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

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Item Type:Article
Title:The NSP3 protein of SARS-CoV-2 binds fragile X mental retardation proteins to disrupt UBAP2L interactions
Creators Name:Garvanska, D.H. and Alvarado, R.E. and Mundt, F.O. and Lindqvist, R. and Duel, J.K. and Coscia, F. and Nilsson, E. and Lokugamage, K. and Johnson, B.A. and Plante, J.A. and Morris, D.R. and Vu, M.N. and Estes, L.K. and McLeland, A.M. and Walker, J. and Crocquet-Valdes, P.A. and Mendez, B.L. and Plante, K.S. and Walker, D.H. and Weisser, M.B. and Överby, A.K. and Mann, M. and Menachery, V.D. and Nilsson, J.
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.
Keywords:SARS-CoV-2, Fragile X Syndrome, UBAP2L, Stress Granules, NSP3
Source:EMBO Reports
Publisher:EMBO Press
Page Range:902-926
Date:13 February 2024
Official Publication:https://doi.org/10.1038/s44319-023-00043-z
PubMed:View item in PubMed

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