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

Journal Article · · Nature Microbiology
 [1];  [2];  [3];  [1];  [4];  [1]; ORCiD logo [3];  [1]; ORCiD logo [2]
  1. Univ. of Texas Southwestern Medical Center, Dallas, TX (United States)
  2. Vanderbilt Univ. School of Medicine, Nashville, TN (United States)
  3. Icahn School of Medicine at Mount Sinai, New York, NY (United States)
  4. Xiamen Univ. (China)
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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 factors; 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 nucleoporins. 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. Here, 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.

Research Organization:
Argonne National Laboratory (ANL), Argonne, IL (United States)
Sponsoring Organization:
USDOE Office of Science (SC); NIAID; National Institutes of Health (NIH)
Grant/Contract Number:
HHSN272201400008C; U19AI135972; R01 GM113874; R01 AI125524
OSTI ID:
1593437
Journal Information:
Nature Microbiology, Vol. 4, Issue 10; ISSN 2058-5276
Publisher:
Nature Publishing GroupCopyright Statement
Country of Publication:
United States
Language:
ENGLISH
Citation Metrics:
Cited by: 26 works
Citation information provided by
Web of Science

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Cited By (3)

Into the basket and beyond: the journey of mRNA through the nuclear pore complex journal January 2020
Molecular recognition of a host protein by NS1 of pandemic and seasonal influenza A viruses journal March 2020
Mechanisms of nuclear mRNA export: A structural perspective journal September 2019

Figures / Tables (4)

Fig. 1(p. 15)figure Fig. 1
Figure-2(p. 17)figure Figure-2
Fig. 3(p. 19)figure Fig. 3
Fig. 4(p. 20)figure Fig. 4

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Related Subjects

59 BASIC BIOLOGICAL SCIENCES
influenza virus
RNA transport
X-ray crystallography