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, Kristen W. Lynch

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9 Scopus citations

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.

Original languageEnglish (US)
Article number2407
JournalNature communications
Volume9
Issue number1
DOIs
StatePublished - Dec 1 2018

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ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

Thompson, M. G., Muñoz-Moreno, R., Bhat, P., Roytenberg, R., Lindberg, J., Gazzara, M. R., Mallory, M. J., Zhang, K., García-Sastre, A., Fontoura, B. M. A., & Lynch, K. W. (2018). Co-regulatory activity of hnRNP K and NS1-BP in influenza and human mRNA splicing. Nature communications, 9(1), [2407]. https://doi.org/10.1038/s41467-018-04779-4