An Overlapping Protein-Coding Region in Influenza A Virus Segment 3 Modulates the Host Response

Abstract

Influenza's Cryptic Constraint Because of the well-known pandemic potential of influenza viruses, it is important to understand the range of molecular interactions between the virus and its host. Despite years of intensive research on the virus, Jagger et al. (p. 199 , published online 28 June; see the Perspective by Yewdell and Ince ) have found that the influenza A virus has been hiding a gene in its small negative-sense RNA genome. An overlapping open reading frame was found contained in the PA viral RNA polymerase gene, which is accessed by ribosomal frameshifting to produce a fusion protein containing the N-terminal messenger RNA (mRNA) endonuclease domain of PA and an alternative C-terminal X domain. The resulting polypeptide, PA-X, selectively degrades host mRNAs and, in a mouse model of infection, modulated cellular immune responses, thus limiting viral pathogenesis.

Nuclease escape elements protect messenger RNA against cleavage by multiple viral endonucleases

“…To test this hypothesis, we assessed whether the presence of the SRE impacted the ability of a panel of homologous and heterologous mRNA-specific viral endonucleases to degrade a target mRNA. In addition to HSV-1 vhs, these included homologs of KSHV SOX from the related gammaherpesviruses Epstein-Barr virus (EBV; BGLF5) and murine gammaherpesvirus 68 (MHV68; muSOX), as well as the heterologous host shutoff endonuclease from influenza A virus (IAV; PA-X) [3,17,39]. As anticipated, the control GFP mRNA was readily degraded in 293T cells co-transfected with plasmids expressing each of the viral endonucleases as measured by RTqPCR (Fig 1A).…”

“…This 'host shutoff' phenotype can be triggered through a range of mechanisms that operate at nearly every stage of the gene expression cascade. Viruses whose host shutoff strategies involve the induction of widespread mRNA decay include the alpha and gammaherpesviruses, vaccinia virus (VACV), influenza A virus (IAV), and SARS coronavirus (SCoV) [1][2][3][4][5] In each of the above cases, mRNA degradation is induced via one or more internal endonucleolytic cleavages in the target mRNA or, in the case of VACV, direct removal of the mRNA 5' cap [5][6][7][8][9]. This is invariably followed by exonucleolytic degradation of the cleaved fragment(s) by components of the mammalian RNA decay machinery such as Xrn1 [1,10,11].…”

Identification of an overprinting gene in Merkel cell polyomavirus provides evolutionary insight into the birth of viral genes

“…However, conserved features are evident in ALTO comparisons among closely related Almipolyomaviruses (SI Appendix, Alignment S2) and reveal that, in the region of overlap, neither ALTO nor LT appears to have consistently higher sequence conservation, making it unclear which reading frame has been more highly constrained during evolution (SI Appendix, Table S4). Interestingly, unlike some structured overprinted/overprinted pairs, including the recently discovered influenza A PA-X protein and the PA protein it overprints (15), neither ALTO nor the overprinted region of LT is predicted to contain substantial protein structure (SI Appendix, Fig. S1).…”

Influenza neuraminidase operates via a nucleophilic mechanism and can be targeted by covalent inhibitors

“…The influenza A virus genome comprises 8 negative strand RNA segments encoding 13 proteins 5 . Two major glycoproteins, hemagglutinin (HA) and NA, as well as the M2 ion channel, are on the surface of the virions and are therefore highly accessible targets for drug development 6,7 .…”