Systematic Identification of Regulators of Oxidative Stress Reveals Non-canonical Roles for Peroxisomal Import and the Pentose Phosphate Pathway

Michael M. Dubreuil, David W. Morgens, Kanji Okumoto, Masanori Honsho, Kévin Contrepois, Brittany Lee-McMullen, Gavin Mc Allister Traber, Ria S. Sood, Scott J. Dixon, Michael P. Snyder, Yukio Fujiki, Michael C. Bassik

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Reactive oxygen species (ROS) play critical roles in metabolism and disease, yet a comprehensive analysis of the cellular response to oxidative stress is lacking. To systematically identify regulators of oxidative stress, we conducted genome-wide Cas9/CRISPR and shRNA screens. This revealed a detailed picture of diverse pathways that control oxidative stress response, ranging from the TCA cycle and DNA repair machineries to iron transport, trafficking, and metabolism. Paradoxically, disrupting the pentose phosphate pathway (PPP) at the level of phosphogluconate dehydrogenase (PGD) protects cells against ROS. This dramatically alters metabolites in the PPP, consistent with rewiring of upper glycolysis to promote antioxidant production. In addition, disruption of peroxisomal import unexpectedly increases resistance to oxidative stress by altering the localization of catalase. Together, these studies provide insights into the roles of peroxisomal matrix import and the PPP in redox biology and represent a rich resource for understanding the cellular response to oxidative stress. Despite its importance in metabolism and disease, a comprehensive analysis of the cellular response to oxidative stress is lacking. Here, Dubreuil et al. use genome-wide screens to identify cellular regulators of oxidative stress. They investigate paradoxical mechanisms by which disruption of the pentose phosphate and peroxisomal import pathways protect cells.

元の言語英語
ページ(範囲)1417-1433.e7
ジャーナルCell Reports
30
発行部数5
DOI
出版物ステータス出版済み - 2 4 2020

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)

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    Dubreuil, M. M., Morgens, D. W., Okumoto, K., Honsho, M., Contrepois, K., Lee-McMullen, B., Traber, G. M. A., Sood, R. S., Dixon, S. J., Snyder, M. P., Fujiki, Y., & Bassik, M. C. (2020). Systematic Identification of Regulators of Oxidative Stress Reveals Non-canonical Roles for Peroxisomal Import and the Pentose Phosphate Pathway. Cell Reports, 30(5), 1417-1433.e7. https://doi.org/10.1016/j.celrep.2020.01.013