The NSP3 protein of SARS-CoV-2 binds fragile X mental retardation proteins to disrupt UBAP2L interactions
Authors
- 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
Journal
- EMBO Reports
Citation
- EMBO Rep 25 (2): 902-926
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.