RNA ligands activate the Machupo virus polymerase and guide promoter usage

Jesse D. Pyle, Sean P.J. Whelan

Research output: Contribution to journalArticle

5 Scopus citations

Abstract

Segmented negative-sense (SNS) RNA viruses initiate infection by delivering into cells a suite of genomic RNA segments, each sheathed by the viral nucleocapsid protein and bound by the RNAdependent RNA-polymerase (RdRP). For the orthomyxovirus influenza and the bunyavirus La Crosse, the 5' end of the genomic RNA binds as a hook-like structure proximal to the active site of the RdRP. Using an in vitro assay for the RNA-dependent RNApolymerase (RdRP) of the arenavirus Machupo (MACV), we demonstrate that the 5' genomic and antigenomic RNAs of both small and large genome segments stimulate activity in a promoter-specific manner. Functional probing of the activating RNAs identifies intramolecular base-pairing between positions +1 and +7 and a pseudotemplated 5' terminal guanine residue as key for activation. Binding of structured 5' RNAs is a conserved feature of all SNS RNA virus polymerases, implying that promoter-specific RdRP activation extends beyond the arenaviruses. The 5' RNAs and the RNA binding pocket itself represent targets for therapeutic intervention.

Original languageEnglish
Pages (from-to)10518-10524
Number of pages7
JournalProceedings of the National Academy of Sciences of the United States of America
Volume116
Issue number21
DOIs
StatePublished - Jan 1 2019
Externally publishedYes

Keywords

  • Arenavirus
  • Influenza virus
  • RNA replication
  • RNA-dependent RNA polymerase
  • Segmented negative-sense RNA virus

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