A phenolic small molecule inhibitor of RNase L prevents cell death from ADAR1 deficiency.

Autor:	Daou S; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada.; Centre for Systems Biology, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, M5G 1X5, Canada., Talukdar M; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada.; Centre for Systems Biology, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, M5G 1X5, Canada., Tang J; State Key Laboratory of Chemical Oncogenomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, 518055 Shenzhen, China., Dong B; Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195., Banerjee S; Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195., Li Y; Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104., Duffy NM; Centre for Systems Biology, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, M5G 1X5, Canada., Ogunjimi AA; Centre for Systems Biology, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, M5G 1X5, Canada., Gaughan C; Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195., Jha BK; Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH 44195., Gish G; Centre for Systems Biology, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, M5G 1X5, Canada., Tavernier N; Centre for Systems Biology, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, M5G 1X5, Canada., Mao D; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada.; Centre for Systems Biology, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, M5G 1X5, Canada., Weiss SR; Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104., Huang H; State Key Laboratory of Chemical Oncogenomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, 518055 Shenzhen, China; huang.hao@pku.edu.cn silverr@ccf.org sicheri@lunenfeld.ca., Silverman RH; Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195; huang.hao@pku.edu.cn silverr@ccf.org sicheri@lunenfeld.ca., Sicheri F; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada; huang.hao@pku.edu.cn silverr@ccf.org sicheri@lunenfeld.ca.; Centre for Systems Biology, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, M5G 1X5, Canada.; Department of Biochemistry, University of Toronto, Toronto, ON M5S 1A8, Canada.
Jazyk:	angličtina
Zdroj:	Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2020 Oct 06; Vol. 117 (40), pp. 24802-24812. Date of Electronic Publication: 2020 Sep 21.
DOI:	10.1073/pnas.2006883117
Abstrakt:	The oligoadenylate synthetase (OAS)-RNase L system is an IFN-inducible antiviral pathway activated by viral infection. Viral double-stranded (ds) RNA activates OAS isoforms that synthesize the second messenger 2-5A, which binds and activates the pseudokinase-endoribonuclease RNase L. In cells, OAS activation is tamped down by ADAR1, an adenosine deaminase that destabilizes dsRNA. Mutation of ADAR1 is one cause of Aicardi-Goutières syndrome (AGS), an interferonopathy in children. ADAR1 deficiency in human cells can lead to RNase L activation and subsequent cell death. To evaluate RNase L as a possible therapeutic target for AGS, we sought to identify small-molecule inhibitors of RNase L. A 500-compound library of protein kinase inhibitors was screened for modulators of RNase L activity in vitro. We identified ellagic acid (EA) as a hit with 10-fold higher selectivity against RNase L compared with its nearest paralog, IRE1. SAR analysis identified valoneic acid dilactone (VAL) as a superior inhibitor of RNase L, with 100-fold selectivity over IRE1. Mechanism-of-action analysis indicated that EA and VAL do not bind to the pseudokinase domain of RNase L despite acting as ATP competitive inhibitors of the protein kinase CK2. VAL is nontoxic and functional in cells, although with a 1,000-fold decrease in potency, as measured by RNA cleavage activity in response to treatment with dsRNA activator or by rescue of cell lethality resulting from self dsRNA induced by ADAR1 deficiency. These studies lay the foundation for understanding novel modes of regulating RNase L function using small-molecule inhibitors and avenues of therapeutic potential. Competing Interests: The authors declare no competing interest. (Copyright © 2020 the Author(s). Published by PNAS.)
Databáze:	MEDLINE
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