eIF2B as a Target for Viral Evasion of PKR-Mediated Translation Inhibition

ABSTRACT RNA-activated protein kinase (PKR) is a major innate immune factor that senses viral double-stranded RNA (dsRNA) and phosphorylates eukaryotic initiation factor (eIF) 2α. Phosphorylation of the α subunit converts the eIF2αβγ complex into a stoichiometric inhibitor of eukaryotic initiation f...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Jennifer Deborah Wuerth, Matthias Habjan, Markus Kainulainen, Besim Berisha, Damien Bertheloot, Giulio Superti-Furga, Andreas Pichlmair, Friedemann Weber
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2020
Materias:	PKR phospho-eIF2α translation inhibition integrated stress response viral PKR antagonist eIF2B Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/6612551f840f4040b082cf031bc00604
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:6612551f840f4040b082cf031bc00604
record_format	dspace
spelling	oai:doaj.org-article:6612551f840f4040b082cf031bc006042021-11-15T15:56:44ZeIF2B as a Target for Viral Evasion of PKR-Mediated Translation Inhibition10.1128/mBio.00976-202150-7511https://doaj.org/article/6612551f840f4040b082cf031bc006042020-08-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00976-20https://doaj.org/toc/2150-7511ABSTRACT RNA-activated protein kinase (PKR) is a major innate immune factor that senses viral double-stranded RNA (dsRNA) and phosphorylates eukaryotic initiation factor (eIF) 2α. Phosphorylation of the α subunit converts the eIF2αβγ complex into a stoichiometric inhibitor of eukaryotic initiation factor eIF2B, thus halting mRNA translation. To escape this protein synthesis shutoff, viruses have evolved countermechanisms such as dsRNA sequestration, eIF-independent translation by an internal ribosome binding site, degradation of PKR, or dephosphorylation of PKR or of phospho-eIF2α. Here, we report that sandfly fever Sicilian phlebovirus (SFSV) confers such a resistance without interfering with PKR activation or eIF2α phosphorylation. Rather, SFSV expresses a nonstructural protein termed NSs that strongly binds to eIF2B. Although NSs still allows phospho-eIF2α binding to eIF2B, protein synthesis and virus replication are unhindered. Hence, SFSV encodes a unique PKR antagonist that acts by rendering eIF2B resistant to the inhibitory action of bound phospho-eIF2α. IMPORTANCE RNA-activated protein kinase (PKR) is one of the most powerful antiviral defense factors of the mammalian host. PKR acts by phosphorylating mRNA translation initiation factor eIF2α, thereby converting it from a cofactor to an inhibitor of mRNA translation that strongly binds to initiation factor eIF2B. To sustain synthesis of their proteins, viruses are known to counteract this on the level of PKR or eIF2α or by circumventing initiation factor-dependent translation altogether. Here, we report a different PKR escape strategy executed by sandfly fever Sicilian virus (SFSV), a member of the increasingly important group of phleboviruses. We found that the nonstructural protein NSs of SFSV binds to eIF2B and protects it from inactivation by PKR-generated phospho-eIF2α. Protein synthesis is hence maintained and the virus can replicate despite ongoing full-fledged PKR signaling in the infected cells. Thus, SFSV has evolved a unique strategy to escape the powerful antiviral PKR.Jennifer Deborah WuerthMatthias HabjanMarkus KainulainenBesim BerishaDamien BerthelootGiulio Superti-FurgaAndreas PichlmairFriedemann WeberAmerican Society for MicrobiologyarticlePKRphospho-eIF2αtranslation inhibitionintegrated stress responseviral PKR antagonisteIF2BMicrobiologyQR1-502ENmBio, Vol 11, Iss 4 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	PKR phospho-eIF2α translation inhibition integrated stress response viral PKR antagonist eIF2B Microbiology QR1-502
spellingShingle	PKR phospho-eIF2α translation inhibition integrated stress response viral PKR antagonist eIF2B Microbiology QR1-502 Jennifer Deborah Wuerth Matthias Habjan Markus Kainulainen Besim Berisha Damien Bertheloot Giulio Superti-Furga Andreas Pichlmair Friedemann Weber eIF2B as a Target for Viral Evasion of PKR-Mediated Translation Inhibition
