The NSP3 protein of SARS-CoV-2 binds fragile X mental retardation proteins to disrupt UBAP2L interactions

Dimitriya H. Garvanska, R. Elias Alvarado, Filip Oskar Mundt, Richard Lindqvist, Josephine Kerzel Duel, Fabian Coscia, Emma Nilsson, Kumari Lokugamage, Bryan A. Johnson, Jessica A. Plante, Dorothea R. Morris, Michelle N. Vu, Leah K. Estes, Alyssa M. McLeland, Jordyn Walker, Patricia A. Crocquet-Valdes, Blanca Lopez Mendez, Kenneth S. Plante, David H. Walker, Melanie Bianca WeisserAnna K. Överby, Matthias Mann, Vineet D. Menachery, Jakob Nilsson

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Pages (from-to)902-926
Number of pages25
JournalEMBO reports
Volume25
Issue number2
DOIs
StatePublished - Feb 13 2024

Keywords

  • Fragile X Syndrome
  • NSP3
  • SARS-CoV-2
  • Stress Granules
  • UBAP2L

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Genetics

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