Serine-Arginine Protein Kinase 1 Regulates Ebola Virus Transcription

ABSTRACT Ebola virus (EBOV) causes a severe and often fatal disease for which no approved vaccines or antivirals are currently available. EBOV VP30 has been described as a viral phosphoprotein, and nonphosphorylated VP30 is essential and sufficient to support secondary transcription in an EBOV-speci...

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Autores principales:	Yuki Takamatsu, Verena Krähling, Larissa Kolesnikova, Sandro Halwe, Clemens Lier, Stefan Baumeister, Takeshi Noda, Nadine Biedenkopf, Stephan Becker
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2020
Materias:	VP30 Ebola virus kinase protein phosphorylation transcription Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/52d9451f5a344f14979b4b3d93fcf85a
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spelling	oai:doaj.org-article:52d9451f5a344f14979b4b3d93fcf85a2021-11-15T15:56:58ZSerine-Arginine Protein Kinase 1 Regulates Ebola Virus Transcription10.1128/mBio.02565-192150-7511https://doaj.org/article/52d9451f5a344f14979b4b3d93fcf85a2020-02-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.02565-19https://doaj.org/toc/2150-7511ABSTRACT Ebola virus (EBOV) causes a severe and often fatal disease for which no approved vaccines or antivirals are currently available. EBOV VP30 has been described as a viral phosphoprotein, and nonphosphorylated VP30 is essential and sufficient to support secondary transcription in an EBOV-specific minigenome system; however, phosphorylatable serine residues near the N terminus of VP30 are required to support primary viral transcription as well as the reinitiation of VP30-mediated transcription at internal EBOV genes. While the dephosphorylation of VP30 by the cellular phosphatase PP2A was found to be mediated by nucleoprotein, the VP30-specific kinases and the role of phosphorylation remain unknown. Here, we report that serine-arginine protein kinase 1 (SRPK1) and SRPK2 phosphorylate serine 29 of VP30, which is located in an N-terminal R26xxS29 motif. Interaction with VP30 via the R26xxS29 motif recruits SRPK1 into EBOV-induced inclusion bodies, the sites of viral RNA synthesis, and an inhibitor of SRPK1/SRPK2 downregulates primary viral transcription. When the SRPK1 recognition motif of VP30 was mutated in a recombinant EBOV, virus replication was severely impaired. It is presumed that the interplay between SRPK1 and PP2A in the EBOV inclusions provides a comprehensive regulatory circuit to ensure the activity of VP30 in EBOV transcription. Thus, the identification of SRPK1 is an important mosaic stone that completes our picture of the players involved in Ebola virus transcription regulation. IMPORTANCE The largest Ebola virus (EBOV) epidemic in West Africa ever caused more than 28,000 cases and 11,000 deaths, and the current EBOV epidemic in the Democratic Republic of the Congo continues, with more than 3,000 cases to date. Therefore, it is essential to develop antivirals against EBOV. Recently, an inhibitor of the cellular phosphatase PP2A-mediated dephosphorylation of the EBOV transcription factor VP30 has been shown to suppress the spread of Ebola virus. Here, we identified the protein kinase SRPK1 as a VP30-specific kinase that phosphorylates serine 29, the same residue that is dephosphorylated by PP2A. SRPK1-mediated phosphorylation of serine 29 enabled primary viral transcription. Mutation of the SRPK1 recognition motif in VP30 resulted in significant growth inhibition of EBOV. Similarly, elevation of the phosphorylation status of serine 29 by overexpression of SRPK1 inhibited EBOV growth, highlighting the importance of reversible phosphorylation of VP30 as a potential therapeutic target.Yuki TakamatsuVerena KrählingLarissa KolesnikovaSandro HalweClemens LierStefan BaumeisterTakeshi NodaNadine BiedenkopfStephan BeckerAmerican Society for MicrobiologyarticleVP30Ebola viruskinaseprotein phosphorylationtranscriptionMicrobiologyQR1-502ENmBio, Vol 11, Iss 1 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	VP30 Ebola virus kinase protein phosphorylation transcription Microbiology QR1-502
