A conserved region of nonstructural protein 1 from alphacoronaviruses inhibits host gene expression and is critical for viral virulence

Zhou Shen, Gang Wang, Yiling Yang, Jiale Shi, Liurong Fang, Fang Li, Shaobo Xiao, Zhen F. Fu, Guiqing Peng

Research output: Contribution to journalArticlepeer-review

51 Scopus citations


Coronaviruses are enveloped, single-stranded RNA viruses that are distributed worldwide. They include transmissible gastroenteritis virus (TGEV), porcine epidemic diarrhea virus (PEDV), and the human coronaviruses severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV), many of which seriously endanger human health and well-being. Only alphacoronaviruses and betacoronaviruses harbor nonstructural protein 1 (nsp1), which performs multiple functions in inhibiting antiviral host responses. The role of the C terminus of betacoronavirus nsp1 in virulence has been characterized, but the location of the alphacoronavirus nsp1 region that is important for virulence remains unclear. Here, using TGEV nsp1 as a model to explore the function of this protein in alphacoronaviruses, we demonstrate that alphacoronavirus nsp1 inhibits host gene expression. Solving the crystal structure of full-length TGEV at 1.85-Å resolution and conducting several biochemical analyses, we observed that a specific motif (amino acids 91-95) of alphacoronavirus nsp1 is a conserved region that inhibits host protein synthesis. Using a reverse-genetics system based on CRISPR/ Cas9 technology to construct a recombinant TGEV in which this specific nsp1 motif was altered, we found that this mutation does not affect virus replication in cell culture but significantly reduces TGEV pathogenicity in pigs. Taken together, our findings suggest that alphacoronavirus nsp1 is an essential virulence determinant, providing a potential paradigm for the development of a new attenuated vaccine based on modified nsp1.

Original languageEnglish (US)
Pages (from-to)13606-13618
Number of pages13
JournalJournal of Biological Chemistry
Issue number37
StatePublished - Sep 13 2019

Bibliographical note

Funding Information:
This work was supported by National Natural Science Foundation of China Grants 31873020 and 31722056, National Key Research and Development Plan of China Grant 2018YFD0500102, and Huazhong Agricultural Univer-sity Scientific and Technological Self-Innovation Foundation Program 2662017PY028. The authors declare that they have no conflicts of interest with the contents of this article.

Publisher Copyright:
© 2019 Shen et al. Published under exclusive license by The American Society for Biochemistry and Molecular Biology, Inc.


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