SND1 binds SARS-CoV-2 negative-sense RNA and promotes viral RNA synthesis through NSP9

Nora Schmidt; Sabina Ganskih; Yuanjie Wei; Alexander Gabel; Sebastian Zielinski; Hasmik Keshishian; Caleb A. Lareau; Liv Zimmermann; Jana Makroczyova; Cadence Pearce; Karsten Krey; Thomas Hennig; Sebastian Stegmaier; Lambert Moyon; Marc Horlacher; Simone Werner; Jens Aydin; Marco Olguin-Nava; Ramya Potabattula; Anuja Kibe; Lars Dölken; Redmond P. Smyth; Neva Caliskan; Annalisa Marsico; Christine Krempl; Jochen Bodem; Andreas Pichlmair; Steven A. Carr; Petr Chlanda; Florian Erhard; Mathias Munschauer

doi:10.1016/j.cell.2023.09.002

SND1 binds SARS-CoV-2 negative-sense RNA and promotes viral RNA synthesis through NSP9

Nora Schmidt, Sabina Ganskih, Yuanjie Wei, Alexander Gabel, Sebastian Zielinski, Hasmik Keshishian, Caleb A. Lareau, Liv Zimmermann, Jana Makroczyova, Cadence Pearce, Karsten Krey, Thomas Hennig, Sebastian Stegmaier, Lambert Moyon, Marc Horlacher, Simone Werner, Jens Aydin, Marco Olguin-Nava, Ramya Potabattula, Anuja KibeLars Dölken, Redmond P. Smyth, Neva Caliskan, Annalisa Marsico, Christine Krempl, Jochen Bodem, Andreas Pichlmair, Steven A. Carr, Petr Chlanda, Florian Erhard, Mathias Munschauer

Medicine and Health

Research output: Contribution to journal › Article › peer-review

14 Scopus citations

Abstract

Regulation of viral RNA biogenesis is fundamental to productive SARS-CoV-2 infection. To characterize host RNA-binding proteins (RBPs) involved in this process, we biochemically identified proteins bound to genomic and subgenomic SARS-CoV-2 RNAs. We find that the host protein SND1 binds the 5′ end of negative-sense viral RNA and is required for SARS-CoV-2 RNA synthesis. SND1-depleted cells form smaller replication organelles and display diminished virus growth kinetics. We discover that NSP9, a viral RBP and direct SND1 interaction partner, is covalently linked to the 5′ ends of positive- and negative-sense RNAs produced during infection. These linkages occur at replication-transcription initiation sites, consistent with NSP9 priming viral RNA synthesis. Mechanistically, SND1 remodels NSP9 occupancy and alters the covalent linkage of NSP9 to initiating nucleotides in viral RNA. Our findings implicate NSP9 in the initiation of SARS-CoV-2 RNA synthesis and unravel an unsuspected role of a cellular protein in orchestrating viral RNA production.

Original language	English
Pages (from-to)	4834-4850.e23
Journal	Cell
Volume	186
Issue number	22
DOIs	https://doi.org/10.1016/j.cell.2023.09.002
State	Published - 26 Oct 2023

Keywords

RNA binding proteins
RNA biology
RNA interactome
RNA virus
SARS-CoV-2
host factors
omics technologies
proteomics
systems biology
virus host interactions

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10.1016/j.cell.2023.09.002

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Schmidt, N., Ganskih, S., Wei, Y., Gabel, A., Zielinski, S., Keshishian, H., Lareau, C. A., Zimmermann, L., Makroczyova, J., Pearce, C., Krey, K., Hennig, T., Stegmaier, S., Moyon, L., Horlacher, M., Werner, S., Aydin, J., Olguin-Nava, M., Potabattula, R., ... Munschauer, M. (2023). SND1 binds SARS-CoV-2 negative-sense RNA and promotes viral RNA synthesis through NSP9. Cell, 186(22), 4834-4850.e23. https://doi.org/10.1016/j.cell.2023.09.002

@article{fbb1dd30aad045759f87987582d4a6e6,

title = "SND1 binds SARS-CoV-2 negative-sense RNA and promotes viral RNA synthesis through NSP9",

abstract = "Regulation of viral RNA biogenesis is fundamental to productive SARS-CoV-2 infection. To characterize host RNA-binding proteins (RBPs) involved in this process, we biochemically identified proteins bound to genomic and subgenomic SARS-CoV-2 RNAs. We find that the host protein SND1 binds the 5′ end of negative-sense viral RNA and is required for SARS-CoV-2 RNA synthesis. SND1-depleted cells form smaller replication organelles and display diminished virus growth kinetics. We discover that NSP9, a viral RBP and direct SND1 interaction partner, is covalently linked to the 5′ ends of positive- and negative-sense RNAs produced during infection. These linkages occur at replication-transcription initiation sites, consistent with NSP9 priming viral RNA synthesis. Mechanistically, SND1 remodels NSP9 occupancy and alters the covalent linkage of NSP9 to initiating nucleotides in viral RNA. Our findings implicate NSP9 in the initiation of SARS-CoV-2 RNA synthesis and unravel an unsuspected role of a cellular protein in orchestrating viral RNA production.",

keywords = "RNA binding proteins, RNA biology, RNA interactome, RNA virus, SARS-CoV-2, host factors, omics technologies, proteomics, systems biology, virus host interactions",

