Structural basis for influenza virus NS1 protein block of mRNA nuclear export

Ke Zhang, Yihu Xie, Raquel Muñoz-Moreno, Juan Wang, Liang Zhang, Matthew Esparza, Adolfo García-Sastre, Beatriz M Fontoura, Yi Ren

Research output: Contribution to journalLetter

Abstract

Influenza viruses antagonize key immune defence mechanisms via the virulence factor non-structural protein 1 (NS1). A key mechanism of virulence by NS1 is blocking nuclear export of host messenger RNAs, including those encoding immune factors1–3; however, the direct cellular target of NS1 and the mechanism of host mRNA export inhibition are not known. Here, we identify the target of NS1 as the mRNA export receptor complex, nuclear RNA export factor 1–nuclear transport factor 2-related export protein 1 (NXF1–NXT1), which is the principal receptor mediating docking and translocation of mRNAs through the nuclear pore complex via interactions with nucleoporins4,5. We determined the crystal structure of NS1 in complex with NXF1–NXT1 at 3.8 Å resolution. The structure reveals that NS1 prevents binding of NXF1–NXT1 to nucleoporins, thereby inhibiting mRNA export through the nuclear pore complex into the cytoplasm for translation. We demonstrate that a mutant influenza virus deficient in binding NXF1–NXT1 does not block host mRNA export and is attenuated. This attenuation is marked by the release of mRNAs encoding immune factors from the nucleus. In sum, our study uncovers the molecular basis of a major nuclear function of influenza NS1 protein that causes potent blockage of host gene expression and contributes to inhibition of host immunity.

Original languageEnglish (US)
JournalNature Microbiology
DOIs
StatePublished - Jan 1 2019

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Viral Structural Proteins
Cell Nucleus Active Transport
Orthomyxoviridae
Messenger RNA
Proteins
Nuclear Pore
Nuclear Pore Complex Proteins
Nuclear RNA
Immunologic Factors
Virulence Factors
Human Influenza
Virulence
Immunity
Cytoplasm
Gene Expression

ASJC Scopus subject areas

  • Microbiology
  • Immunology
  • Applied Microbiology and Biotechnology
  • Genetics
  • Microbiology (medical)
  • Cell Biology

Cite this

Zhang, K., Xie, Y., Muñoz-Moreno, R., Wang, J., Zhang, L., Esparza, M., ... Ren, Y. (2019). Structural basis for influenza virus NS1 protein block of mRNA nuclear export. Nature Microbiology. https://doi.org/10.1038/s41564-019-0482-x

Structural basis for influenza virus NS1 protein block of mRNA nuclear export. / Zhang, Ke; Xie, Yihu; Muñoz-Moreno, Raquel; Wang, Juan; Zhang, Liang; Esparza, Matthew; García-Sastre, Adolfo; Fontoura, Beatriz M; Ren, Yi.

In: Nature Microbiology, 01.01.2019.

Research output: Contribution to journalLetter

Zhang, K, Xie, Y, Muñoz-Moreno, R, Wang, J, Zhang, L, Esparza, M, García-Sastre, A, Fontoura, BM & Ren, Y 2019, 'Structural basis for influenza virus NS1 protein block of mRNA nuclear export', Nature Microbiology. https://doi.org/10.1038/s41564-019-0482-x
Zhang, Ke ; Xie, Yihu ; Muñoz-Moreno, Raquel ; Wang, Juan ; Zhang, Liang ; Esparza, Matthew ; García-Sastre, Adolfo ; Fontoura, Beatriz M ; Ren, Yi. / Structural basis for influenza virus NS1 protein block of mRNA nuclear export. In: Nature Microbiology. 2019.
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