TY - JOUR

T1 - The NSP3 protein of SARS-CoV-2 binds fragile X mental retardation proteins to disrupt UBAP2L interactions

AU - Garvanska, Dimitriya H

AU - Alvarado, R Elias

AU - Mundt, Filip Oskar

AU - Lindqvist, Richard

AU - Duel, Josephine Kerzel

AU - Coscia, Fabian

AU - Nilsson, Emma

AU - Lokugamage, Kumari

AU - Johnson, Bryan A

AU - Plante, Jessica A

AU - Morris, Dorothea R

AU - Vu, Michelle N

AU - Estes, Leah K

AU - McLeland, Alyssa M

AU - Walker, Jordyn

AU - Crocquet-Valdes, Patricia A

AU - Mendez, Blanca Lopez

AU - Plante, Kenneth S

AU - Walker, David H

AU - Weisser, Melanie Bianca

AU - Överby, Anna K

AU - Mann, Matthias

AU - Menachery, Vineet D

AU - Nilsson, Jakob

N1 - © 2024. The Author(s).

PY - 2024

Y1 - 2024

N2 - 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.

AB - 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.

U2 - 10.1038/s44319-023-00043-z

DO - 10.1038/s44319-023-00043-z

M3 - Journal article

C2 - 38177924

JO - E M B O Reports

JF - E M B O Reports

SN - 1469-221X

ER -