Mouse Norovirus Infection Arrests Host Cell Translation Uncoupled from the Stress Granule-PKR-eIF2α Axis

ABSTRACT The integrated stress response (ISR) is a cellular response system activated upon different types of stresses, including viral infection, to restore cellular homeostasis. However, many viruses manipulate this response for their own advantage. In this study, we investigated the association b...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Svenja Fritzlar, Turgut E. Aktepe, Yi-Wei Chao, Nathan D. Kenney, Michael R. McAllaster, Craig B. Wilen, Peter A. White, Jason M. Mackenzie
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2019
Materias:	integrated stress response mouse norovirus protein kinase R protein translation stress granules eIF2α Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/db7b8cd4f9884341ab531a32a8b1cc2e
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:db7b8cd4f9884341ab531a32a8b1cc2e
record_format	dspace
spelling	oai:doaj.org-article:db7b8cd4f9884341ab531a32a8b1cc2e2021-11-15T15:55:25ZMouse Norovirus Infection Arrests Host Cell Translation Uncoupled from the Stress Granule-PKR-eIF2α Axis10.1128/mBio.00960-192150-7511https://doaj.org/article/db7b8cd4f9884341ab531a32a8b1cc2e2019-06-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00960-19https://doaj.org/toc/2150-7511ABSTRACT The integrated stress response (ISR) is a cellular response system activated upon different types of stresses, including viral infection, to restore cellular homeostasis. However, many viruses manipulate this response for their own advantage. In this study, we investigated the association between murine norovirus (MNV) infection and the ISR and demonstrate that MNV regulates the ISR by activating and recruiting key ISR host factors. We observed that during MNV infection, there is a progressive increase in phosphorylated eukaryotic initiation factor 2α (p-eIF2α), resulting in the suppression of host translation, and yet MNV translation still progresses under these conditions. Interestingly, the shutoff of host translation also impacts the translation of key signaling cytokines such as beta interferon, interleukin-6, and tumor necrosis factor alpha. Our subsequent analyses revealed that the phosphorylation of eIF2α was mediated via protein kinase R (PKR), but further investigation revealed that PKR activation, phosphorylation of eIF2α, and translational arrest were uncoupled during infection. We further observed that stress granules (SGs) are not induced during MNV infection and that MNV can restrict SG nucleation and formation. We observed that MNV recruited the key SG nucleating protein G3BP1 to its replication sites and intriguingly the silencing of G3BP1 negatively impacts MNV replication. Thus, it appears that MNV utilizes G3BP1 to enhance replication but equally to prevent SG formation, suggesting an anti-MNV property of SGs. Overall, this study highlights MNV manipulation of SGs, PKR, and translational control to regulate cytokine translation and to promote viral replication. IMPORTANCE Viruses hijack host machinery and regulate cellular homeostasis to actively replicate their genome, propagate, and cause disease. In retaliation, cells possess various defense mechanisms to detect, destroy, and clear infecting viruses, as well as signal to neighboring cells to inform them of the imminent threat. In this study, we demonstrate that the murine norovirus (MNV) infection stalls host protein translation and the production of antiviral and proinflammatory cytokines. However, virus replication and protein translation still ensue. We show that MNV further prevents the formation of cytoplasmic RNA granules, called stress granules (SGs), by recruiting the key host protein G3BP1 to the MNV replication complex, a recruitment that is crucial to establishing and maintaining virus replication. Thus, MNV promotes immune evasion of the virus by altering protein translation. Together, this evasion strategy delays innate immune responses to MNV infection and accelerates disease onset.Svenja FritzlarTurgut E. AktepeYi-Wei ChaoNathan D. KenneyMichael R. McAllasterCraig B. WilenPeter A. WhiteJason M. MackenzieAmerican Society for Microbiologyarticleintegrated stress responsemouse norovirusprotein kinase Rprotein translationstress granuleseIF2αMicrobiologyQR1-502ENmBio, Vol 10, Iss 3 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	integrated stress response mouse norovirus protein kinase R protein translation stress granules eIF2α Microbiology QR1-502
spellingShingle	integrated stress response mouse norovirus protein kinase R protein translation stress granules eIF2α Microbiology QR1-502 Svenja Fritzlar Turgut E. Aktepe Yi-Wei Chao Nathan D. Kenney Michael R. McAllaster Craig B. Wilen Peter A. White Jason M. Mackenzie Mouse Norovirus Infection Arrests Host Cell Translation Uncoupled from the Stress Granule-PKR-eIF2α Axis
