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Regulation of influenza a virus mRNA splicing by CLK1

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Item Type:Article
Title:Regulation of influenza a virus mRNA splicing by CLK1
Creators Name:Artarini, A. and Meyer, M. and Shin, Y.J. and Huber, K. and Hilz, N. and Bracher, F. and Eros, D. and Orfi, L. and Keri, G. and Goedert, S. and Neuenschwander, M. and von Kries, J. and Domovich-Eisenberg, Y. and Dekel, N. and Szabadkai, I. and Lebendiker, M. and Horváth, Z. and Danieli, T. and Livnah, O. and Moncorgé, O. and Frise, R. and Barclay, W. and Meyer, T.F. and Karlas, A.
Abstract:Influenza A virus carries eight negative single-stranded RNAs and uses spliced mRNAs to increase the number of proteins produced from them. Several genome-wide screens for essential host factors for influenza A virus replication revealed a necessity for splicing and splicing-related factors, including Cdc-like kinase 1 (CLK1). This CLK family kinase plays a role in alternative splicing regulation through phosphorylation of serine-arginine rich (SR) proteins. To examine the influence that modulation of splicing regulation has on influenza infection, we analyzed the effect of CLK1 knockdown and inhibition. CLK1 knockdown in A549 cells reduced influenza A/WSN/33 virus replication and increased the level of splicing of segment 7, encoding the viral M1 and M2 proteins. CLK1-/- mice infected with influenza A/England/195/2009 (H1N1pdm09) virus supported lower levels of virus replication than wild-type mice. Screening of newly developed CLK inhibitors revealed several compounds that have an effect on the level of splicing of influenza A gene segment M in different models and decrease influenza A/WSN/33 virus replication in A549 cells. The promising inhibitor KH-CB19, an indole-based enaminonitrile with unique binding mode for CLK1, and its even more selective analogue NIH39 showed high specificity towards CLK1 and had a similar effect on influenza mRNA splicing regulation. Taken together, our findings indicate that targeting host factors that regulate splicing of influenza mRNAs may represent a novel therapeutic approach.
Keywords:SR Proteins, Host-Directed Therapy, NIH39, KH-CB19, VCC463764, VCC0801741, Animals, Mice
Source:Antiviral Research
ISSN:0166-3542
Publisher:Elsevier (The Netherlands)
Volume:168
Page Range:187-196
Date:August 2019
Official Publication:https://doi.org/10.1016/j.antiviral.2019.06.003
PubMed:View item in PubMed

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