The Cellular NMD Pathway Restricts Zika Virus Infection and Is Targeted by the Viral Capsid Protein

ABSTRACT Zika virus (ZIKV) infection of neural progenitor cells (NPCs) in utero is associated with neurological disorders, such as microcephaly, but a detailed molecular understanding of ZIKV-induced pathogenesis is lacking. Here we show that in vitro ZIKV infection of human cells, including NPCs, c...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Krystal A. Fontaine, Kristoffer E. Leon, Mir M. Khalid, Sakshi Tomar, David Jimenez-Morales, Mariah Dunlap, Julia A. Kaye, Priya S. Shah, Steve Finkbeiner, Nevan J. Krogan, Melanie Ott
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2018
Materias:	Zika virus nonsense-mediated mRNA decay pathway virus-host interactions Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/ad85e194b2514640959c6776d3129874
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:ad85e194b2514640959c6776d3129874
record_format	dspace
spelling	oai:doaj.org-article:ad85e194b2514640959c6776d31298742021-11-15T15:52:19ZThe Cellular NMD Pathway Restricts Zika Virus Infection and Is Targeted by the Viral Capsid Protein10.1128/mBio.02126-182150-7511https://doaj.org/article/ad85e194b2514640959c6776d31298742018-12-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.02126-18https://doaj.org/toc/2150-7511ABSTRACT Zika virus (ZIKV) infection of neural progenitor cells (NPCs) in utero is associated with neurological disorders, such as microcephaly, but a detailed molecular understanding of ZIKV-induced pathogenesis is lacking. Here we show that in vitro ZIKV infection of human cells, including NPCs, causes disruption of the nonsense-mediated mRNA decay (NMD) pathway. NMD is a cellular mRNA surveillance mechanism that is required for normal brain size in mice. Using affinity purification-mass spectrometry, we identified multiple cellular NMD factors that bind to the viral capsid protein, including the central NMD regulator up-frameshift protein 1 (UPF1). Endogenous UPF1 interacted with the ZIKV capsid protein in coimmunoprecipitation experiments, and capsid expression posttranscriptionally downregulated UPF1 protein levels, a process that we confirmed occurs during ZIKV infection. Cellular fractionation studies show that the ZIKV capsid protein specifically targets nuclear UPF1 for degradation via the proteasome. A further decrease in UPF1 levels by RNAi significantly enhanced ZIKV infection in NPC cultures, consistent with a model in which NMD restricts ZIKV infection in the fetal brain. We propose that ZIKV, via the capsid protein, has evolved a strategy to lower UPF1 levels and dampen antiviral activities of NMD, which in turn contributes to neuropathology in vivo. IMPORTANCE Zika virus (ZIKV) is a significant global health threat, as infection has been linked to serious neurological complications, including microcephaly. Using a human stem cell-derived neural progenitor model system, we find that a critical cellular quality control process called the nonsense-mediated mRNA decay (NMD) pathway is disrupted during ZIKV infection. Importantly, disruption of the NMD pathway is a known cause of microcephaly and other neurological disorders. We further identify an interaction between the capsid protein of ZIKV and up-frameshift protein 1 (UPF1), the master regulator of NMD, and show that ZIKV capsid targets UPF1 for degradation. Together, these results offer a new mechanism for how ZIKV infection can cause neuropathology in the developing brain.Krystal A. FontaineKristoffer E. LeonMir M. KhalidSakshi TomarDavid Jimenez-MoralesMariah DunlapJulia A. KayePriya S. ShahSteve FinkbeinerNevan J. KroganMelanie OttAmerican Society for MicrobiologyarticleZika virusnonsense-mediated mRNA decay pathwayvirus-host interactionsMicrobiologyQR1-502ENmBio, Vol 9, Iss 6 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	Zika virus nonsense-mediated mRNA decay pathway virus-host interactions Microbiology QR1-502
spellingShingle	Zika virus nonsense-mediated mRNA decay pathway virus-host interactions Microbiology QR1-502 Krystal A. Fontaine Kristoffer E. Leon Mir M. Khalid Sakshi Tomar David Jimenez-Morales Mariah Dunlap Julia A. Kaye Priya S. Shah Steve Finkbeiner Nevan J. Krogan Melanie Ott The Cellular NMD Pathway Restricts Zika Virus Infection and Is Targeted by the Viral Capsid Protein
