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

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

EMBO reports (2024-01-05)
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 Weisser, Anna K Överby, Matthias Mann, Vineet D Menachery, Jakob Nilsson
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.