A dual-role of SARS-CoV-2 nucleocapsid protein in regulating innate immune response

Yinghua Zhao,Ping Wu,Wenfang Wang,Liyan Sui,Guangyun Tan,Guoqing Wang,Zhijun Hou,Quan Liu,Zedong Wang,Yang Yu

doi:10.1038/s41392-021-00742-w

Abstract

The recently emerged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which is the causative agent of ongoing global pandemic of COVID-19, may trigger immunosuppression in the early stage and overactive immune response in the late stage of infection; However, the underlying mechanisms are not well understood. Here we demonstrated that the SARS-CoV-2 nucleocapsid (N) protein dually regulated innate immune responses, i.e., the low-dose N protein suppressed type I interferon (IFN-I) signaling and inflammatory cytokines, whereas high-dose N protein promoted IFN-I signaling and inflammatory cytokines. Mechanistically, the SARS-CoV-2 N protein dually regulated the phosphorylation and nuclear translocation of IRF3, STAT1, and STAT2. Additionally, low-dose N protein combined with TRIM25 could suppress the ubiquitination and activation of retinoic acid-inducible gene I (RIG-I). Our findings revealed a regulatory mechanism of innate immune responses by the SARS-CoV-2 N protein, which would contribute to understanding the pathogenesis of SARS-CoV-2 and other SARS-like coronaviruses, and development of more effective strategies for controlling COVID-19.

Highlights

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a new member in the Coronaviridae family that is genetically related to SARS-CoV and Middle East respiratory syndrome coronavirus (MERS-CoV).[1,2] Hundreds millions of people have suffered from Coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2
We found that low-dose (0.25 μg) 2 nucleocapsid (2N) significantly reduced the promoter activity of IFN-β and interferon-stimulated response elements (ISRE) induced by compared with poly(I:C)-activated vector control, probably due to a weak activation of IFN-I signaling by poly(I:C) in the study (Fig. 2a–c), but the decreasing trend was consistent with previous investigations.[19,20]
These results showed that low-dose SARS-CoV-2 and SARS- assays showed that 2N interacted with endogenous STAT2 (Fig. 3e), CoV N proteins suppress the expression of IFN-I and interferon stimulated genes (ISGs), while but not with interferon regulatory factor 3 (IRF3) and STAT1 (Fig. 3f, g)

Summary

Introduction

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a new member in the Coronaviridae family that is genetically related to SARS-CoV and Middle East respiratory syndrome coronavirus (MERS-CoV).[1,2] Hundreds millions of people have suffered from Coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 (https://covid19.who.int/). SARS-CoV-2 triggers an immunosuppression in the early stage of infection, which contributes to uncontrolled coronaviral replication.[4,5,6] This overwhelming coronaviral replication, in turn, stimulates an aberrant unchecked cytokine release, known as “cytokine storm”, resulting to severe acute respiratory distress syndrome (ARDS), pneumonia, and multiple organs failure.[7,8] Understanding the underlying mechanisms is conducive to the development of more effective strategies for COVID-19

Methods

Results

Conclusion