terms: D000818:Animals; D017173:Caenorhabditis elegans / Q000235:genetics; D015536:Down-Regulation / Q000235:genetics; D004721:Endoplasmic Reticulum / Q000235:genetics*; D059865:Endoplasmic Reticulum Stress / Q000235:genetics*; D056890:Eukaryota / Q000235:genetics; D006706:Homeostasis / Q000235:genetics*; D010545:Peroxides / Q000378:metabolism; D014176:Protein Biosynthesis / Q000235:genetics*; D040901:Proteomics / Q000379:methods; D017382:Reactive Oxygen Species / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000502:physiology; D014158:Transcription, Genetic / Q000235:genetics; D056811:Unfolded Protein Response / Q000235:genetics; D019892:eIF-2 Kinase / Q000235:genetics
chemical_list: D010545:Peroxides; D017382:Reactive Oxygen Species; D019892:eIF-2 Kinase