The NSP3 protein of SARS-CoV-2 binds fragile X mental retardation proteins to disrupt UBAP2L interactions.
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Garvanska DH, Alvarado RE, Mundt FO, Lindqvist R, Duel JK, Coscia F, Nilsson E, Lokugamage K, Johnson BA, Plante JA, Morris DR, Vu MN, Estes LK, McLeland AM, Walker J, Crocquet-Valdes PA, Mendez BL, Plante KS, Walker DH, Weisser MB, Överby AK, Mann M, Menachery VD, Nilsson J
EMBO Rep - (-) -
[2024-01-02; online 2024-01-02]
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.
PubMed 38177924
DOI 10.1038/s44319-023-00043-z
Crossref 10.1038/s44319-023-00043-z
pii: 10.1038/s44319-023-00043-z