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The NSP3 protein of SARS-CoV-2 binds fragile X mental retardation proteins to disrupt UBAP2L interactions
Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Department of Microbiology and Immunology, University of Texas Medical Branch, TX, Galveston, United States; Institute for Translational Sciences, University of Texas Medical Branch, TX, Galveston, United States.
Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
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2024 (English)In: EMBO Reports, ISSN 1469-221X, E-ISSN 1469-3178, Vol. 25, no 2, p. 902-926Article in journal (Refereed) Published
Abstract [en]

Viruses interact with numerous host factors to facilitate viral replication and to dampen antiviral defense mechanisms. We currently have a limited mechanistic understanding of how SARS-CoV-2 binds host factors and the functional role of these interactions. Here, we uncover a novel interaction between the viral NSP3 protein and the fragile X mental retardation proteins (FMRPs: FMR1, FXR1-2). SARS-CoV-2 NSP3 mutant viruses preventing FMRP binding have attenuated replication in vitro and reduced levels of viral antigen in lungs during the early stages of infection. We show that a unique peptide motif in NSP3 binds directly to the two central KH domains of FMRPs and that this interaction is disrupted by the I304N mutation found in a patient with fragile X syndrome. NSP3 binding to FMRPs disrupts their interaction with the stress granule component UBAP2L through direct competition with a peptide motif in UBAP2L to prevent FMRP incorporation into stress granules. Collectively, our results provide novel insight into how SARS-CoV-2 hijacks host cell proteins and provides molecular insight into the possible underlying molecular defects in fragile X syndrome.

Place, publisher, year, edition, pages
Springer Nature, 2024. Vol. 25, no 2, p. 902-926
Keywords [en]
Fragile X Syndrome, NSP3, SARS-CoV-2, Stress Granules, UBAP2L
National Category
Infectious Medicine Biochemistry and Molecular Biology
Identifiers
URN: urn:nbn:se:umu:diva-221660DOI: 10.1038/s44319-023-00043-zPubMedID: 38177924Scopus ID: 2-s2.0-85185482825OAI: oai:DiVA.org:umu-221660DiVA, id: diva2:1842173
Funder
Swedish Research Council, 2018-05851Available from: 2024-03-04 Created: 2024-03-04 Last updated: 2024-03-04Bibliographically approved

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Lindquist, RichardNilsson, EmmaÖverby, Anna K.

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