description	ABSTRACT RNA-activated protein kinase (PKR) is a major innate immune factor that senses viral double-stranded RNA (dsRNA) and phosphorylates eukaryotic initiation factor (eIF) 2α. Phosphorylation of the α subunit converts the eIF2αβγ complex into a stoichiometric inhibitor of eukaryotic initiation factor eIF2B, thus halting mRNA translation. To escape this protein synthesis shutoff, viruses have evolved countermechanisms such as dsRNA sequestration, eIF-independent translation by an internal ribosome binding site, degradation of PKR, or dephosphorylation of PKR or of phospho-eIF2α. Here, we report that sandfly fever Sicilian phlebovirus (SFSV) confers such a resistance without interfering with PKR activation or eIF2α phosphorylation. Rather, SFSV expresses a nonstructural protein termed NSs that strongly binds to eIF2B. Although NSs still allows phospho-eIF2α binding to eIF2B, protein synthesis and virus replication are unhindered. Hence, SFSV encodes a unique PKR antagonist that acts by rendering eIF2B resistant to the inhibitory action of bound phospho-eIF2α. IMPORTANCE RNA-activated protein kinase (PKR) is one of the most powerful antiviral defense factors of the mammalian host. PKR acts by phosphorylating mRNA translation initiation factor eIF2α, thereby converting it from a cofactor to an inhibitor of mRNA translation that strongly binds to initiation factor eIF2B. To sustain synthesis of their proteins, viruses are known to counteract this on the level of PKR or eIF2α or by circumventing initiation factor-dependent translation altogether. Here, we report a different PKR escape strategy executed by sandfly fever Sicilian virus (SFSV), a member of the increasingly important group of phleboviruses. We found that the nonstructural protein NSs of SFSV binds to eIF2B and protects it from inactivation by PKR-generated phospho-eIF2α. Protein synthesis is hence maintained and the virus can replicate despite ongoing full-fledged PKR signaling in the infected cells. Thus, SFSV has evolved a unique strategy to escape the powerful antiviral PKR.
format	article
author	Jennifer Deborah Wuerth Matthias Habjan Markus Kainulainen Besim Berisha Damien Bertheloot Giulio Superti-Furga Andreas Pichlmair Friedemann Weber
author_facet	Jennifer Deborah Wuerth Matthias Habjan Markus Kainulainen Besim Berisha Damien Bertheloot Giulio Superti-Furga Andreas Pichlmair Friedemann Weber
author_sort	Jennifer Deborah Wuerth
title	eIF2B as a Target for Viral Evasion of PKR-Mediated Translation Inhibition
title_short	eIF2B as a Target for Viral Evasion of PKR-Mediated Translation Inhibition
title_full	eIF2B as a Target for Viral Evasion of PKR-Mediated Translation Inhibition
title_fullStr	eIF2B as a Target for Viral Evasion of PKR-Mediated Translation Inhibition
title_full_unstemmed	eIF2B as a Target for Viral Evasion of PKR-Mediated Translation Inhibition
title_sort	eif2b as a target for viral evasion of pkr-mediated translation inhibition
publisher	American Society for Microbiology
publishDate	2020
url	https://doaj.org/article/6612551f840f4040b082cf031bc00604
work_keys_str_mv	AT jenniferdeborahwuerth eif2basatargetforviralevasionofpkrmediatedtranslationinhibition AT matthiashabjan eif2basatargetforviralevasionofpkrmediatedtranslationinhibition AT markuskainulainen eif2basatargetforviralevasionofpkrmediatedtranslationinhibition AT besimberisha eif2basatargetforviralevasionofpkrmediatedtranslationinhibition AT damienbertheloot eif2basatargetforviralevasionofpkrmediatedtranslationinhibition AT giuliosupertifurga eif2basatargetforviralevasionofpkrmediatedtranslationinhibition AT andreaspichlmair eif2basatargetforviralevasionofpkrmediatedtranslationinhibition AT friedemannweber eif2basatargetforviralevasionofpkrmediatedtranslationinhibition
_version_	1718427092290371584

eIF2B as a Target for Viral Evasion of PKR-Mediated Translation Inhibition

Ejemplares similares