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Cryptic proteins translated from deletion-containing viral genomes dramatically expand the influenza virus proteome.

Jordan N RanumMitchell P LedwithFadi Ghassan AlnajiMeghan DiefenbacherRichard J OrtonElizabeth SloanMelissa GüerecaElizabeth M FeltmanKatherine SmollettAna da Silva FilipeMichaela J ConleyAlistair B RussellChristopher B BrookeEdward C HutchinsonAndrew Mehle
Published in: Nucleic acids research (2024)
Productive infections by RNA viruses require faithful replication of the entire genome. Yet many RNA viruses also produce deletion-containing viral genomes (DelVGs), aberrant replication products with large internal deletions. DelVGs interfere with the replication of wild-type virus and their presence in patients is associated with better clinical outcomes. The DelVG RNA itself is hypothesized to confer this interfering activity. DelVGs antagonize replication by out-competing the full-length genome and triggering innate immune responses. Here, we identify an additionally inhibitory mechanism mediated by a new class of viral proteins encoded by DelVGs. We identified hundreds of cryptic viral proteins translated from DelVGs. These DelVG-encoded proteins (DPRs) include canonical viral proteins with large internal deletions, as well as proteins with novel C-termini translated from alternative reading frames. Many DPRs retain functional domains shared with their full-length counterparts, suggesting they may have activity during infection. Mechanistic studies of DPRs derived from the influenza virus protein PB2 showed that they poison replication of wild-type virus by acting as dominant-negative inhibitors of the viral polymerase. These findings reveal that DelVGs have a dual inhibitory mechanism, acting at both the RNA and protein level. They further show that DPRs have the potential to dramatically expand the functional proteomes of diverse RNA viruses.
Keyphrases
  • sars cov
  • wild type
  • immune response
  • end stage renal disease
  • chronic kidney disease
  • nucleic acid
  • newly diagnosed
  • inflammatory response
  • dendritic cells
  • small molecule
  • peritoneal dialysis