tetano
Editor, Senior Moderator
Nucleic Acids Res
. 2024 Feb 26:gkae133.
doi: 10.1093/nar/gkae133. Online ahead of print. Cryptic proteins translated from deletion-containing viral genomes dramatically expand the influenza virus proteome
Jordan N Ranum[SUP] 1 [/SUP], Mitchell P Ledwith[SUP] 1 [/SUP], Fadi G Alnaji[SUP] 2 [/SUP], Meghan Diefenbacher[SUP] 2 [/SUP], Richard Orton[SUP] 3 [/SUP], Elizabeth Sloan[SUP] 3 [/SUP], Melissa Güereca[SUP] 4 [/SUP], Elizabeth M Feltman[SUP] 1 [/SUP], Katherine Smollett[SUP] 3 [/SUP], Ana da Silva Filipe[SUP] 3 [/SUP], Michaela Conley[SUP] 3 [/SUP], Alistair B Russell[SUP] 4 [/SUP], Christopher B Brooke[SUP] 2 5 [/SUP], Edward Hutchinson[SUP] 3 [/SUP], Andrew Mehle[SUP] 1 [/SUP]
Affiliations
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.
. 2024 Feb 26:gkae133.
doi: 10.1093/nar/gkae133. Online ahead of print. Cryptic proteins translated from deletion-containing viral genomes dramatically expand the influenza virus proteome
Jordan N Ranum[SUP] 1 [/SUP], Mitchell P Ledwith[SUP] 1 [/SUP], Fadi G Alnaji[SUP] 2 [/SUP], Meghan Diefenbacher[SUP] 2 [/SUP], Richard Orton[SUP] 3 [/SUP], Elizabeth Sloan[SUP] 3 [/SUP], Melissa Güereca[SUP] 4 [/SUP], Elizabeth M Feltman[SUP] 1 [/SUP], Katherine Smollett[SUP] 3 [/SUP], Ana da Silva Filipe[SUP] 3 [/SUP], Michaela Conley[SUP] 3 [/SUP], Alistair B Russell[SUP] 4 [/SUP], Christopher B Brooke[SUP] 2 5 [/SUP], Edward Hutchinson[SUP] 3 [/SUP], Andrew Mehle[SUP] 1 [/SUP]
Affiliations
- PMID: 38407436
- DOI: 10.1093/nar/gkae133
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.