Journal Article

Structural and Biological Basis of Alphacoronavirus nsp1 Associated with Host Proliferation and Immune Evasion

Zhang, Guangxu, Xiao, Shaobo, Fu, Zhen, Shen, Zhou, Yang, Siqi, Peng, Guiqing, Yang, Yiling

2020

Overview

Non-structural protein 1 (nsp1) is only characterized in alphacoronaviruses (α-CoVs) and betacoronaviruses (β-CoVs). There have been extensive researches on how the β-CoVs nsp1 regulates viral virulence by inhibiting host protein synthesis, but the regulatory mechanism of the α-CoVs nsp1 is still unclear. Here, we report the 2.1-Å full-length crystal structure of nsp1 in emerging porcine SADS-CoV and the 1.8-Å full-length crystal structure of nsp1 in the highly lethal cat FIPV. Although they belong to different subtypes of α-CoVs, these viruses all have a bucket-shaped fold composed of six β-sheets, similar to the crystal structure of PEDV and TGEV nsp1. Comparing the above four structures, we found that the structure of α-CoVs nsp1 in the same subtype was more conserved. We then selected mammalian cells that were treated with SADS-CoV and FIPV nsp1 for RNA sequencing analysis and found that nsp1 had a specific inhibitory effect on interferon (IFN) and cell cycle genes. Using the Renilla luciferase (Rluc) assay and Western blotting, we confirmed that seven representative α-CoVs nsp1s could significantly inhibit the phosphorylation of STAT1-S727 and interfere with the effect of IFN-I. Moreover, the cell cycle experiment confirmed that α-CoVs nsp1 could encourage host cells to stay in the G0/G1 phase. Based on these findings, we not only greatly improved the crystal structure data on α-CoVs nsp1, but we also speculated that α-CoVs nsp1 regulated host proliferation and immune evasion-related biological functions by inhibiting the synthesis of host proteins, thus creating an environment conducive to the virus.

• Publisher: MDPI AG,MDPI
• Subject: Alphacoronavirus / alphacoronavirus nsp1 / Cell cycle / cellular immune response / Cloning / Coronaviruses / Crystal structure / Crystallization / Diarrhea / E coli / Epidemics / G1 phase / Gene expression / genes / Hogs / Immune evasion / Immune response / infectious disease / Interferon / interferons / interphase / luciferase / Mammalian cells / Mammals / Phosphorylation / Polyethylene glycol / Protein biosynthesis / Protein synthesis / Proteins / Renilla / Respiratory diseases / Ribonucleic acid / RNA / RNA sequence / Sequence analysis / Severe acute respiratory syndrome coronavirus 2 / Software / Stat1 protein / structure-function / swine / viral nonstructural proteins / Virulence / Viruses / Western blotting