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

Matthew G. Thompson, Raquel Muñoz-Moreno, Prasanna Bhat, Renat Roytenberg, John Lindberg, Matthew R. Gazzara, Michael J. Mallory, Ke Zhang, Adolfo García-Sastre, Beatriz M. A. Fontoura and Kristen W. Lynch ()
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Matthew G. Thompson: University of Pennsylvania
Raquel Muñoz-Moreno: Icahn School of Medicine at Mount Sinai
Prasanna Bhat: UT Southwestern Medical Center
Renat Roytenberg: University of Pennsylvania
John Lindberg: University of Pennsylvania
Matthew R. Gazzara: University of Pennsylvania
Michael J. Mallory: University of Pennsylvania
Ke Zhang: UT Southwestern Medical Center
Adolfo García-Sastre: Icahn School of Medicine at Mount Sinai
Beatriz M. A. Fontoura: UT Southwestern Medical Center
Kristen W. Lynch: University of Pennsylvania

Nature Communications, 2018, vol. 9, issue 1, 1-12

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-04779-4

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