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Nat Commun. 2018 Jun 19;9(1):2407. doi: 10.1038/s41467-018-04779-4.

Co-regulatory activity of hnRNP K and NS1-BP in influenza and human mRNA splicing.

Author information

1
Departments of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, 422 Curie Blvd, Philadelphia, PA, 19104, USA.
2
Department of Microbiology, Icahn School of Medicine at Mount Sinai, 1468 Madison Ave., Box 1124, New York, NY, 10029, USA.
3
Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, 1468 Madison Ave., Box 1124, New York, NY, 10029, USA.
4
Department of Cell Biology, UT Southwestern Medical Center, 6000 Harry Hines Blvd., Dallas, TX, 75390, USA.
5
Department of Medicine, Division of Infectious Diseases, Icahn School of Medicine at Mount Sinai, 1468 Madison Ave., Box 1124, New York, NY, 10029, USA.
6
Departments of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, 422 Curie Blvd, Philadelphia, PA, 19104, USA. klync@pennmedicine.upenn.edu.

Abstract

Three of the eight RNA segments encoded by the influenza A virus (IAV) undergo alternative splicing to generate distinct proteins. Previously, we found that host proteins hnRNP K and NS1-BP regulate IAV M segment splicing, but the mechanistic details were unknown. Here we show NS1-BP and hnRNP K bind M mRNA downstream of the M2 5' splice site (5'ss). NS1-BP binds most proximal to the 5'ss, partially overlapping the U1 snRNP binding site, while hnRNP K binds further downstream and promotes U1 snRNP recruitment. Mutation of either or both the hnRNP K and NS1-BP-binding sites results in M segment mis-splicing and attenuated IAV replication. Additionally, we show that hnRNP K and NS1-BP regulate host splicing events and that viral infection causes mis-splicing of some of these transcripts. Therefore, our proposed mechanism of hnRNP K/NS1-BP mediated IAV M splicing provides potential targets of antiviral intervention and reveals novel host functions for these proteins.

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