description	ABSTRACT Zika virus (ZIKV) infection of neural progenitor cells (NPCs) in utero is associated with neurological disorders, such as microcephaly, but a detailed molecular understanding of ZIKV-induced pathogenesis is lacking. Here we show that in vitro ZIKV infection of human cells, including NPCs, causes disruption of the nonsense-mediated mRNA decay (NMD) pathway. NMD is a cellular mRNA surveillance mechanism that is required for normal brain size in mice. Using affinity purification-mass spectrometry, we identified multiple cellular NMD factors that bind to the viral capsid protein, including the central NMD regulator up-frameshift protein 1 (UPF1). Endogenous UPF1 interacted with the ZIKV capsid protein in coimmunoprecipitation experiments, and capsid expression posttranscriptionally downregulated UPF1 protein levels, a process that we confirmed occurs during ZIKV infection. Cellular fractionation studies show that the ZIKV capsid protein specifically targets nuclear UPF1 for degradation via the proteasome. A further decrease in UPF1 levels by RNAi significantly enhanced ZIKV infection in NPC cultures, consistent with a model in which NMD restricts ZIKV infection in the fetal brain. We propose that ZIKV, via the capsid protein, has evolved a strategy to lower UPF1 levels and dampen antiviral activities of NMD, which in turn contributes to neuropathology in vivo. IMPORTANCE Zika virus (ZIKV) is a significant global health threat, as infection has been linked to serious neurological complications, including microcephaly. Using a human stem cell-derived neural progenitor model system, we find that a critical cellular quality control process called the nonsense-mediated mRNA decay (NMD) pathway is disrupted during ZIKV infection. Importantly, disruption of the NMD pathway is a known cause of microcephaly and other neurological disorders. We further identify an interaction between the capsid protein of ZIKV and up-frameshift protein 1 (UPF1), the master regulator of NMD, and show that ZIKV capsid targets UPF1 for degradation. Together, these results offer a new mechanism for how ZIKV infection can cause neuropathology in the developing brain.
format	article
author	Krystal A. Fontaine Kristoffer E. Leon Mir M. Khalid Sakshi Tomar David Jimenez-Morales Mariah Dunlap Julia A. Kaye Priya S. Shah Steve Finkbeiner Nevan J. Krogan Melanie Ott
author_facet	Krystal A. Fontaine Kristoffer E. Leon Mir M. Khalid Sakshi Tomar David Jimenez-Morales Mariah Dunlap Julia A. Kaye Priya S. Shah Steve Finkbeiner Nevan J. Krogan Melanie Ott
author_sort	Krystal A. Fontaine
title	The Cellular NMD Pathway Restricts Zika Virus Infection and Is Targeted by the Viral Capsid Protein
title_short	The Cellular NMD Pathway Restricts Zika Virus Infection and Is Targeted by the Viral Capsid Protein
title_full	The Cellular NMD Pathway Restricts Zika Virus Infection and Is Targeted by the Viral Capsid Protein
title_fullStr	The Cellular NMD Pathway Restricts Zika Virus Infection and Is Targeted by the Viral Capsid Protein
title_full_unstemmed	The Cellular NMD Pathway Restricts Zika Virus Infection and Is Targeted by the Viral Capsid Protein
title_sort	cellular nmd pathway restricts zika virus infection and is targeted by the viral capsid protein
publisher	American Society for Microbiology
publishDate	2018
url	https://doaj.org/article/ad85e194b2514640959c6776d3129874
work_keys_str_mv	AT krystalafontaine thecellularnmdpathwayrestrictszikavirusinfectionandistargetedbytheviralcapsidprotein AT kristoffereleon thecellularnmdpathwayrestrictszikavirusinfectionandistargetedbytheviralcapsidprotein AT mirmkhalid thecellularnmdpathwayrestrictszikavirusinfectionandistargetedbytheviralcapsidprotein AT sakshitomar thecellularnmdpathwayrestrictszikavirusinfectionandistargetedbytheviralcapsidprotein AT davidjimenezmorales thecellularnmdpathwayrestrictszikavirusinfectionandistargetedbytheviralcapsidprotein AT mariahdunlap thecellularnmdpathwayrestrictszikavirusinfectionandistargetedbytheviralcapsidprotein AT juliaakaye thecellularnmdpathwayrestrictszikavirusinfectionandistargetedbytheviralcapsidprotein AT priyasshah thecellularnmdpathwayrestrictszikavirusinfectionandistargetedbytheviralcapsidprotein AT stevefinkbeiner thecellularnmdpathwayrestrictszikavirusinfectionandistargetedbytheviralcapsidprotein AT nevanjkrogan thecellularnmdpathwayrestrictszikavirusinfectionandistargetedbytheviralcapsidprotein AT melanieott thecellularnmdpathwayrestrictszikavirusinfectionandistargetedbytheviralcapsidprotein AT krystalafontaine cellularnmdpathwayrestrictszikavirusinfectionandistargetedbytheviralcapsidprotein AT kristoffereleon cellularnmdpathwayrestrictszikavirusinfectionandistargetedbytheviralcapsidprotein AT mirmkhalid cellularnmdpathwayrestrictszikavirusinfectionandistargetedbytheviralcapsidprotein AT sakshitomar cellularnmdpathwayrestrictszikavirusinfectionandistargetedbytheviralcapsidprotein AT davidjimenezmorales cellularnmdpathwayrestrictszikavirusinfectionandistargetedbytheviralcapsidprotein AT mariahdunlap cellularnmdpathwayrestrictszikavirusinfectionandistargetedbytheviralcapsidprotein AT juliaakaye cellularnmdpathwayrestrictszikavirusinfectionandistargetedbytheviralcapsidprotein AT priyasshah cellularnmdpathwayrestrictszikavirusinfectionandistargetedbytheviralcapsidprotein AT stevefinkbeiner cellularnmdpathwayrestrictszikavirusinfectionandistargetedbytheviralcapsidprotein AT nevanjkrogan cellularnmdpathwayrestrictszikavirusinfectionandistargetedbytheviralcapsidprotein AT melanieott cellularnmdpathwayrestrictszikavirusinfectionandistargetedbytheviralcapsidprotein
_version_	1718427295263227904

The Cellular NMD Pathway Restricts Zika Virus Infection and Is Targeted by the Viral Capsid Protein

Ejemplares similares