spellingShingle	VP30 Ebola virus kinase protein phosphorylation transcription Microbiology QR1-502 Yuki Takamatsu Verena Krähling Larissa Kolesnikova Sandro Halwe Clemens Lier Stefan Baumeister Takeshi Noda Nadine Biedenkopf Stephan Becker Serine-Arginine Protein Kinase 1 Regulates Ebola Virus Transcription
description	ABSTRACT Ebola virus (EBOV) causes a severe and often fatal disease for which no approved vaccines or antivirals are currently available. EBOV VP30 has been described as a viral phosphoprotein, and nonphosphorylated VP30 is essential and sufficient to support secondary transcription in an EBOV-specific minigenome system; however, phosphorylatable serine residues near the N terminus of VP30 are required to support primary viral transcription as well as the reinitiation of VP30-mediated transcription at internal EBOV genes. While the dephosphorylation of VP30 by the cellular phosphatase PP2A was found to be mediated by nucleoprotein, the VP30-specific kinases and the role of phosphorylation remain unknown. Here, we report that serine-arginine protein kinase 1 (SRPK1) and SRPK2 phosphorylate serine 29 of VP30, which is located in an N-terminal R26xxS29 motif. Interaction with VP30 via the R26xxS29 motif recruits SRPK1 into EBOV-induced inclusion bodies, the sites of viral RNA synthesis, and an inhibitor of SRPK1/SRPK2 downregulates primary viral transcription. When the SRPK1 recognition motif of VP30 was mutated in a recombinant EBOV, virus replication was severely impaired. It is presumed that the interplay between SRPK1 and PP2A in the EBOV inclusions provides a comprehensive regulatory circuit to ensure the activity of VP30 in EBOV transcription. Thus, the identification of SRPK1 is an important mosaic stone that completes our picture of the players involved in Ebola virus transcription regulation. IMPORTANCE The largest Ebola virus (EBOV) epidemic in West Africa ever caused more than 28,000 cases and 11,000 deaths, and the current EBOV epidemic in the Democratic Republic of the Congo continues, with more than 3,000 cases to date. Therefore, it is essential to develop antivirals against EBOV. Recently, an inhibitor of the cellular phosphatase PP2A-mediated dephosphorylation of the EBOV transcription factor VP30 has been shown to suppress the spread of Ebola virus. Here, we identified the protein kinase SRPK1 as a VP30-specific kinase that phosphorylates serine 29, the same residue that is dephosphorylated by PP2A. SRPK1-mediated phosphorylation of serine 29 enabled primary viral transcription. Mutation of the SRPK1 recognition motif in VP30 resulted in significant growth inhibition of EBOV. Similarly, elevation of the phosphorylation status of serine 29 by overexpression of SRPK1 inhibited EBOV growth, highlighting the importance of reversible phosphorylation of VP30 as a potential therapeutic target.
format	article
author	Yuki Takamatsu Verena Krähling Larissa Kolesnikova Sandro Halwe Clemens Lier Stefan Baumeister Takeshi Noda Nadine Biedenkopf Stephan Becker
author_facet	Yuki Takamatsu Verena Krähling Larissa Kolesnikova Sandro Halwe Clemens Lier Stefan Baumeister Takeshi Noda Nadine Biedenkopf Stephan Becker
author_sort	Yuki Takamatsu
title	Serine-Arginine Protein Kinase 1 Regulates Ebola Virus Transcription
title_short	Serine-Arginine Protein Kinase 1 Regulates Ebola Virus Transcription
title_full	Serine-Arginine Protein Kinase 1 Regulates Ebola Virus Transcription
title_fullStr	Serine-Arginine Protein Kinase 1 Regulates Ebola Virus Transcription
title_full_unstemmed	Serine-Arginine Protein Kinase 1 Regulates Ebola Virus Transcription
title_sort	serine-arginine protein kinase 1 regulates ebola virus transcription
publisher	American Society for Microbiology
publishDate	2020
url	https://doaj.org/article/52d9451f5a344f14979b4b3d93fcf85a
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Serine-Arginine Protein Kinase 1 Regulates Ebola Virus Transcription

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