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Direct interaction between human DDX1 and SARS-CoV-2 nucleocapsid protein is regulated by phosphorylation
Liangjun Wang1, Ryan M Baxley1, David A Largaespada2
1Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, Minnesota, USA.
The Journal of Biological Chemistry
|March 28, 2026
Summary
The SARS-CoV-2 nucleocapsid (N) protein binds human RNA helicases DDX1 and DDX21 through distinct mechanisms. DDX1 binding is phosphorylation-dependent, while DDX21 interaction is RNA-regulated and phosphorylation-independent.
Area of Science:
- Virology
- Molecular Biology
- Structural Biology
Background:
- The SARS-CoV-2 nucleocapsid (N) protein is crucial for viral replication.
- N protein interactions with host factors are key to viral lifecycle.
- Host RNA helicases are implicated in viral processes.
Purpose of the Study:
- To elucidate the distinct mechanisms of SARS-CoV-2 N protein interaction with human RNA helicases DDX1 and DDX21.
- To investigate the role of N protein phosphorylation and RNA in these interactions.
Main Methods:
- Co-immunoprecipitation assays in HEK293 cells.
- Site-directed mutagenesis (SR deletion, serine-to-alanine substitutions).
- In vitro peptide binding assays and RNase treatment.
Main Results:
- DDX1 binding to N protein is dependent on the serine-arginine (SR) region and its phosphorylation status.
- DDX21 interaction with N protein is independent of SR phosphorylation and requires N- and C-terminal domains, enhanced by RNase treatment.
- Domain mapping identified specific binding interfaces on DDX1 and DDX21.
Conclusions:
- SARS-CoV-2 N protein employs distinct strategies to engage DDX1 (phosphorylation-dependent) and DDX21 (phosphorylation-independent, RNA-regulated).
- These findings reveal mechanistic insights into how the virus hijacks host helicases for replication.
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