SARS-CoV-2 nucleocapsid protein delays cell cycle in S-phase

The emergence of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) as the causative agent of COVID-19 precipitated a global health crisis of unprecedented scale. SARS-CoV-2 has been shown to interfere specifically with S phase progression during early stages of infection. Nucleocapsid (N) is an important structural protein. The abundance and early presence of N suggest that the N protein may play a pivotal role in determining the fate of host cells post-infection, including in cell cycle regulation. Our observations reveal that the SARS-CoV-2 N protein actually induces S phase arrest by promoting S phase entry and simultaneously blocking exit from this phase, which is different from previous report G1/S blockage, others describe G1 and G2/M arrest. Prolonged cell cycle arrest is frequently linked to cell death, while our data suggests the N protein curtails cell proliferation, slowing down cell growth without actively triggering cell death. Intriguingly, removing the N-arm, SR-rich region, CTD, or C-tail each abolishes the N protein’s ability to suppress cell growth, whereas deletion of the NTD does not impact this capability, nor does it affect S phase arrest. All told, the SARS-CoV-2 N protein emerges as a multifunctional actor, not only driving key aspects of viral replication but also exerting significant effects on host cell physiology by modulating cell cycle progression and growth.