description	ABSTRACT The integrated stress response (ISR) is a cellular response system activated upon different types of stresses, including viral infection, to restore cellular homeostasis. However, many viruses manipulate this response for their own advantage. In this study, we investigated the association between murine norovirus (MNV) infection and the ISR and demonstrate that MNV regulates the ISR by activating and recruiting key ISR host factors. We observed that during MNV infection, there is a progressive increase in phosphorylated eukaryotic initiation factor 2α (p-eIF2α), resulting in the suppression of host translation, and yet MNV translation still progresses under these conditions. Interestingly, the shutoff of host translation also impacts the translation of key signaling cytokines such as beta interferon, interleukin-6, and tumor necrosis factor alpha. Our subsequent analyses revealed that the phosphorylation of eIF2α was mediated via protein kinase R (PKR), but further investigation revealed that PKR activation, phosphorylation of eIF2α, and translational arrest were uncoupled during infection. We further observed that stress granules (SGs) are not induced during MNV infection and that MNV can restrict SG nucleation and formation. We observed that MNV recruited the key SG nucleating protein G3BP1 to its replication sites and intriguingly the silencing of G3BP1 negatively impacts MNV replication. Thus, it appears that MNV utilizes G3BP1 to enhance replication but equally to prevent SG formation, suggesting an anti-MNV property of SGs. Overall, this study highlights MNV manipulation of SGs, PKR, and translational control to regulate cytokine translation and to promote viral replication. IMPORTANCE Viruses hijack host machinery and regulate cellular homeostasis to actively replicate their genome, propagate, and cause disease. In retaliation, cells possess various defense mechanisms to detect, destroy, and clear infecting viruses, as well as signal to neighboring cells to inform them of the imminent threat. In this study, we demonstrate that the murine norovirus (MNV) infection stalls host protein translation and the production of antiviral and proinflammatory cytokines. However, virus replication and protein translation still ensue. We show that MNV further prevents the formation of cytoplasmic RNA granules, called stress granules (SGs), by recruiting the key host protein G3BP1 to the MNV replication complex, a recruitment that is crucial to establishing and maintaining virus replication. Thus, MNV promotes immune evasion of the virus by altering protein translation. Together, this evasion strategy delays innate immune responses to MNV infection and accelerates disease onset.
format	article
author	Svenja Fritzlar Turgut E. Aktepe Yi-Wei Chao Nathan D. Kenney Michael R. McAllaster Craig B. Wilen Peter A. White Jason M. Mackenzie
author_facet	Svenja Fritzlar Turgut E. Aktepe Yi-Wei Chao Nathan D. Kenney Michael R. McAllaster Craig B. Wilen Peter A. White Jason M. Mackenzie
author_sort	Svenja Fritzlar
title	Mouse Norovirus Infection Arrests Host Cell Translation Uncoupled from the Stress Granule-PKR-eIF2α Axis
title_short	Mouse Norovirus Infection Arrests Host Cell Translation Uncoupled from the Stress Granule-PKR-eIF2α Axis
title_full	Mouse Norovirus Infection Arrests Host Cell Translation Uncoupled from the Stress Granule-PKR-eIF2α Axis
title_fullStr	Mouse Norovirus Infection Arrests Host Cell Translation Uncoupled from the Stress Granule-PKR-eIF2α Axis
title_full_unstemmed	Mouse Norovirus Infection Arrests Host Cell Translation Uncoupled from the Stress Granule-PKR-eIF2α Axis
title_sort	mouse norovirus infection arrests host cell translation uncoupled from the stress granule-pkr-eif2α axis
publisher	American Society for Microbiology
publishDate	2019
url	https://doaj.org/article/db7b8cd4f9884341ab531a32a8b1cc2e
work_keys_str_mv	AT svenjafritzlar mousenorovirusinfectionarrestshostcelltranslationuncoupledfromthestressgranulepkreif2aaxis AT turguteaktepe mousenorovirusinfectionarrestshostcelltranslationuncoupledfromthestressgranulepkreif2aaxis AT yiweichao mousenorovirusinfectionarrestshostcelltranslationuncoupledfromthestressgranulepkreif2aaxis AT nathandkenney mousenorovirusinfectionarrestshostcelltranslationuncoupledfromthestressgranulepkreif2aaxis AT michaelrmcallaster mousenorovirusinfectionarrestshostcelltranslationuncoupledfromthestressgranulepkreif2aaxis AT craigbwilen mousenorovirusinfectionarrestshostcelltranslationuncoupledfromthestressgranulepkreif2aaxis AT peterawhite mousenorovirusinfectionarrestshostcelltranslationuncoupledfromthestressgranulepkreif2aaxis AT jasonmmackenzie mousenorovirusinfectionarrestshostcelltranslationuncoupledfromthestressgranulepkreif2aaxis
_version_	1718427183195619328

Mouse Norovirus Infection Arrests Host Cell Translation Uncoupled from the Stress Granule-PKR-eIF2α Axis

Ejemplares similares