학술논문
The NSP3 protein of SARS-CoV-2 binds fragile X mental retardation proteins to disrupt UBAP2L interactions
Document Type
Author
Garvanska, Dimitriya H.; Alvarado, R. Elias; Mundt, Filip Oskar; Lindquist, Richard, 1985; Duel, Josephine Kerzel; Coscia, Fabian; Nilsson, Emma; Lokugamage, Kumari; Johnson, Bryan A.; Plante, Jessica A.; Morris, Dorothea R.; Vu, Michelle N.; Estes, Leah K.; McLeland, Alyssa M.; Walker, Jordyn; Crocquet-Valdes, Patricia A.; Mendez, Blanca Lopez; Plante, Kenneth S.; Walker, David H.; Weisser, Melanie Bianca; Överby, Anna K.; Mann, Matthias; Menachery, Vineet D.; Nilsson, Jakob
Source
EMBO Reports. 25(2):902-926
Subject
Language
English
ISSN
1469-221X
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.