Closing in on the causes of host shutoff

How influenza virus A drives virus-induced host shutoff When a virus enters a cell it relies on the molecular machinery of its host to help it replicate. In particular, the virus relies on the ribosomes in the host cell to translate viral messenger RNA (mRNA) into polypeptides. Many viruses also impair the translation of cellular mRNA, via a process termed “host shutoff”, in order to prevent the production of anti-viral, host defense proteins. For example, poliovirus does this by inactivating a translation factor that is required to load ribosomes onto host mRNAs, all of which have a type of “cap” called an “m7G cap”. Moreover, while the translation of these mRNAs is being suppressed, host ribosomes are involved in the translation of poliovirus mRNA, which does not have a cap: this is possible without the translation factor because poliovirus mRNA has an internal entry site for ribosomes. However, the mechanisms responsible for host shutoff in viruses that have mRNAs with m7G-caps, such as influenza A virus, have remained enigmatic.

A new paper in eLife shows that in Influenza virus-infected cells host and viral mRNAs were both translated with similar efficiencies, indicating that viral mRNAs were not preferentially translated relative to host mRNAs. Instead, Influenza virus-induced host shutoff primarily originates from a reduced abundance of cellular mRNA and from the high levels of viral mRNA in both the nucleus and cytoplasm. Fluorescence-based measurements confirmed these findings and revealed that the reduced abundance of cellular mRNA has its origins in the nucleus. This likely involves an RNA endoribonuclease called PA-X, which is encoded in the genome of Influenza virus, stimulating the decay of cellular mRNA.

A systematic view on influenza induced host shutoff. (2016) eLife 5: e18311. doi: 10.7554/eLife.18311
Host shutoff is a common strategy used by viruses to repress cellular mRNA translation and concomitantly allow the efficient translation of viral mRNAs. Here we use RNA-sequencing and ribosome profiling to explore the mechanisms that are being utilized by the Influenza A virus (IAV) to induce host shutoff. We show that viral transcripts are not preferentially translated and instead the decline in cellular protein synthesis is mediated by viral takeover on the mRNA pool. Our measurements also uncover strong variability in the levels of cellular transcripts reduction, revealing that short transcripts are less affected by IAV. Interestingly, these mRNAs that are refractory to IAV infection are enriched in cell maintenance processes such as oxidative phosphorylation. Furthermore, we show that the continuous oxidative phosphorylation activity is important for viral propagation. Our results advance our understanding of IAV-induced shutoff, and suggest a mechanism that facilitates the translation of genes with important housekeeping functions.

eLife: Virology: Closing in on the causes of host shutoff. doi: 10.7554/eLife.20755

This entry was posted in Microbiology and tagged , , , , . Bookmark the permalink.