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


  • D.H. Garvanska
  • R.E. Alvarado
  • F.O. Mundt
  • R. Lindqvist
  • J.K. Duel
  • F. Coscia
  • E. Nilsson
  • K. Lokugamage
  • B.A. Johnson
  • J.A. Plante
  • D.R. Morris
  • M.N. Vu
  • L.K. Estes
  • A.M. McLeland
  • J. Walker
  • P.A. Crocquet-Valdes
  • B.L. Mendez
  • K.S. Plante
  • D.H. Walker
  • M.B. Weisser
  • A.K. Överby
  • M. Mann
  • V.D. Menachery
  • J. Nilsson


  • EMBO Reports


  • EMBO Rep 25 (2): 902-926


  • 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.