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Archaeal Kink-Turn Binding Protein Mediates Inhibition of Orthomyxovirus Splicing Biology.
Oishi, Kohei; Blanco-Melo, Daniel; Kurland, Andrew P; Johnson, Jeffrey R; tenOever, Benjamin R.
Affiliation
  • Oishi K; Department of Microbiology, New York University, Grossman School of Medicine, New York, New York, USA.
  • Blanco-Melo D; Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
  • Kurland AP; Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
  • Johnson JR; Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
  • tenOever BR; Department of Microbiology, New York University, Grossman School of Medicine, New York, New York, USA.
J Virol ; 97(4): e0181322, 2023 04 27.
Article in En | MEDLINE | ID: mdl-36943134
ABSTRACT
Despite lacking a DNA intermediate, orthomyxoviruses complete their replication cycle in the nucleus and generate multiple transcripts by usurping the host splicing machinery. This biology results in dynamic changes of relative viral transcripts over time and dictates the replicative phase of the infection. Here, we demonstrate that the family of archaeal L7Ae proteins uniquely inhibit the splicing biology of influenza A virus, influenza B virus, and Salmon isavirus, revealing a common strategy utilized by Orthomyxoviridae members to achieve this dynamic. L7Ae-mediated inhibition of virus biology was lost with the generation of a splicing-independent strain of influenza A virus and attempts to select for an escape mutant resulted in variants that conformed to host splicing biology at significant cost to their overall fitness. As L7Ae recognizes conventional kink turns in various RNAs, these data implicate the formation of a similar structure as a shared strategy adopted by this virus family to coordinate their replication cycle. IMPORTANCE Here, we demonstrate that a family of proteins from archaea specifically inhibit this splicing biology of all tested members of the Orthomyxoviridae family. We show that this inhibition extends to influenza A virus, influenza B virus, and isavirus genera, while having no significant impact on the mammalian transcriptome or proteome. Attempts to generate an escape mutant against L7Ae-mediated inhibition resulted in mutations surrounding the viral splice sites and a significant loss of viral fitness. Together, these findings reveal a unique biology shared among diverse members of the Orthomyxoviridae family that may serve as a means to generate future universal therapeutics.
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Full text: 1 Database: MEDLINE Main subject: Orthomyxoviridae / RNA Splicing / Archaeal Proteins Limits: Animals / Humans Language: En Journal: J Virol Year: 2023 Type: Article Affiliation country: United States

Full text: 1 Database: MEDLINE Main subject: Orthomyxoviridae / RNA Splicing / Archaeal Proteins Limits: Animals / Humans Language: En Journal: J Virol Year: 2023 Type: Article Affiliation country: United States