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Proc Natl Acad Sci U S A. 2018 Dec 26;115(52):E12218-E12227. doi: 10.1073/pnas.1818012115. Epub 2018 Dec 11.

Structural-functional interactions of NS1-BP protein with the splicing and mRNA export machineries for viral and host gene expression.

Author information

1
Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390.
2
Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390.
3
Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390.
4
Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390.
5
Department of Bioinformatics, University of Texas Southwestern Medical Center, Dallas, TX 75390.
6
Department of Biochemistry and Biophysics, University of Pennsylvania School of Medicine, Philadelphia, PA 19104.
7
Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
8
Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
9
Division of Infectious Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
10
Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390; Yuhmin.Chook@utsouthwestern.edu Beatriz.Fontoura@UTSouthwestern.edu.
11
Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390; Yuhmin.Chook@utsouthwestern.edu Beatriz.Fontoura@UTSouthwestern.edu.

Abstract

The influenza virulence factor NS1 protein interacts with the cellular NS1-BP protein to promote splicing and nuclear export of the viral M mRNAs. The viral M1 mRNA encodes the M1 matrix protein and is alternatively spliced into the M2 mRNA, which is translated into the M2 ion channel. These proteins have key functions in viral trafficking and budding. To uncover the NS1-BP structural and functional activities in splicing and nuclear export, we performed proteomics analysis of nuclear NS1-BP binding partners and showed its interaction with constituents of the splicing and mRNA export machineries. NS1-BP BTB domains form dimers in the crystal. Full-length NS1-BP is a dimer in solution and forms at least a dimer in cells. Mutations suggest that dimerization is important for splicing. The central BACK domain of NS1-BP interacts directly with splicing factors such as hnRNP K and PTBP1 and with the viral NS1 protein. The BACK domain is also the site for interactions with mRNA export factor Aly/REF and is required for viral M mRNA nuclear export. The crystal structure of the C-terminal Kelch domain shows that it forms a β-propeller fold, which is required for the splicing function of NS1-BP. This domain interacts with the polymerase II C-terminal domain and SART1, which are involved in recruitment of splicing factors and spliceosome assembly, respectively. NS1-BP functions are not only critical for processing a subset of viral mRNAs but also impact levels and nuclear export of a subset of cellular mRNAs encoding factors involved in metastasis and immunity.

KEYWORDS:

Kelch; NS1 protein; influenza virus; mRNA export; splicing

PMID:
30538201
PMCID:
PMC6310826
DOI:
10.1073/pnas.1818012115
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

The authors declare no conflict of interest.

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