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

Research output: Contribution to journalArticle

9 Citations (Scopus)

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

Fingerprint

Heterogeneous-Nuclear Ribonucleoprotein K
influenza
splicing
Human Influenza
Influenza A virus
viruses
Viruses
Messenger RNA
U1 Small Nuclear Ribonucleoproteins
RNA Splice Sites
proteins
Binding Sites
Alternative Splicing
infectious diseases
Virus Diseases
Virus Replication
mutations
Antiviral Agents
Proteins
RNA

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., ... 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

Co-regulatory activity of hnRNP K and NS1-BP in influenza and human mRNA splicing. / Thompson, Matthew G.; Muñoz-Moreno, Raquel; Bhat, Prasanna; Roytenberg, Renat; Lindberg, John; Gazzara, Matthew R.; Mallory, Michael J.; Zhang, Ke; García-Sastre, Adolfo; Fontoura, Beatriz M.A.; Lynch, Kristen W.

In: Nature Communications, Vol. 9, No. 1, 2407, 01.12.2018.

Research output: Contribution to journalArticle

Thompson, MG, Muñoz-Moreno, R, Bhat, P, Roytenberg, R, Lindberg, J, Gazzara, MR, Mallory, MJ, Zhang, K, García-Sastre, A, Fontoura, BMA & Lynch, KW 2018, 'Co-regulatory activity of hnRNP K and NS1-BP in influenza and human mRNA splicing', Nature Communications, vol. 9, no. 1, 2407. https://doi.org/10.1038/s41467-018-04779-4
Thompson MG, Muñoz-Moreno R, Bhat P, Roytenberg R, Lindberg J, Gazzara MR et al. Co-regulatory activity of hnRNP K and NS1-BP in influenza and human mRNA splicing. Nature Communications. 2018 Dec 1;9(1). 2407. https://doi.org/10.1038/s41467-018-04779-4
Thompson, Matthew G. ; Muñoz-Moreno, Raquel ; Bhat, Prasanna ; Roytenberg, Renat ; Lindberg, John ; Gazzara, Matthew R. ; Mallory, Michael J. ; Zhang, Ke ; García-Sastre, Adolfo ; Fontoura, Beatriz M.A. ; Lynch, Kristen W. / Co-regulatory activity of hnRNP K and NS1-BP in influenza and human mRNA splicing. In: Nature Communications. 2018 ; Vol. 9, No. 1.
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