Regulation of influenza a virus mRNA splicing by CLK1

Anita Artarini, Michael Meyer, Yu Jin Shin, Kilian Huber, Nikolaus Hilz, Franz Bracher, Daniel Eros, L. Őrfi, Gyorgy Keri, Sigrid Goedert, Martin Neuenschwander, Jens von Kries, Yael Domovich-Eisenberg, Noa Dekel, István Szabadkai, Mario Lebendiker, Zoltán Horváth, Tsafi Danieli, Oded Livnah, Olivier MoncorgéRebecca Frise, Wendy Barclay, Thomas F. Meyer, Alexander Karlas

Research output: Contribution to journalArticle

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, which encodes 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.

Original languageEnglish
Pages (from-to)187-196
Number of pages10
JournalAntiviral Research
Volume168
DOIs
Publication statusPublished - Aug 1 2019

Fingerprint

Orthomyxoviridae
Human Influenza
Phosphotransferases
Messenger RNA
Virus Replication
Influenza A virus
Proteins
Alternative Splicing
England
Serine
Arginine
Phosphorylation
Genome
RNA
Viruses
Infection
Genes

Keywords

  • Host-directed therapy
  • KH-CB19
  • NIH39
  • SR proteins
  • VCC0801741
  • VCC463764

ASJC Scopus subject areas

  • Pharmacology
  • Virology

Cite this

Artarini, A., Meyer, M., Shin, Y. J., Huber, K., Hilz, N., Bracher, F., ... Karlas, A. (2019). Regulation of influenza a virus mRNA splicing by CLK1. Antiviral Research, 168, 187-196. https://doi.org/10.1016/j.antiviral.2019.06.003

Regulation of influenza a virus mRNA splicing by CLK1. / Artarini, Anita; Meyer, Michael; Shin, Yu Jin; Huber, Kilian; Hilz, Nikolaus; Bracher, Franz; Eros, Daniel; Őrfi, L.; Keri, Gyorgy; Goedert, Sigrid; Neuenschwander, Martin; von Kries, Jens; Domovich-Eisenberg, Yael; Dekel, Noa; Szabadkai, István; Lebendiker, Mario; Horváth, Zoltán; Danieli, Tsafi; Livnah, Oded; Moncorgé, Olivier; Frise, Rebecca; Barclay, Wendy; Meyer, Thomas F.; Karlas, Alexander.

In: Antiviral Research, Vol. 168, 01.08.2019, p. 187-196.

Research output: Contribution to journalArticle

Artarini, A, Meyer, M, Shin, YJ, Huber, K, Hilz, N, Bracher, F, Eros, D, Őrfi, L, Keri, G, Goedert, S, Neuenschwander, M, von Kries, J, Domovich-Eisenberg, Y, Dekel, N, Szabadkai, I, Lebendiker, M, Horváth, Z, Danieli, T, Livnah, O, Moncorgé, O, Frise, R, Barclay, W, Meyer, TF & Karlas, A 2019, 'Regulation of influenza a virus mRNA splicing by CLK1', Antiviral Research, vol. 168, pp. 187-196. https://doi.org/10.1016/j.antiviral.2019.06.003
Artarini A, Meyer M, Shin YJ, Huber K, Hilz N, Bracher F et al. Regulation of influenza a virus mRNA splicing by CLK1. Antiviral Research. 2019 Aug 1;168:187-196. https://doi.org/10.1016/j.antiviral.2019.06.003
Artarini, Anita ; Meyer, Michael ; Shin, Yu Jin ; Huber, Kilian ; Hilz, Nikolaus ; Bracher, Franz ; Eros, Daniel ; Őrfi, L. ; Keri, Gyorgy ; Goedert, Sigrid ; Neuenschwander, Martin ; von Kries, Jens ; Domovich-Eisenberg, Yael ; Dekel, Noa ; Szabadkai, István ; Lebendiker, Mario ; Horváth, Zoltán ; Danieli, Tsafi ; Livnah, Oded ; Moncorgé, Olivier ; Frise, Rebecca ; Barclay, Wendy ; Meyer, Thomas F. ; Karlas, Alexander. / Regulation of influenza a virus mRNA splicing by CLK1. In: Antiviral Research. 2019 ; Vol. 168. pp. 187-196.
@article{13346aa73ad545efb0c3a13f808b0ddc,
title = "Regulation of influenza a virus mRNA splicing by CLK1",
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, which encodes 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 = "Host-directed therapy, KH-CB19, NIH39, SR proteins, VCC0801741, VCC463764",
author = "Anita Artarini and Michael Meyer and Shin, {Yu Jin} and Kilian Huber and Nikolaus Hilz and Franz Bracher and Daniel Eros and L. Őrfi and Gyorgy Keri and Sigrid Goedert and Martin Neuenschwander and {von Kries}, Jens and Yael Domovich-Eisenberg and Noa Dekel and Istv{\'a}n Szabadkai and Mario Lebendiker and Zolt{\'a}n Horv{\'a}th and Tsafi Danieli and Oded Livnah and Olivier Moncorg{\'e} and Rebecca Frise and Wendy Barclay and Meyer, {Thomas F.} and Alexander Karlas",
year = "2019",
month = "8",
day = "1",
doi = "10.1016/j.antiviral.2019.06.003",
language = "English",
volume = "168",
pages = "187--196",
journal = "Antiviral Research",
issn = "0166-3542",
publisher = "Elsevier",

}

TY - JOUR

T1 - Regulation of influenza a virus mRNA splicing by CLK1

AU - Artarini, Anita

AU - Meyer, Michael

AU - Shin, Yu Jin

AU - Huber, Kilian

AU - Hilz, Nikolaus

AU - Bracher, Franz

AU - Eros, Daniel

AU - Őrfi, L.

AU - Keri, Gyorgy

AU - Goedert, Sigrid

AU - Neuenschwander, Martin

AU - von Kries, Jens

AU - Domovich-Eisenberg, Yael

AU - Dekel, Noa

AU - Szabadkai, István

AU - Lebendiker, Mario

AU - Horváth, Zoltán

AU - Danieli, Tsafi

AU - Livnah, Oded

AU - Moncorgé, Olivier

AU - Frise, Rebecca

AU - Barclay, Wendy

AU - Meyer, Thomas F.

AU - Karlas, Alexander

PY - 2019/8/1

Y1 - 2019/8/1

N2 - 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, which encodes 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.

AB - 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, which encodes 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.

KW - Host-directed therapy

KW - KH-CB19

KW - NIH39

KW - SR proteins

KW - VCC0801741

KW - VCC463764

UR - http://www.scopus.com/inward/record.url?scp=85067251549&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85067251549&partnerID=8YFLogxK

U2 - 10.1016/j.antiviral.2019.06.003

DO - 10.1016/j.antiviral.2019.06.003

M3 - Article

AN - SCOPUS:85067251549

VL - 168

SP - 187

EP - 196

JO - Antiviral Research

JF - Antiviral Research

SN - 0166-3542

ER -