Trends in Microbiology
Volume 8, Issue 8, 1 August 2000, Pages 376-383
Journal home page for Trends in Microbiology

Review
Selective nuclear export of viral mRNAs in influenza-virus-infected cells

https://doi.org/10.1016/S0966-842X(00)01794-7Get rights and content

Abstract

The NS1A protein of influenza A virus specifically inhibits the cellular machinery that processes the 3′ ends of cellular pre-mRNAs by targeting two of the essential proteins of this machinery. Because the virus does not use this cellular machinery to synthesize the 3′ poly(A) ends of viral mRNA, the nuclear export of cellular but not viral mRNAs is selectively inhibited.

Section snippets

Nuclear export of mRNA

All mRNAs that are synthesized in the nucleus must be exported to the cytoplasm for translation. Export occurs through nuclear pore complexes, large structures composed of many different proteins called nucleoporins8. The nuclear export of cellular mRNAs is mediated by several proteins that are bound to them and their pre-mRNA precursors9. The hnRNP proteins, abundant nuclear proteins that are bound to pre-mRNAs and mRNAs in the nucleus, have been implicated in the nuclear export of mRNAs. Many

NS1A and the inhibition of nuclear export

The NS1 protein of influenza A virus (NS1A) was identified in 1971 (Ref. 26), but little progress in elucidating its function was made until the early 1990s. Transient transfection experiments established that one of its functions is the inhibition of the nuclear export of poly(A)-containing spliced mRNAs, that is, mRNAs without introns27, 28, 29, 30. Nuclear export of mRNAs is inhibited only when they contain a poly(A) tail produced by the cellular cleavage/polyadenylation system; NS1A does

CPSF and PABII

NS1A specifically inhibits the cellular 3′-end processing machinery by targeting two proteins: the human 30-kDa subunit of the cleavage and polyadenylation specificity factor (CPSF)39 and poly(A)-binding protein II (PABII)40. It is likely that these proteins bind to non-overlapping regions of the NS1A protein effector domain, and can therefore bind NS1A simultaneously40. These two cellular factors have different functions (Fig. 2). CPSF binds to the AAUAAA poly(A) signal located 10–30 nt

Roles of the NS1A effector domain

Several lines of evidence have established that the NS1A effector domain is required for the inhibition of 3′-end processing of cellular pre-mRNAs. Both the 30-kDa CPSF subunit and PABII bind to the effector domain, and its deletion eliminates the ability of NS1A to inhibit 3′ poly(A) processing39, 40. A requirement for the RNA-binding domain, as well as the effector domain, in the inhibition of 3′ poly(A) processing was suggested by early mutagenesis experiments, which indicated that mutations

Conclusions and remaining issues

Influenza virus NS1A blocks the nuclear export of cellular mRNAs by binding to, and inhibiting the function of, two cellular proteins that are required for the 3′-end processing of cellular pre-mRNAs39, 40. The inhibition of the cellular 3′-end-processing machinery should not block the formation of the 3′ poly(A) tails of viral mRNAs because the tails are produced by the viral polymerase, and not by the cellular 3′-end processing machinery6, 7. In fact, the influenza viral mRNAs in infected

Questions for future research

  • What is the mechanism by which influenza viral mRNAs are exported from the nucleus of infected cells?

  • Does the PABII protein participate in the nuclear export of cellular poly(A)-containing mRNAs?

  • What amino acid sequences of the influenza virus NS1A protein interact with the cellular 30-kDa CPSF and PABII proteins, and are similar interacting sequences found in cellular proteins?

Acknowledgements

The work carried out in the authors’ laboratory is supported by National Institutes of Health grant AI 11772 to R.M.K.

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