The ongoing 2019 novel coronavirus disease (COVID-19) caused by SARS-CoV-2 has posed a worldwide pandemic and a major global public health threat. The severity and mortality of COVID-19 are associated with virus-induced dysfunctional inflammatory responses and cytokine storms. However, the interplay between host inflammatory responses and SARS-CoV-2 infection remains largely unknown. Here, we demonstrate that SARS-CoV-2 nucleocapsid (N) protein, the major structural protein of the virion, promotes the virus-triggered activation of NF-κB signaling. After binding to viral RNA, N protein robustly undergoes liquid–liquid phase separation (LLPS), which recruits TAK1 and IKK complex, the key kinases of NF-κB signaling, to enhance NF-κB activation.
Fig: N protein of SARS-CoV-2 enhances SARS-CoV-2-triggered NF-κB signaling. aVolcano plot of DEGs comparing SARS-CoV-2 infection cells versus negative control (NC). Calu3 cells were infected SARS-CoV-2 at MOI = 0.05 for 24, 48, and 72 h. RNA-seq was performed on poly(A)-enriched total RNA
Moreover, 1,6-hexanediol, the inhibitor of LLPS, can attenuate the phase separation of N protein and restrict its regulatory functions in NF-κB activation. These results suggest that LLPS of N protein provides a platform to induce NF-κB hyper-activation, which could be a potential therapeutic target against COVID-19 severe pneumonia.
Wu, Y., Ma, L., Cai, S. et al. RNA-induced liquid phase separation of SARS-CoV-2 nucleocapsid protein facilitates NF-κB hyper-activation and inflammation. Sig Transduct Target Ther 6, 167 (2021). https://doi.org/10.1038/s41392-021-00575-7