author = "Nora Schmidt and Sabina Ganskih and Yuanjie Wei and Alexander Gabel and Sebastian Zielinski and Hasmik Keshishian and Lareau, {Caleb A.} and Liv Zimmermann and Jana Makroczyova and Cadence Pearce and Karsten Krey and Thomas Hennig and Sebastian Stegmaier and Lambert Moyon and Marc Horlacher and Simone Werner and Jens Aydin and Marco Olguin-Nava and Ramya Potabattula and Anuja Kibe and Lars D{\"o}lken and Smyth, {Redmond P.} and Neva Caliskan and Annalisa Marsico and Christine Krempl and Jochen Bodem and Andreas Pichlmair and Carr, {Steven A.} and Petr Chlanda and Florian Erhard and Mathias Munschauer",

note = "Publisher Copyright: {\textcopyright} 2023 The Author(s)",

year = "2023",

month = oct,

day = "26",

doi = "10.1016/j.cell.2023.09.002",

language = "English",

volume = "186",

pages = "4834--4850.e23",

journal = "Cell",

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Schmidt, N, Ganskih, S, Wei, Y, Gabel, A, Zielinski, S, Keshishian, H, Lareau, CA, Zimmermann, L, Makroczyova, J, Pearce, C, Krey, K, Hennig, T, Stegmaier, S, Moyon, L, Horlacher, M, Werner, S, Aydin, J, Olguin-Nava, M, Potabattula, R, Kibe, A, Dölken, L, Smyth, RP, Caliskan, N, Marsico, A, Krempl, C, Bodem, J, Pichlmair, A, Carr, SA, Chlanda, P, Erhard, F & Munschauer, M 2023, 'SND1 binds SARS-CoV-2 negative-sense RNA and promotes viral RNA synthesis through NSP9', Cell, vol. 186, no. 22, pp. 4834-4850.e23. https://doi.org/10.1016/j.cell.2023.09.002

TY - JOUR

T1 - SND1 binds SARS-CoV-2 negative-sense RNA and promotes viral RNA synthesis through NSP9

AU - Schmidt, Nora

AU - Ganskih, Sabina

AU - Wei, Yuanjie

AU - Gabel, Alexander

AU - Zielinski, Sebastian

AU - Keshishian, Hasmik

AU - Lareau, Caleb A.

AU - Zimmermann, Liv

AU - Makroczyova, Jana

AU - Pearce, Cadence

AU - Krey, Karsten

AU - Hennig, Thomas

AU - Stegmaier, Sebastian

AU - Moyon, Lambert

AU - Horlacher, Marc

AU - Werner, Simone

AU - Aydin, Jens

AU - Olguin-Nava, Marco

AU - Potabattula, Ramya

AU - Kibe, Anuja

AU - Dölken, Lars

AU - Smyth, Redmond P.

AU - Caliskan, Neva

AU - Marsico, Annalisa

AU - Krempl, Christine

AU - Bodem, Jochen

AU - Pichlmair, Andreas

AU - Carr, Steven A.

AU - Chlanda, Petr

AU - Erhard, Florian

AU - Munschauer, Mathias

PY - 2023/10/26

Y1 - 2023/10/26

N2 - Regulation of viral RNA biogenesis is fundamental to productive SARS-CoV-2 infection. To characterize host RNA-binding proteins (RBPs) involved in this process, we biochemically identified proteins bound to genomic and subgenomic SARS-CoV-2 RNAs. We find that the host protein SND1 binds the 5′ end of negative-sense viral RNA and is required for SARS-CoV-2 RNA synthesis. SND1-depleted cells form smaller replication organelles and display diminished virus growth kinetics. We discover that NSP9, a viral RBP and direct SND1 interaction partner, is covalently linked to the 5′ ends of positive- and negative-sense RNAs produced during infection. These linkages occur at replication-transcription initiation sites, consistent with NSP9 priming viral RNA synthesis. Mechanistically, SND1 remodels NSP9 occupancy and alters the covalent linkage of NSP9 to initiating nucleotides in viral RNA. Our findings implicate NSP9 in the initiation of SARS-CoV-2 RNA synthesis and unravel an unsuspected role of a cellular protein in orchestrating viral RNA production.

AB - Regulation of viral RNA biogenesis is fundamental to productive SARS-CoV-2 infection. To characterize host RNA-binding proteins (RBPs) involved in this process, we biochemically identified proteins bound to genomic and subgenomic SARS-CoV-2 RNAs. We find that the host protein SND1 binds the 5′ end of negative-sense viral RNA and is required for SARS-CoV-2 RNA synthesis. SND1-depleted cells form smaller replication organelles and display diminished virus growth kinetics. We discover that NSP9, a viral RBP and direct SND1 interaction partner, is covalently linked to the 5′ ends of positive- and negative-sense RNAs produced during infection. These linkages occur at replication-transcription initiation sites, consistent with NSP9 priming viral RNA synthesis. Mechanistically, SND1 remodels NSP9 occupancy and alters the covalent linkage of NSP9 to initiating nucleotides in viral RNA. Our findings implicate NSP9 in the initiation of SARS-CoV-2 RNA synthesis and unravel an unsuspected role of a cellular protein in orchestrating viral RNA production.

KW - RNA binding proteins

KW - RNA biology

KW - RNA interactome

KW - RNA virus

KW - SARS-CoV-2

KW - host factors

KW - omics technologies

KW - proteomics

KW - systems biology

KW - virus host interactions

UR - http://www.scopus.com/inward/record.url?scp=85174660187&partnerID=8YFLogxK

U2 - 10.1016/j.cell.2023.09.002

DO - 10.1016/j.cell.2023.09.002

M3 - Article

C2 - 37794589

AN - SCOPUS:85174660187

SN - 0092-8674

VL - 186

SP - 4834-4850.e23

JO - Cell

JF - Cell

IS - 22

ER -

SND1 binds SARS-CoV-2 negative-sense RNA and promotes viral RNA synthesis through NSP9

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Keywords

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