The SARS-CoV-2 nucleocapsid protein: its role in the viral life cycle, structure and functions, and use as a potential target in the development of vaccines and diagnostics

Abstract

Coronavirus disease 2019 (COVID-19) continues to take a heavy toll on personal health, healthcare systems, and economies around the globe. Scientists are expending tremendous effort to develop diagnostic technologies for detecting positive infections within the shortest possible time, and vaccines and drugs specifically for the prevention and treatment of COVID-19 disease. At the same time, emerging novel variants have raised serious concerns about vaccine efficacy. The SARS-CoV-2 nucleocapsid (N) protein plays an important role in the coronavirus life cycle, and participates in various vital activities after virus invasion. It has attracted a large amount of attention for vaccine and drug development. Here, we summarize the latest research of the N protein, including its role in the SARS-CoV-2 life cycle, structure and function, and post-translational modifications in addition to its involvement in liquid–liquid phase separation (LLPS) and use as a basis for the development of vaccines and diagnostic techniques.

PACT inhibits the replication of SARS‐CoV‐2 through the blockage of GSK‐3β‐N‐nsp3 cascade

“…N protein is well known for its function in increasing the replication of viral genomic/subgenomic RNAs. 14,15,46 Its RNA-binding ability could prevent PRRs and host RNase from recognizing the viral RNAs, resulting in the evasion of host antiviral response and less degradation of viral RNAs. 47,48 Moreover, the interaction between N protein and viral genomic RNAs could promote phase separation.…”

“…Different from the other three structural proteins, S, E, and M, focusing their responsibilities as the membrane protein, N, a highly conserved protein of different CoVs, performed multiple functions, including forming the nucleocapsids with genomic RNA, promoting virion assembly, evading the host antiviral immune response, and enhancing the replication of viral RNAs 14 . Viral genome‐wide protein‐protein interaction screening identified some viral interaction partners of N 15 .…”

“…13 Different from the other three structural proteins, S, E, and M, focusing their responsibilities as the membrane protein, N, a highly conserved protein of different CoVs, performed multiple functions, including forming the nucleocapsids with genomic RNA, promoting virion assembly, evading the host antiviral immune response, and enhancing the replication of viral RNAs. 14 Viral genome-wide protein-protein interaction screening identified some viral interaction partners of N. 15 Among them, nsp3, an interaction partner of nsp12, likely introduces N into the RTC-mediated replication of viral RNAs, because inhibition in the N-nsp3 interaction decreased the synthesis of viral genomic and subgenomic RNAs. 15 N protein performs its viral genomic RNA-binding function through its N-terminal domain (NTD) and C-terminal domain (CTD), between which is a serine-arginine-rich (SR) domain.…”

Next-Generation Vaccines against COVID-19 Variants: Beyond the Spike Protein

“…Indeed, efforts a decade ago were aimed at investigating N protein as a potential vaccine immunogen against coronaviruses. The COVID-19 pandemic has led to new light being shed on these investigations [61,73,[76][77][78]. Several N-based vaccine immunogens have been developed via various technologies.…”

SARS-CoV-2 and the DNA damage response

“…Through binding to the viral RNA genome, it is involved in the creation of the ribonucleoprotein complexes that regulate replication and viral RNA synthesis. Binding of viral RNA to N protein causes liquid–liquid phase separation; this enhances the interaction of RNA with the RdRP complex, favouring viral replication [112–116].…”