Nsp3-N interactions are critical for SARS-CoV-2 fitness and virulence

Pengfei Li; Biyun Xue; Nicholas Schnicker; Lok-Yin Wong; David Meyerholz; Stanley Perlman

doi:10.1073/pnas.2305674120

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Nsp3-N interactions are critical for SARS-CoV-2 fitness and virulence

Journal article

Open access

Peer reviewed

Nsp3-N interactions are critical for SARS-CoV-2 fitness and virulence

Pengfei Li, Biyun Xue, Nicholas Schnicker, Lok-Yin Wong, David Meyerholz and Stanley Perlman

Proceedings of the National Academy of Sciences - PNAS, Vol.120(31), e2305674120

08/01/2023

DOI: 10.1073/pnas.2305674120

PMCID: PMC10400999

PMID: 37487098

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Abstract

SARS-CoV-2, the causative agent of COVID-19 encodes at least 16 nonstructural proteins of variably understood function. Nsp3, the largest nonstructural protein contains several domains, including a SARS-unique domain (SUD), which occurs only in Sarbecovirus. The SUD has a role in preferentially enhancing viral translation. During isolation of mouse-adapted SARS-CoV-2, we isolated an attenuated virus that contained a single mutation in a linker region of nsp3 (nsp3-S676T). The S676T mutation decreased virus replication in cultured cells and primary human cells and in mice. Nsp3-S676T alleviated the SUD translational enhancing ability by decreasing the interaction between two translation factors, Paip1 and PABP1. We also identified a compensatory mutation in the nucleocapsid (N) protein (N-S194L) that restored the virulent phenotype, without directly binding to SUD. Together, these results reveal an aspect of nsp3-N interactions, which impact both SARS-CoV-2 replication and, consequently, pathogenesis.

Mutation

Pathogenesis

Translation

COVID-19

Nonstructural proteins

Nucleocapsids

Phenotypes

Proteins

Replication

Severe acute respiratory syndrome coronavirus 2

Viral diseases

Virulence

Viruses

Details

Title: Subtitle: Nsp3-N interactions are critical for SARS-CoV-2 fitness and virulence
Creators: Pengfei Li - University of Iowa
Biyun Xue - University of Iowa
Nicholas Schnicker - University of Iowa
Lok-Yin Wong - University of Iowa
David Meyerholz - University of Iowa
Stanley Perlman - University of Iowa
Resource Type: Journal article
Publication Details: Proceedings of the National Academy of Sciences - PNAS, Vol.120(31), e2305674120
DOI: 10.1073/pnas.2305674120
PMID: 37487098
PMCID: PMC10400999
NLM abbreviation: Proc Natl Acad Sci U S A
ISSN: 0027-8424
eISSN: 1091-6490
Publisher: National Academy of Sciences
Grant note: DOI: 10.13039/100015691, name: HHS | NIH | NIAID | Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases, award: P01 AI060699; DOI: 10.13039/100000060, name: HHS | NIH | National Institute of Allergy and Infectious Diseases, award: R01 AI129269
Language: English
Date published: 08/01/2023
Academic Unit: Molecular Physiology and Biophysics; Microbiology and Immunology; Stead Family Department of Pediatrics; Pathology; Iowa Neuroscience Institute; Infectious Disease (Pediatrics); Internal Medicine
Record Identifier: 9984447953202771

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