The NSP3 protein of SARS-CoV-2 binds fragile X mental retardation proteins to disrupt UBAP2L interactions
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The NSP3 protein of SARS-CoV-2 binds fragile X mental retardation proteins to disrupt UBAP2L interactions. / Garvanska, Dimitriya H; Alvarado, R Elias; Mundt, Filip Oskar; Lindqvist, Richard; 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.
In: EMBO Reports, Vol. 25, No. 2, 2024, p. 902–926.Research output: Contribution to journal › Journal article › Research › peer-review
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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
VL - 25
SP - 902
EP - 926
JO - E M B O Reports
JF - E M B O Reports
SN - 1469-221X
IS - 2
ER -
ID: 378869365