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

ABSTRACT: Non-structural protein 1 (nsp1) is only characterized in alphacoronaviruses (?-CoVs) and betacoronaviruses (?-CoVs). There have been extensive researches on how the ?-CoVs nsp1 regulates viral virulence by inhibiting host protein synthesis, but the regulatory mechanism of the ?-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 ?-CoVs, these viruses all have a bucket-shaped fold composed of six ?-sheets, similar to the crystal structure of PEDV and TGEV nsp1. Comparing the above four structures, we found that the structure of ?-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 ?-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 ?-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 ?-CoVs nsp1, but we also speculated that ?-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.

SUBMITTER: Shen Z

PROVIDER: S-EPMC7472224 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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

Shen Zhou Z Yang Yiling Y Yang Siqi S Zhang Guangxu G Xiao Shaobo S Fu Zhen F ZF Peng Guiqing G

Viruses 20200728 8

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 bel ...[more]

PMID: 32731335

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Project description:Porcine epidemic diarrhea virus (PEDV), an enteropathogenic Alphacoronavirus, has caused enormous economic losses in the pork industry. Nonstructural protein 1 (nsp1) is a characteristic feature of alpha- and betacoronaviruses, which exhibits both functional conservation and mechanistic diversity in inhibiting host gene expression and antiviral responses. However, the detailed structure and molecular mechanisms underlying the Alphacoronavirus nsp1 inhibition of host gene expression remain unclear. Here, we report the first full-length crystal structure of Alphacoronavirus nsp1 from PEDV. The structure displays a six-stranded ?-barrel fold in the middle of two ?-helices. The core structure of PEDV nsp1 shows high similarity to those of severe acute respiratory syndrome coronavirus (SARS-CoV) nsp1 and transmissible gastroenteritis virus (TGEV) nsp1, despite its low degree of sequence homology. Using ribopuromycylation and Renilla luciferase reporter assays, we showed that PEDV nsp1 can dramatically inhibit general host gene expression. Furthermore, three motifs (amino acids [aa] 67 to 71, 78 to 85, and 103 to 110) of PEDV nsp1 create a stable functional region for inhibiting protein synthesis, differing considerably from Betacoronavirus nsp1. These results elucidate the detailed structural basis through which PEDV nsp1 inhibits host gene expression, providing insight into the development of a new attenuated vaccine with nsp1 modifications.IMPORTANCE Porcine epidemic diarrhea virus (PEDV) has led to tremendous economic losses in the global swine industry. PEDV nsp1 plays a crucial role in inhibiting host gene expression, but its functional mechanism remains unclear. Here, we report the full-length structure of PEDV nsp1, the first among coronaviruses to be reported. The 1.25-Å resolution crystal structure of PEDV nsp1 shows high similarity to severe acute respiratory syndrome coronavirus (SARS-CoV) nsp113-128 and transmissible gastroenteritis virus (TGEV) nsp11-104, despite a lack of sequence homology. Structural and biochemical characterization demonstrated that PEDV nsp1 possesses a stable functional region for inhibition of host protein synthesis, which is formed by loops at residues 67 to 71, 78 to 85, and 103 to 110. The different functional regions in PEDV nsp1 and SARS-CoV nsp1 may explain their distinct mechanisms. Importantly, our structural data are conducive to understanding the mechanism of PEDV nsp1 inhibition of the expression of host genes and may aid in the development of a new attenuated vaccine.

Dataset Information

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

Publications

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

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