Cellular NS1-BP protein interacts with the mRNA export receptor NXF1 to mediate nuclear export of influenza virus M mRNAs

Ke Zhang; Tolga Cagatay; Dongqi Xie; Alexia E Angelos; Serena Cornelius; Vasilisa Aksenova; Sadaf Aslam; Zhiyu He; Matthew Esparza; Ashley Vazhavilla; Mary Dasso; Adolfo García-Sastre; Yi Ren; Beatriz M A Fontoura

doi:10.1016/j.jbc.2024.107871

Cellular NS1-BP protein interacts with the mRNA export receptor NXF1 to mediate nuclear export of influenza virus M mRNAs

J Biol Chem. 2024 Oct 9;300(11):107871. doi: 10.1016/j.jbc.2024.107871. Online ahead of print.

Authors

Affiliations

¹ Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, Texas, USA; Shanghai Institute of Immunity and Infection, Chinese Academy of Sciences, Shanghai, China.
² Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
³ Department of Biochemistry, Center for Structural Biology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
⁴ Division of Molecular and Cellular Biology, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA.
⁵ Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
⁶ Shanghai Institute of Immunity and Infection, Chinese Academy of Sciences, Shanghai, China.
⁷ Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York, USA; Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA; Division of Infectious Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA; Department of Pathology, Molecular and Cell-Based Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA; The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA; The Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
⁸ Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, Texas, USA. Electronic address: beatriz.fontoura@utsouthwestern.edu.

PMID: 39384042
DOI: 10.1016/j.jbc.2024.107871

Abstract

Influenza A viruses have eight genomic RNAs that are transcribed in the host cell nucleus. Two of the viral mRNAs undergo alternative splicing. The M1 mRNA encodes the matrix protein 1 (M1) and is also spliced into M2 mRNA, which encodes the proton channel matrix protein 2 (M2). Our previous studies have shown that the cellular Non-Structural protein 1 (NS1)-binding protein (NS1-BP) interacts with the viral NS1 and M1 mRNA to promote M1 to M2 splicing. Another pool of NS1 protein binds the mRNA export receptor nuclear RNA export factor-1 (NXF1), leading to nuclear retention of cellular mRNAs. Here, we show a series of biochemical and cell biological findings that suggest a model for nuclear export of M1 and M2 mRNAs despite the mRNA nuclear export inhibition imposed by the viral NS1 protein. NS1-BP competes with NS1 for NXF1 binding, allowing the recruitment of NXF1 to the M mRNAs after splicing. NXF1 then binds germinal center-associated nuclear protein, a member of the transcription and export complex-2. Although both NS1 and NS1-BP remain in complex with germinal center-associated nuclear protein-NXF1, they dissociate once this complex docks at the nuclear pore complex, and the M mRNAs are translocated to the cytoplasm. Since this mRNA nuclear export pathway is key for expression of M1 and M2 proteins that function in viral intracellular trafficking and budding, these viral-host interactions are critical for influenza virus replication.

Keywords: GANP (germinal center–associated nuclear protein); M1 (matrix protein 1 of influenza virus); NS1 (Non-Structural protein 1 of influenza A virus); NS1-BP (cellular NS1-binding protein); NXF1 (nuclear RNA export factor-1); NXT1 (nuclear transport factor 2–like export factor 1); TREX-2 (transcription and export complex-2); influenza virus; mRNA export.