Journal
MOLECULES AND CELLS
Volume 45, Issue 12, Pages 911-922Publisher
KOREAN SOC MOLECULAR & CELLULAR BIOLOGY
DOI: 10.14348/molcells.2022.0130
Keywords
Axin; Delta and Omicron variants; glycogen synthase kinase-3; nucleocapsid; phosphorylation; severe acute respiratory syndrome coronavirus 2
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Funding
- National Research Foundation of Korea [NRF-2020R1I1A1A01072977]
- Korean government (MSIP)
- Kore-an government (MOE)
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The N protein of SARS-CoV-2 is phosphorylated by GSK-3, and this phosphorylation is critical for viral replication. This study identified the GSK-3 interacting domain (GID) and mutations in N that contribute to increased phosphorylation, potentially influencing the evolution of variants.
A structural protein of SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2), nucleocapsid (N) protein is phosphorylated by glycogen synthase kinase (GSK)-3 on the serine/arginine (SR) rich motif located in disordered regions. Although phosphorylation by GSK-3 beta constitutes a critical event for viral replication, the molecular mechanism underlying N phosphorylation is not well understood. In this study, we found the putative alpha-helix L/FxxxL/AxxRL motif known as the GSK-3 interacting domain (GID), found in many endogenous GSK-3 beta binding proteins, such as Axins, FRATs, WWOX, and GSKIP. Indeed, N interacts with GSK-3 beta similarly to Axin, and Leu to Glu substitution of the GID abolished the interaction, with loss of N phosphorylation. The N phosphorylation is also required for its structural loading in a virus-like particle (VLP). Compared to other coronaviruses, N of Sarbecovirus lineage including bat RaTG13 harbors a CDK1-primed phosphorylation site and Gly-rich linker for enhanced phosphorylation by GSK-3 beta. Furthermore, we found that the S202R mutant found in Delta and R203K/G204R mutant found in the Omicron variant allow increased abundance and hyper-phosphorylation of N. Our observations suggest that GID and mutations for increased phosphorylation in N may have contributed to the evolution of variants.
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