@article{d6999670ec2f4789b9d01e19cd2c659d,
title = "Concerted 2-5A-Mediated mRNA Decay and Transcription Reprogram Protein Synthesis in the dsRNA Response",
abstract = "Viral and endogenous double-stranded RNA (dsRNA) is a potent trigger for programmed RNA degradation by the 2-5A/RNase L complex in cells of all mammals. This 2-5A-mediated decay (2-5AMD) is a conserved stress response switching global protein synthesis from homeostasis to production of interferons (IFNs). To understand this mechanism, we examined 2-5AMD in human cells and found that it triggers polysome collapse characteristic of inhibited translation initiation. We determined that translation initiation complexes and ribosomes purified from translation-arrested cells remain functional. However, spike-in RNA sequencing (RNA-seq) revealed cell-wide decay of basal mRNAs accompanied by rapid accumulation of mRNAs encoding innate immune proteins. Our data attribute this 2-5AMD evasion to better stability of defense mRNAs and positive feedback in the IFN response amplified by RNase L-resistant molecules. We conclude that 2-5AMD and transcription act in concert to refill mammalian cells with defense mRNAs, thereby “prioritizing” the synthesis of innate immune proteins.",
keywords = "RNase L, dsRNA, innate immunity, interferon, mRNA decay, reprogramming, translation",
author = "Sneha Rath and Eliza Prangley and Jesse Donovan and Kaitlin Demarest and Wingreen, {Ned S.} and Yigal Meir and Alexei Korennykh",
note = "Funding Information: The authors thank Prof. Kevan Shokat for the gift of INK128 and helpful discussions, Dr. Paul Copeland (Rutgers University) for the gift of internal ribosome entry site (IRES)-containing dual luciferase plasmid, staff at the Proteomics and Mass Spectrometry Core facility, and staff at the Genomics Core Facility at Princeton University. We are grateful to Prof. Zemer Gitai and Dr. Sophia Li for help with polysome analysis and Prof. Bonnie Bassler, Prof. Martin Jonikas, and Prof. Sabine Petry for sharing instrumental resources, and we thank members of the Korennykh lab for great help throughout the project. This study was funded by the NIH (grant 1R01GM110161-01 to A.K. and grants 5T32GM007388 and F99 CA212468-01 to S.R.), the Sidney Kimmel Foundation (grant AWD1004002 to A.K.), the Burroughs Wellcome Foundation (grant 1013579 to A.K.), The Vallee Foundation (grant AWD1004949 to A.K.), and the National Science Foundation, through the Center for the Physics of Biological Function (grant PHY-1734030 to N.S.W.). S.R. and E.P. conducted the core experimental work. J.D. and K.D. conducted select experiments. N.S.W. and Y.M. conducted theoretical analysis of decay and transcription kinetics. S.R. E.P. and A.K. wrote the manuscript. A.K. supervised the work. The authors declare no competing interests. Funding Information: The authors thank Prof. Kevan Shokat for the gift of INK128 and helpful discussions, Dr. Paul Copeland (Rutgers University) for the gift of internal ribosome entry site (IRES)-containing dual luciferase plasmid, staff at the Proteomics and Mass Spectrometry Core facility, and staff at the Genomics Core Facility at Princeton University. We are grateful to Prof. Zemer Gitai and Dr. Sophia Li for help with polysome analysis and Prof. Bonnie Bassler, Prof. Martin Jonikas, and Prof. Sabine Petry for sharing instrumental resources, and we thank members of the Korennykh lab for great help throughout the project. This study was funded by the NIH (grant 1R01GM110161-01 to A.K. and grants 5T32GM007388 and F99 CA212468-01 to S.R.), the Sidney Kimmel Foundation (grant AWD1004002 to A.K.), the Burroughs Wellcome Foundation (grant 1013579 to A.K.), The Vallee Foundation (grant AWD1004949 to A.K.), and the National Science Foundation , through the Center for the Physics of Biological Function (grant PHY-1734030 to N.S.W.). Publisher Copyright: {\textcopyright} 2019 Elsevier Inc.",
year = "2019",
month = sep,
day = "19",
doi = "https://doi.org/10.1016/j.molcel.2019.07.027",
language = "English",
volume = "75",
pages = "1218--1228.e6",
journal = "Molecular Cell",
issn = "1097-2765",
publisher = "Cell Press",
number = "6",
}