Abstract |
While SARS-CoV-2 continues to adapt for human infection and transmission, genetic variation outside of the spike gene remains largely unexplored. This study investigates a highly variable region at residues 203-205 in the SARS-CoV-2 nucleocapsid protein. Recreating a mutation found in the alpha and omicron variants in an early pandemic (WA-1) background, we find that the R203K+G204R mutation is sufficient to enhance replication, fitness, and pathogenesis of SARS-CoV-2. The R203K+G204R mutant corresponds with increased viral RNA and protein both in vitro and in vivo. Importantly, the R203K+G204R mutation increases nucleocapsid phosphorylation and confers resistance to inhibition of the GSK-3 kinase, providing a molecular basis for increased virus replication. Notably, analogous alanine substitutions at positions 203+204 also increase SARS-CoV-2 replication and augment phosphorylation, suggesting that infection is enhanced through ablation of the ancestral 'RG' motif. Overall, these results demonstrate that variant mutations outside spike are key components in SARS-CoV-2's continued adaptation to human infection.
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Authors | Bryan A Johnson, Yiyang Zhou, Kumari G Lokugamage, Michelle N Vu, Nathen Bopp, Patricia A Crocquet-Valdes, Birte Kalveram, Craig Schindewolf, Yang Liu, Dionna Scharton, Jessica A Plante, Xuping Xie, Patricia Aguilar, Scott C Weaver, Pei-Yong Shi, David H Walker, Andrew L Routh, Kenneth S Plante, Vineet D Menachery |
Journal | PLoS pathogens
(PLoS Pathog)
Vol. 18
Issue 6
Pg. e1010627
(06 2022)
ISSN: 1553-7374 [Electronic] United States |
PMID | 35728038
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, P.H.S.)
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Chemical References |
- Spike Glycoprotein, Coronavirus
- spike protein, SARS-CoV-2
- Glycogen Synthase Kinase 3
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Topics |
- COVID-19
(genetics)
- Glycogen Synthase Kinase 3
- Humans
- Mutation
- Nucleocapsid
- SARS-CoV-2
(genetics)
- Spike Glycoprotein, Coronavirus
(genetics)
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